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New Developments in Hypertrophic Cardiomyopathy
Accepted Manuscript New developments in hypertrophic cardiomyopathy Robert M. Cooper, MBChB MRCP PhD, Claire E. Raphael, MBBS MRCP PhD, Max Liebregts, MD, Nandan S. Anavekar, MBBCh FACC, Josef Veselka, MD PhD PII:
S0828-282X(17)30371-9
DOI:
10.1016/j.cjca.2017.07.007
Reference:
CJCA 2477
To appear in:
Canadian Journal of Cardiology
Received Date: 21 May 2017 Revised Date:
4 July 2017
Accepted Date: 11 July 2017
Please cite this article as: Cooper RM, Raphael CE, Liebregts M, Anavekar NS, Veselka J, New developments in hypertrophic cardiomyopathy, Canadian Journal of Cardiology (2017), doi: 10.1016/ j.cjca.2017.07.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
New developments in hypertrophic cardiomyopathy
Robert M Cooper MBChB MRCP PhD
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Corresponding author [email protected] Department of Cardiology
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Liverpool Heart and Chest Hospital Thomas Drive
L14 3PE United Kingdom
Claire E Raphael MBBS MRCP PhD
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Department of Cardiovascular Diseases
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Liverpool
Mayo Clinic, Rochester, MN USA
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Max Liebregts MD Department of Cardiology
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St Antonius Ziekenhuis, Nieuwegein
Nandan S Anavekar MBBCh FACC Department of Cardiovascular Diseases Mayo Clinic, Rochester, MN USA
Josef Veselka MD PhD Department of Cardiology, Motol University Hospital and 2nd Medical School, Charles University, Prague
ACCEPTED MANUSCRIPT Brief summary:
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We discuss new developments in the investigation and management of HCM. Imaging including novel cardiac MRI techniques and echocardiography are included, along with new insights into the mechanisms of abnormal perfusion. Innovative approaches to the management of LVOT obstruction are covered, both surgical and non-surgical. We examine the evidence for the use of risk stratification models for sudden cardiac death and consider the importance of AF. Novel medications targeting HCM related abnormalities are also reviewed.
Abstract
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Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden death in the young and an important cause of heart failure at any age. In this review we discuss advances in investigation and management of this heterogenous disease.
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Improved cardiac imaging has allowed us to detail many of the structural abnormalities while the use of new techniques, predominantly in cardiac MRI, has given us a greater insight in to tissue architecture, mechanism of contractile abnormalities and function. Risk stratification remains challenging due to the low event rate in clinical studies. Multi centre registries have improved risk stratification for sudden cardiac death and multiple models may be used to aid decision making for implantable defibrillator therapy.
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We discuss the current state of non-surgical septal reduction therapy and results of multi centre registries. New approaches to septal reduction therapy including refinement of alcohol ablation and non-coronary interventions such as radiofrequency ablation of the septum show great promise. Surgical myectomy remains a major part of treatment; a greater recognition of abnormalities of the mitral valve apparatus can allow improved surgical options. Myocardial perfusion abnormalities are known to predict adverse outcome in HCM and we discuss underlying mechanisms and relevance to management.
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The off-label use of currently licensed medicines such as ranolazine, perhexiline, calcium channel blockers and renin-angiotensin system antagonists are discussed. A novel approach to medical treatment of the underlying sarcomeric disorder has been investigated and shows great potential.
Disclosures: All authors – nothing to disclose
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Introduction:
Hypertrophic cardiomyopathy (HCM) is an inherited disease characterised by otherwise unexplained
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hypertrophy of the myocardium. HCM has an estimated phenotypic prevalence of 1 in 500 and
possible genotypic prevalence of 1 in 2001. The management of HCM has evolved since the first descriptions and early recognition and management can effectively treat symptoms in the majority of patients. Better risk stratification models borne out of multi-center registries also allow more
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accurate identification of patients suitable for implantable cardioverter defibrillators (ICDs) as
primary prevention for sudden cardiac death2. There has been increased interest in HCM recently with a significant rise in targeted research, including the development of multiple international
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registries2-4. Here we focus on some areas of interest and recent development in the understanding and management of HCM.
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Imaging;
Echocardiography has been and remains the mainstay of the imaging evaluation in HCM, as it is portable and provides the best characterization of the physiologic abnormalities related to diastolic and systolic function, intraventricular obstruction and valvular abnormalities. Cardiovascular
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magnetic resonance (CMR) allows detailed description of the morphologic abnormalities seen in HCM and its ability to characterize tissue changes provides further understanding of the disease
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pathobiology and may support risk stratification algorithms. The goals of the imaging evaluation are to delineate the cardiac anatomy, to assess the implications of the anatomic findings on cardiac function, to evaluate ischemia and to monitor the efficacy of therapy5. The anatomic considerations at initial diagnosis include qualification and quantification of hypertrophy, assessment of the mitral apparatus, assessment of location and severity of intraventricular obstruction and the assessment of tissue characteristics that may signify underlying fibrotic change. Pathologic hypertrophy is considered in the presence of unexplained wall thickness >15mm in any myocardial segment or asymmetric septal hypertrophy with a septal to posterior wall thickness ratio >1.3 in normotensive individuals or >1.5 in hypertensive individuals5. The use of a wall thickness ratio in those with wall thickness <15mm remains controversial in some arenas and is
ACCEPTED MANUSCRIPT less secure than absolute width. In those with an established diagnosis of HCM in a first degree family member lower cut off values may be used; an absolute wall thickness ≥13mm is diagnostic of HCM6. Two dimensional echocardiography is often regarded the initial step in evaluation of hypertrophy. However, echocardiography is dependent upon available acoustic windows and may be limited by
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constraints of lateral resolution. In these instances, CMR may be considered as an alternative initial imaging investigation. Indeed, CMR is more sensitive than echocardiography in the detection of segmental wall abnormalities and apical HCM7.
Myocardial tissue abnormalities are best assessed using CMR. Myocardial fibrosis is common and
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found in up to two thirds of patients 8 9. Late gadolinium enhancement (LGE) allows assessment of abnormalities of the extracellular milieu and is assumed to represent replacement fibrosis9 10. The
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pattern of LGE is variable but is usually a patchy, mid myocardial distribution, particularly in areas of maximal hypertrophy and the right ventricular septal insertion sites. LGE is a strong independent predictor of adverse outcome6 11, both SCD events and progression to heart failure symptoms11 12. However, lack of an accepted methodologic standard in addition to the technical variability in LGE imaging means that LGE quantification is not routinely performed as part of standard practice. Although LGE is a good tool for detecting replacement myocardial fibrosis, detection of diffuse
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interstitial fibrosis remains challenging, since normal myocardium is required as a reference. A promising new CMR technique is T1 mapping, which unlike LGE does not rely upon nulling techniques and allows for fibrosis identification even in the absence of Gadolinium administration. Several investigators have begun to look at T1 mapping within HCM13 14. However, no clinical
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outcome studies with T1 mapping have been conducted yet.
Assessment of left ventricular ejection fraction in HCM may be misleading. Small cavity size can result in a normal or supranormal ejection fraction, even when systolic function is impaired. The supranormal ejection fraction may also be related to a proposed hypercontractility associated with HCM15, which contributes to poor diastolic function.
It may also predict the development of
ventricular hypertrophy in those with a sarcomeric mutation and normal cardiac dimensions16. Diastolic dysfunction can be assessed using tissue echocardiographic Doppler studies and myocardial tagging by CMR; these methods have described some of the abnormalities in left ventricular filling5 17
. Recent developments in diffusion tensor CMR (DT-CMR) have provided a new level of insight. DT-
CMR assesses the myocardial microstructure dynamics and has demonstrated abnormalities in the
ACCEPTED MANUSCRIPT behaviour of the sheetlets that underlie the laminar nature of the myocardium. In healthy hearts these move from a more wall-parallel orientation in diastole to a more wall-perpendicular orientation in systole, a process integral to radial wall thickening. In HCM sheetlets in diastole occupy a systolic –like alignment, exhibiting a failure of diastolic relaxation and relatively immobile sheetlets. This is in accord with the low strain indices seen on echocardiography and tagging
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sequences18. 3D printing has been used as an extension of imaging in many areas of cardiology19, particularly in the congenital heart disease population. Models are also in use in HCM clinics to describe structural abnormalities and principles of the diagnosis. Any high quality imaging can be used to create a
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model but CT and CMR are most commonly chosen. In addition to patient education, models are
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also in use to guide structural interventions, including myectomy20.
Arrhythmia:
Sudden cardiac death risk stratification:
The most feared complication of HCM is sudden cardiac death (SCD). Although the incidence of SCD
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in the entire HCM population is low (0.5 to 1% per year), there is a small subgroup of patients who are at an increased risk6 and timely identification of these individuals is vital but challenging. When a HCM patient survives an episode of ventricular fibrillation or sustained ventricular tachycardia, all HCM guidelines recommend prophylactic ICD implantation for secondary prevention6 21 22. However,
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determining indications for prophylactic ICD implantation in primary prevention remains a challenge. The 2003 ACCF/ESC guidelines used 5 conventional risk factors to estimate the risk for SCD: (1) a family history of SCD, (2) maximal left ventricular wall thickness (LVWT) ≥30mm, (3) unexplained
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syncope, (4) non-sustained ventricular tachycardia, and (5) abnormal blood pressure response to exercise. The expert opinion recommendation stated that the presence of multiple conventional risk factors justified prophylactic treatment with an ICD for primary prevention22. From 2011 the American and European HCM guidelines diverged in their approach to SCD risk stratification. The 2011 ACCF/AHA guidelines are similar to the 2003 ACC/ESC guidelines in using the conventional risk factors for SCD, with the modification that the individual risk factors of family history of SCD, maximal LVWT ≥30 mm, and unexplained syncope alone were also considered sufficient for an ICD recommendation21. In 2014, a novel approach was introduced by the HCM Outcomes Investigators. Their model (HCM Risk-SCD) was based on an initial systematic review, identifying risk factors independently associated with SCD in at least one published multivariable analysis. A subsequent
ACCEPTED MANUSCRIPT univariate Cox regression analysis on a population of 3675 consecutive HCM patients found seven out of the eight pre-specified risk factors to be associated with SCD at a 15% significance level: left ventricular outflow tract (LVOT) gradient, left atrial diameter, age (inverse correlation), and conventional risk factors 1-4 (above). Abnormal blood pressure response on exercise was not included as it had not been independently associated with SCD in previous multivariate survival
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analysis. These predictors and their respective statistical weights were used to build an equation that estimated the risk of SCD in 5 years for an individual patient with HCM. The model was internally validated using bootstrapping and incorporated in the 2014 ESC guidelines2 6. It is
accessible as an online calculator which directly produces the corresponding ESC recommendation (>6%/5 years: ICD should be considered; 4–6%/5 years: ICD may be considered; <4%/5 years: ICD
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generally not indicated).
The first external validation study comparing these prediction models was conducted by Vriesendorp
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et al. in 706 HCM patients23. They found the HCM Risk-SCD model (C-statistic 0.69) to perform better than the 2003 ACC/ESC guidelines (C-statistic 0.55) and 2011 ACCF/AHA guidelines (C-statistic 0.60). The number needed to treat (NNT) with ICD therapy to prevent one case of SCD in 5 years was 17, compared to a NNT of 16 in the original study2. The NNT when using the 2003 and 2011 guidelines were found to be 22 and 20, respectively. In contrast, a second validation study by Maron et al.
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found the HCM Risk-SCD model to perform poorly in a cohort of 1629 consecutive HCM patients, where only 11% of patients who experienced a SCD event, and only 26% of patients who received an appropriate ICD intervention, respectively, were found to have a high predicted risk (≥6%/5 years) consistent with an ICD recommendation24. However, no direct comparisons with SCD risk
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stratification according to the 2003 ACC/ESC and 2011 ACCF/AHA guidelines were made. A study in a South-American HCM population of 502 patients found the HCM Risk-SCD model to be a very good predictor of SCD with a C-statistic of 0.93, compared to 0.76 and 0.71 when using the 2003 and 2011
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models, respectively25. Finally, a small study of patients who had received a prophylactic ICD for primary prevention found the HCM Risk-SCD model to be the only independent predictor of appropriate ICD therapy26, while none of the 11 patients with estimated low risk using the HCM RiskSCD model experienced appropriate ICD therapy. In aggregate, the aforementioned validation studies suggest that the HCM Risk-SCD model performed better than previous models. The HCM Risk-SCD model has not been validated in patients with obstructive HCM before and after septal reduction therapy. Due to a high LVOT gradient, these patients often have a high calculated 5year SCD risk. Additional studies are warranted to investigate if the calculated risk in these patients is valid for use in decision-making regarding primary prevention after septal reduction therapy. For
ACCEPTED MANUSCRIPT all models, the recommendation is to use the estimated 5-year SCD risk to complement clinical reasoning by providing objective individualised prognostic information2 rather than to determine when to offer ICD implantation2. As our understanding of HCM progresses, it is conceivable that additional risk factors may be added to future models. The use of CMR with LGE for quantification of myocardial fibrosis was
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independently linked to SCD in a large multicenter study of 1293 HCM patients with a continuous relationship between the extent of LGE and risk of SCD (a 40% increase in SCD risk per 10% increase in LGE)27. A subsequent meta-analysis which included 5 additional studies confirmed a correlation between the presence of LGE and risk of SCD but not between the extent of LGE and SCD11.
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Genetic analysis also has the potential to enter SCD risk stratification. Currently, a single
heterozygous sarcomeric mutation should not be used to alter risk stratification. Patients with
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multiple sarcomeric gene mutations have been shown to be at an increased risk of end-stage progression and SCD28 29. With next-generation sequencing it will be possible to screen for a larger number of culprit genes, which may lead to identification of more mutations that can be useful for SCD risk stratification. The much anticipated HCMR study has completed enrolment of over 2700 patients this year and aims to examine the role of genetics, biomarkers and CMR indices such as T1
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mapping in the prediction of SCD.
The decision to implant an ICD for primary prevention is not straightforward and detailed discussions should be had with patients with regards to benefits and risks, especially in the circumstance that one risk model portends a higher risk than another. In general, as the SCD event rate is low in HCM
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models.
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patients, multicenter large scale collaborations are required to optimize future SCD risk prediction
Atrial fibrillation (AF)
The prevalence of AF within HCM populations is estimated to be 18-28%30-32. The age of onset of AF is younger within the HCM population, likely due to increased atrial pressures and remodelling as an adaptation to diastolic dynfunction, possible LVOT obstruction and atrial myopathy. The age at AF diagnosis is reported to be 45-5730 31. The risk of thromboebolism is exaggerated in HCM and aggressive anticoagulation is recommended in both European and American guidelines6 21. Warfarin is proposed to be the medication of choice.
ACCEPTED MANUSCRIPT The use of direct oral anticoagulants (DOAC) has expanded significantly since guidance was published, and the patient population in question are often still in employment. The monitoirng of INRs becomes a challenge and many HCM patients are started on a DOAC to aid compliance of anticoagulation. The CHADSVASC score does not predict risk of thormoboembolism in AF and should not be used33. Anticoaguation is indicated in any HCM patient with observed AF, providing the risk of
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bleeding is not excessive. Restoration of sinus rhythm should be targeted in recent onset AF. This poses more of a challenge than in the structurally normal heart. Amiodarone is recommended but carries risk of side effects with long term use. AF ablation has been attempted but success rates are lower than non-HCM
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patients, with 51.8% of patients free from atrial arrhythmia after multiple procedures (mean 1.4) at 1.8 years, and continued antiarrhythmic use in 42%34. Predictors of failure of treatment included left atrial dilatation, LVOT obstruction, and duration of AF34. Early and aggressive treatment in those with
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a structurally normal heart improves the chances of resoring and maintaining sinus rhythm.
Septal reduction
Left ventricular outflow tract obstruction in HCM is associated with greater morbidity and
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mortality35-39 Relief of obstruction is associated with improvement in symptoms and perhaps outcome3 40-44. The first step in treating obstruction is the introduction of negatively inotropic medications6 21. Severe and highly symptomatic LVOT obstruction despite maximal tolerated medical
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therapy is an indication for septal reduction therapy6 21. Surgical myectomy has been considered the gold standard therapy in septal reduction for decades.45
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Relief of LVOT obstruction was historically achieved by removing of 5–10 g of myocardium from the basal interventricular septum, the Morrow procedure46. A more extended myectomy resecting down to the mid-septum is now used in many expert centres47. Mitral valve (MV) abnormalities in HCM are common48 and often under-recognised on pre-operative imaging studies49. Abnormalities of the valve include leaflet elongation, chordal elongation, dysplasia and prolapse. Papillary muscle abnormalities are also well recognised and include hypertrophy or bifidity, and abnormal origins or insertion directly into the MV5. There is no trial data to guide MV interventions in HCM, however expert consensus is that surgical correction should be considered in patients referred for myectomy. Small series of surgical correction of such abnormalities have shown encouraging results. Cutting thickened secondary MV chordae alters the position of the valve, reducing systolic anterior motion of the MV and hence LVOT obstruction50. In the resection-plication-release method the anterior
ACCEPTED MANUSCRIPT mitral valve leaflet is shortened by plication and abnormal papillary muscle attachments are released51. The use of less invasive methods such as Mitraclip have been explored in those with mild LVH and long anterior MV leaflets contributing to systolic anterior motion and obstruction,52-54 but results are limited to small series. The use of minimally invasive approach for standard myectomy has also been demonstrated to be effective55. Procedural volumes are a strong predictor of
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outcome, with average 30-day mortality rates post-myectomy of 5.2% across the United States56 but <1% in centers with more experience44 47.
Alcohol septal ablation (ASA) was introduced as an alternative therapy to surgical myectomy in the mid 1990s57. The technique involves injection of a small amount (1–3 ml) of desiccated alcohol58 into
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an appropriate septal branch resulting in myocardial necrosis, scarring and subsequent septal shrinking40 43 57 59 60. The alcohol induced scar of the septum widens the LVOT, reduces systolic
anterior motion of the MV and thereby relieves obstruction. Removal of LVOT obstruction by ASA
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has been shown to effectively reduce symptoms40 43 59 60. Results from the largest multinational ASA registry to date showed a 30-day mortality of 1%, a decrease in LVOT gradient of 76%, and 89% of post-ASA patients in NYHA class ≤2 at long-term follow-up.60 Initial fears of the alcohol induced scar increasing the risk of SCD or late LV dysfunction have not been fulfilled, and several studies have shown that patients after ASA have a long-term survival comparable with the sex- and age-matched
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general population43 59 61. Persistent LVOT obstruction (>30mmHg) after ASA has recently been demonstrated to be associated with mortality events (mortality and ICD activation), and achieving a gradient <30mmHg is therefore an appropriate target of septal reduction therapy62. Improving the location of the alcohol induced ablation scar using novel imaging techniques (i.e. pre-procedural
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computed tomography guidance to map septal arteries in the target myocardium) may help to achieve this target in the future63-65. The results of case series in ASA are generally reported from high volume centres, this should be borne in mind when applying conclusions to interventional
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centres that do not perform a large volume of procedures or do not have access to a full heart team. Direct endocardial radiofrequency ablation of the interventricular septum may allow non-surgical septal reduction therapy in those that are unable to undergo myectomy or ASA66 67. The procedure is still in the early phases with less than 100 cases reported so far, but it shows great promise in medium term reduction of LVOT obstruction and associated symptoms68. The use of intracardiac echocardiography merged with electroanatomic mapping systems to accurately identify the SAMseptal contact area and conduction systems has provided important insights into the location and size of the target in non-surgical septal reduction therapy69. The freedom from septal arterial anatomy constraints is very attractive in this procedure, but the method of myocardial damage
ACCEPTED MANUSCRIPT appears to be different in the acute phase, with increased tissue oedema and potential for paradoxical increase in LVOT obstruction in the immediate days after ablation67 69. The decision to pursue septal reduction therapy must be made in an informed setting. Patients will usually prefer a percutaneous solution if it is available so the benefits of surgery must be explained in detail70. Therapeutic decision making should involve the Heart team, comprising the clinical
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cardiologist, imaging cardiologist, interventional cardiologist and cardiovascular surgeon6. This will ensure the correct diagnosis is made and subtle anatomical variations are identified pre-operatively. Procedures are best performed in centers with sufficient procedural volume to minimize
complications. There is a clear learning and safety curve associated with volume of procedures in all
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centres, the definition of this will vary internationally.
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forms of septal reduction, this suggests that these procedures should only be performed in expert
Ischaemia:
Myocardial ischaemia is a key component in the pathophysiology of HCM. It is associated with chest pain, clinical deterioration and diastolic dysfunction71-73. Recurrent bouts of ischaemia may lead to the development of myocardial fibrosis, adverse remodelling of the left ventricle and development
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of systolic dysfunction71 73. Interest in myocardial ischaemia in HCM began with the finding of coagulative necrosis and neutrophilic infiltrate on post mortem, suggesting acute myocardial ischemia74. The landmark study by Cecchi et al demonstrated that hyperaemic perfusion measured
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by positron emission tomography (PET) was a powerful independent predictor of outcome in HCM with a 10 fold increase in relative risk of death and a 20 fold increase in development of heart
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failure, cardiac transplantation and death in patients with severe perfusion abnormalities73. The majority of patients with HCM have abnormal perfusion as assessed using nuclear or other noninvasive techniques. Perfusion abnormalities are typically widespread, subendocardial 75 and present in both hypertrophied and non-hypertrophied segments of the ventricle76. Microvascular dysfunction is often seen in patients with mild or no symptoms and can precede clinical deterioration by several years73. Myocardial ischaemia results from an imbalance between the oxygen consumption of the myocytes and the oxygen supply to these myocytes. In HCM, this may result from increased metabolic demand, increased contractility and increased systolic wall tension. Recent work using wave intensity analysis and CMR describe three mechanisms resulting in reduced myocardial perfusion in
ACCEPTED MANUSCRIPT HCM. Extravascular compression and deformation of the intra-myocardial arterioles during ventricular systole results in high pressures within the microcirculation, decelerating blood flow in the epicardial coronary arteries. Impaired ventricular relaxation and a shorter duration of diastole further reduce coronary perfusion, while transient obstruction of flow in the LVOT can lead to deceleration of blood entering the coronary arteries during systole77.
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The intra-mural arterioles are themselves abnormal, with a thickened intimal and medial layer and reduced luminal area78. However, coronary resistance during diastole is actually lower than in
control patients77 79, suggesting compensatory vasodilatation of the microcirculation to normalize myocardial perfusion at rest at the expense of the coronary flow reserve. In severe disease,
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coronary flow reserve may be almost completely exhausted, with near maximal hyperaemia at rest, leading to symptoms on minimal exertion and frequent bouts of ischemia. Coronary flow abnormalities are common in HCM, with flow reversal often seen during systole and higher flow
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velocities during diastole80. Patients with LVOT obstruction are further disadvantaged by a prolonged systolic duration at the expense of the diastolic phase81, reducing time for coronary filling during diastole. During exercise, diastolic time will be further reduced as the heart rate increases.
Treatment with beta blockers and calcium channel blockers are likely to benefit myocardial perfusion, with increase in diastolic duration as well as reduction in LVOT gradients. Septal
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reduction therapies have been shown to improve myocardial perfusion82 and coronary flow reserve83. Reduction in LVOT gradients will reduce intra-cavity pressures and microvascular compression as well as reducing the proximally coronary flow deceleration resulting from LVOT
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obstruction. Although there is no data to suggest that treatment of perfusion defects will improve outcome or reduce progression to heart failure, examination of the underlying pathophysiology
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suggests this may be of benefit.
Novel approaches in medical therapy Beta blockers, calcium channel blockers and disopyramide all have a place in the treatment of symptomatic LVOT obstruction6 21. Asymptomatic patients without LVOT obstruction do not currently warrant medical therapy6 21. There are however emerging alternative options in HCM. Antifibrotic agents: Spironolactone appeared to be effective in modulating the pathogenesis of fibrosis in animal models but efficacy in human models is still to be elucidated84. The use of other drugs to affect the renin-
ACCEPTED MANUSCRIPT angiotensin-aldosterone system has also been explored85, with encouraging results in preclinical and small human trials. The randomised controlled trial INHERIT did not appear to show any difference in burden of fibrosis as assessed by LGE (along with many other clinical outcome measures) with the use of losartan86. Calcium channel blockers in the preclinical state:
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HCM can have a ‘preclinical’ period. A family member may be found to have a sarcomeric mutation but a structurally normal heart; this could provide an opportunity to modify disease progression. The use of diltiazem was explored in such a manner in a small group of young mutation carriers, where there was the suggestion that progression of the disease was affected in those with an MYBPC3
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mutation16. Metabolic modulators:
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Perhexiline is a metabolic modulator that promotes the use of carbohydrates as the substrate for myocardial energy by inhibiting carnitine-palmitoyltransferase (CPT-1). Sarcomeric mutations in HCM increase calcium sensitivity and ATPase activity and hence the energetic cost of contraction. Modulation of this pathway was proposed to improve the contraction-relaxation cycle in HCM and encouraging results were seen in non-obstructive patients with exercise restriction. An improvement in exercise capacity peakVO2 was observed in a randomised trial using perhexline, but its use is
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restricted somewhat by the narrow therapeutic index and risk of side effects87. Late sodium current appears to be abnormal in HCM, and maintenance of intracellcular sodium levels is critical in calcium metabolism. Inhibition of this sodium current has therefore become a focus for medical therapy. Ranolazine showed promise in this respect in cardiomyocytes isolated
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after myectomy88, murine89 and human models90. A subsequent trial (Gilead LIBERTY-HCM) to explore the utility of the stronger sodium current inhibitor eleclazine was designed to explore the
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effects on exercise capacity in HCM, but sadly has been halted due to adverse effects in a parallel trial in ischaemic cardiomyopathy patients. No reports of effects or risks in HCM patients have been published thus far. 91.
Molecular therapy:
With the recognition that HCM was a disease of the sarcomere that causes hypercontractility there has been some focus on trying to ameliorate the abnormalities at a molecular level15. MYK-461 is a small molecule inhibitor of sarcomere power. This medication has been shown to attenuate the development of some of the hallmark features of HCM such as LVH, hypercontractility (expressed as fractional shortening) and fibrosis when used early in the disease in murine models92. The same molecule was also shown to reduce LVOT obstruction when used in cats with obstructive HCM93. The
ACCEPTED MANUSCRIPT safety of this therapy is currently being explored in humans. This represents an exciting development in HCM but is in a very preliminary stage.
Conclusion:
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Significant progress has been made in many aspects of the understanding and treatment of HCM in the last decade (a summary is provided in Table 1.). This is translating to better care in dealing with the consequences of the disease process, such as LVOT obstruction and prediction and treatment of life threatening arrhythmia. This is in practice in the clinical arena today. There remains some
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regional variability in standard of care available, this may be addressed by creating international standards and centres of excellence to concentrate the complex care that is often required. Perhaps
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more exciting than the change in clinical practice when dealing with the complications of HCM is the prospect of a greater understanding of the underlying pathological mechanisms. These insights could enhance early detection of HCM and allow us the opportunity to treat before some of the advanced complications occur.
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Table 1:
Imaging
Summary of new developments
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Category
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Sudden cardiac death risk stratification
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Septal reduction
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Echo remains the mainstay imaging evaluation and provides best characterization of physiologic abnormalities. Myocardial tissue abnormalities are best assessed with CMR using late Gadolinium enhancement (LGE) and T1 mapping. Diffusion tensor-CMR may provide an insight into the mechanistic myocardial abnormalities of HCM. LGE predicts SCD events and progression to heart failure. The risk of SCD in a general HCM population is low (0.5-1% p.a.). The HCM Risk-SCD risk model is the most accurate to date with some validation studies proving encouraging. This is not validated in those who have undergone septal reduction. Genetic analysis currently does not contribute significantly to risk assessment – this may change soon due to high output next generation sequencing. Effective removal of LVOT obstruction improves symptoms and potentially improves prognosis. Surgical and non-surgical septal reduction should be performed in centres of excellence with high volume of procedures.
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Novel approaches in medical therapy
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Ischaemia
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Surgical correction now often involves extended myectomy and correction of mitral valve abnormalities in addition to the traditional Morrow myectomy. Endocardial radiofrequency ablation of the septum is now a viable alternative in selected centres in those that cannot have surgery or alcohol ablation. The majority of HCM patients have perfusion assess by non-invasive methods. The presence of severe perfusion defects can predict adverse outcome. Perfusion defects result from increased metabolic demands and coronary flow abnormalities. Coronary flow abnormalities include extravascular compression of intramyocardial arterioles, impaired ventricular relaxation and a shorter period of diastole for coronary perfusion and transient obstruction to flow in the LVOT leading to deceleration of flow into the epicardial arteries. Despite encouraging early small trials the use of antifibrotic agents has not proven to be effective at preventing progression of fibrosis in HCM, as the INHERIT study. Calcium channel blockers may provide some benefit in offsetting disease progress in the early preclinical period of MYBPC3 mutation carriers, this was a very small number of patients. Perhexiline can improve exercise capacity in HCM patients. Ranolazine has shown some promise in HCM due to its effect on the surface sodium channels, a trial involving a more potent sodium channel inhibitor Eleclezine (LIBERTY- HCM) faces problems with recruitment. Molecular therapy aimed at inhibiting sarcomere power has shown great promise in early murine and feline studies.
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Table 1: Summary of recent advances in HCM
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Figure legends:
Figure 1: DTCMR images. Sheetlet orientation changes are from blue in diastole to red in systole in normal control subjects. HCM takes a healthy systolic conformation (wall perpendicular sheetlets) but an incomplete diastolic conformation (mix of wall parallel and wall perpendicular sheetlets). Figure 2: An example of a HCM 3D print used for patient education, Figure 3: Septal reduction. Panel A; typical septal hypertrophy with SAM of the MV. Panel B; the target for septal reduction. Panel C; result after septal reduction. Panel D; bSSFP cine of HCM in systole with SAM of the MV (matching panel A). Panel E; LGE image with high signal intensity (infarct of ASA) in the basal septum. Panel F; post-ASA bSSFP cine in systole with septal shrinking and widening of the LVOT, no SAM is seen.
ACCEPTED MANUSCRIPT Figure 4: Panel A; bifid posterior papillary muscle. Panel B; MV prolapse in HCM. Panel C; direct insertion of papillary muscle in to MV. Panel D: Heavily fractionated papillary muscles – one of the anterior muscle moves into the LVOT in systole causing obstruction.
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Figure 5: Mechanisms of perfusion abnormalities in HCM. There are four potential contributing mechanisms to development of myocardial ischemia in HCM. First pass myocardial perfusion imaging using CMR typically demonstrates a circumferential subendocardial perfusion defect following administration of intravenous adenosine (panel A). A negative CMR perfusion scan is shown in panel B for reference.
Acknowledgements:
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Many thanks to Pedro Ferreira and Dr Zohya Khalique from Royal Brompton Hospital for their help with diffusion tensor CMR images.
References
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1. Semsarian C, Ingles J, Maron MS, et al. New perspectives on the prevalence of hypertrophic cardiomyopathy. Journal of the American College of Cardiology 2015;65(12):1249-54. 2. O'Mahony C, Jichi F, Pavlou M, et al. A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM risk-SCD). Eur Heart J 2014;35(30):2010-20. 3. Veselka J, Jensen MK, Liebregts M, et al. Long-term clinical outcome after alcohol septal ablation for obstructive hypertrophic cardiomyopathy: results from the Euro-ASA registry. Eur Heart J 2016;37(19):1517-23. 4. Nagueh SF, Groves BM, Schwartz L, et al. Alcohol septal ablation for the treatment of hypertrophic obstructive cardiomyopathy a multicenter north american registry. JAmCollCardiol 2011;58(22):2322-28. 5. Cardim N, Galderisi M, Edvardsen T, et al. Role of multimodality cardiac imaging in the management of patients with hypertrophic cardiomyopathy: an expert consensus of the European Association of Cardiovascular Imaging Endorsed by the Saudi Heart Association. Eur Heart J Cardiovasc Imaging 2015;16(3):280. 6. Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014. 7. Moon JC, Fisher NG, McKenna WJ, et al. Detection of apical hypertrophic cardiomyopathy by cardiovascular magnetic resonance in patients with non-diagnostic echocardiography. Heart (British Cardiac Society) 2004;90(6):645-9. 8. Bruder O, Wagner A, Jensen CJ, et al. Myocardial scar visualized by cardiovascular magnetic resonance imaging predicts major adverse events in patients with hypertrophic cardiomyopathy. Journal of the American College of Cardiology 2010;56(11):875-87. 9. O'Hanlon R, Grasso A, Roughton M, et al. Prognostic significance of myocardial fibrosis in hypertrophic cardiomyopathy. Journal of the American College of Cardiology 2010;56(11):867-74. 10. Moon JC, Reed E, Sheppard MN, et al. The histologic basis of late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy. Journal of the American College of Cardiology 2004;43(12):2260-4.
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11. Briasoulis A, Mallikethi-Reddy S, Palla M, et al. Myocardial fibrosis on cardiac magnetic resonance and cardiac outcomes in hypertrophic cardiomyopathy: a meta-analysis. Heart (British Cardiac Society) 2015;101(17):1406-11. 12. Weng Z, Yao J, Chan RH, et al. Prognostic Value of LGE-CMR in HCM: A Meta-Analysis. JACC Cardiovascular imaging 2016;9(12):1392-402. 13. Lu M, Zhao S, Yin G, et al. T1 mapping for detection of left ventricular myocardial fibrosis in hypertrophic cardiomyopathy: a preliminary study. European journal of radiology 2013;82(5):e225-31. 14. Puntmann VO, Voigt T, Chen Z, et al. Native T1 mapping in differentiation of normal myocardium from diffuse disease in hypertrophic and dilated cardiomyopathy. JACC Cardiovascular imaging 2013;6(4):475-84. 15. Adhikari AS, Kooiker KB, Sarkar SS, et al. Early-Onset Hypertrophic Cardiomyopathy Mutations Significantly Increase the Velocity, Force, and Actin-Activated ATPase Activity of Human beta-Cardiac Myosin. Cell reports 2016;17(11):2857-64. 16. Ho CY, Cirino AL, Lakdawala NK, et al. Evolution of hypertrophic cardiomyopathy in sarcomere mutation carriers. Heart (British Cardiac Society) 2016. 17. Kim YJ, Choi BW, Hur J, et al. Delayed enhancement in hypertrophic cardiomyopathy: comparison with myocardial tagging MRI. Journal of magnetic resonance imaging : JMRI 2008;27(5):1054-60. 18. Nielles-Vallespin S, Khalique Z, Ferreira PF, et al. Assessment of Myocardial Microstructural Dynamics by In Vivo Diffusion Tensor Cardiac Magnetic Resonance. Journal of the American College of Cardiology 2017;69(6):661-76. 19. Vukicevic M, Mosadegh B, Min JK, et al. Cardiac 3D Printing and its Future Directions. JACC Cardiovascular imaging 2017;10(2):171-84. 20. Yang DH, Kang JW, Kim N, et al. Myocardial 3-Dimensional Printing for Septal Myectomy Guidance in a Patient With Obstructive Hypertrophic Cardiomyopathy. Circulation 2015;132(4):300-1. 21. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011. 22. Maron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. JAmCollCardiol 2003;42(9):1687-713. 23. Vriesendorp PA, Schinkel AF, Liebregts M, et al. Validation of the 2014 European Society of Cardiology guidelines risk prediction model for the primary prevention of sudden cardiac death in hypertrophic cardiomyopathy. Circulation Arrhythmia and electrophysiology 2015;8(4):829-35. 24. Maron BJ, Casey SA, Chan RH, et al. Independent Assessment of the European Society of Cardiology Sudden Death Risk Model for Hypertrophic Cardiomyopathy. The American journal of cardiology 2015;116(5):757-64. 25. Fernandez A, Quiroga A, Ochoa JP, et al. Validation of the 2014 European Society of Cardiology Sudden Cardiac Death Risk Prediction Model in Hypertrophic Cardiomyopathy in a Reference Center in South America. The American journal of cardiology 2016;118(1):121-6. 26. Ruiz-Salas A, Garcia-Pinilla JM, Cabrera-Bueno F, et al. Comparison of the new risk prediction model (HCM Risk-SCD) and classic risk factors for sudden death in patients with hypertrophic cardiomyopathy and defibrillator. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 2016;18(5):773-7.
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27. Chan RH, Maron BJ, Olivotto I, et al. Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy. Circulation 2014;130(6):484-95. 28. Girolami F, Ho CY, Semsarian C, et al. Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations. Journal of the American College of Cardiology 2010;55(14):1444-53. 29. Wang J, Wang Y, Zou Y, et al. Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy. European journal of heart failure 2014;16(9):950-7. 30. Olivotto I, Cecchi F, Casey SA, et al. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation 2001;104(21):2517-24. 31. Kubo T, Kitaoka H, Okawa M, et al. Clinical impact of atrial fibrillation in patients with hypertrophic cardiomyopathy. Results from Kochi RYOMA Study. Circulation journal : official journal of the Japanese Circulation Society 2009;73(9):1599-605. 32. Siontis KC, Geske JB, Ong K, et al. Atrial fibrillation in hypertrophic cardiomyopathy: prevalence, clinical correlations, and mortality in a large high-risk population. Journal of the American Heart Association 2014;3(3):e001002. 33. Guttmann OP, Pavlou M, O'Mahony C, et al. Prediction of thrombo-embolic risk in patients with hypertrophic cardiomyopathy (HCM Risk-CVA). European journal of heart failure 2015;17(8):837-45. 34. Providencia R, Elliott P, Patel K, et al. Catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy: a systematic review and meta-analysis. Heart (British Cardiac Society) 2016;102(19):1533-43. 35. Maron BJ, Maron MS, Wigle ED, et al. The 50-year history, controversy, and clinical implications of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy from idiopathic hypertrophic subaortic stenosis to hypertrophic cardiomyopathy: from idiopathic hypertrophic subaortic stenosis to hypertrophic cardiomyopathy. JAmCollCardiol 2009;54(3):191-200. 36. Maron BJ, Nishimura RA, Danielson GK. Pitfalls in clinical recognition and a novel operative approach for hypertrophic cardiomyopathy with severe outflow obstruction due to anomalous papillary muscle. Circulation 1998;98(23):2505-08. 37. Ommen SR, Nishimura RA. What causes outflow tract obstruction in hypertrophic cardiomyopathy? Heart (British Cardiac Society) 2009;95(21):1725-26. 38. Maron MS, Olivotto I, Zenovich AG, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation 2006;114(21):2232-39. 39. Kofflard MJ, Ten Cate FJ, van der Lee C, et al. Hypertrophic cardiomyopathy in a large community-based population: clinical outcome and identification of risk factors for sudden cardiac death and clinical deterioration. Journal of the American College of Cardiology 2003;41(6):987-93. 40. Jensen MK, Prinz C, Horstkotte D, et al. Alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy: low incidence of sudden cardiac death and reduced risk profile. Heart 2013;99(14):1012-17. 41. McLeod CJ, Ommen SR, Ackerman MJ, et al. Surgical septal myectomy decreases the risk for appropriate implantable cardioverter defibrillator discharge in obstructive hypertrophic cardiomyopathy. European Heart Journal 2007;28(21):2583-88. 42. Sherrid MV, Shetty A, Winson G, et al. Treatment of obstructive hypertrophic cardiomyopathy symptoms and gradient resistant to first-line therapy with beta-blockade or verapamil. Circulation Heart failure 2013;6(4):694-702. 43. Sorajja P, Ommen SR, Holmes DR, et al. Survival After Alcohol Septal Ablation for Obstructive Hypertrophic Cardiomyopathy. Circulation 2012;126(20):2374-80.
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44. Altarabsheh SE, Dearani JA, Burkhart HM, et al. Outcome of septal myectomy for obstructive hypertrophic cardiomyopathy in children and young adults. Ann Thorac Surg 2013;95(2):6639; discussion 69. 45. Maron BJ, Maron MS. The 20 advances that have defined contemporary hypertrophic cardiomyopathy. Trends in Cardiovascular Medicine 2015;25(1):54-64. 46. MORROW AG, Reitz BA, Epstein SE, et al. Operative treatment in hypertrophic subaortic stenosis. Techniques, and the results of pre and postoperative assessments in 83 patients. Circulation 1975;52(1):88-102. 47. Dearani JA, Ommen SR, Gersh BJ, et al. Surgery insight: Septal myectomy for obstructive hypertrophic cardiomyopathy--the Mayo Clinic experience. NatClinPractCardiovascMed 2007;4(9):503-12. 48. Cavalcante JL, Barboza JS, Lever HM. Diversity of mitral valve abnormalities in obstructive hypertrophic cardiomyopathy. Progress in cardiovascular diseases 2012;54(6):517-22. 49. Hong JH, Schaff HV, Nishimura RA, et al. Mitral Regurgitation in Patients With Hypertrophic Obstructive Cardiomyopathy: Implications for Concomitant Valve Procedures. Journal of the American College of Cardiology 2016;68(14):1497-504. 50. Ferrazzi P, Spirito P, Iacovoni A, et al. Transaortic Chordal Cutting: Mitral Valve Repair for Obstructive Hypertrophic Cardiomyopathy With Mild Septal Hypertrophy. Journal of the American College of Cardiology 2015;66(15):1687-96. 51. Swistel DG, Balaram SK. Surgical myectomy for hypertrophic cardiomyopathy in the 21st century, the evolution of the "RPR" repair: resection, plication, and release. Progress in cardiovascular diseases 2012;54(6):498-502. 52. Thomas F, Rader F, Siegel RJ. The Use of MitraClip for Symptomatic Patients with Hypertrophic Obstructive Cardiomyopathy. Cardiology 2017;137(1):58-61. 53. Schafer U, Frerker C, Thielsen T, et al. Targeting systolic anterior motion and left ventricular outflow tract obstruction in hypertrophic obstructed cardiomyopathy with a MitraClip. EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 2015;11(8):942-7. 54. Schafer U, Kreidel F, Frerker C. MitraClip implantation as a new treatment strategy against systolic anterior motion-induced outflow tract obstruction in hypertrophic obstructive cardiomyopathy. Heart, lung & circulation 2014;23(5):e131-5. 55. Mazine A, Ghoneim A, Bouhout I, et al. A Novel Minimally Invasive Approach for Surgical Septal Myectomy. The Canadian journal of cardiology 2016;32(11):1340-47. 56. Kim LK, Swaminathan RV, Looser P, et al. Hospital volume outcomes after septal myectomy and alcohol septal ablation for treatment of obstructive hypertrophic cardiomyopathy: Us nationwide inpatient database, 2003-2011. JAMA cardiology 2016;1(3):324-32. 57. Sigwart U. Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy. The Lancet 1995;346(8969):211-14. 58. Veselka J, Tomašov P, Zemánek D. Long-Term Effects of Varying Alcohol Dosing in Percutaneous Septal Ablation for Obstructive Hypertrophic Cardiomyopathy: A Randomized Study With a Follow-up up to 11 Years. Canadian Journal of Cardiology 2011;27(6):763-67. 59. Veselka J, Krejčí J, Tomašov P, et al. Long-term survival after alcohol septal ablation for hypertrophic obstructive cardiomyopathy: a comparison with general population. European Heart Journal 2014;35(30):2040-45. 60. Veselka J, Jensen MK, Liebregts M, et al. Low procedure-related mortality achieved with alcohol septal ablation in European patients. International Journal of Cardiology 2016;209:194-95. 61. Veselka J, Zemanek D, Jahnlova D, et al. Risk and Causes of Death in Patients After Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy. The Canadian journal of cardiology 2015;31(10):1245-51. 62. Veselka J, Tomašov P, Januška J, et al. Obstruction after alcohol septal ablation is associated with cardiovascular mortality events. Heart (British Cardiac Society) 2016;102(22):1793-96.
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63. Cooper RM, Binukrishnan SR, Shahzad A, et al. Computed Tomography angiography planning identifies the target vessel for optimum infarct location and improves clinical outcome in alcohol septal ablation for hypertrophic obstructive cardiomyopathy. EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 2016. 64. Okayama S, Uemura S, Soeda T, et al. Role of cardiac computed tomography in planning and evaluating percutaneous transluminal septal myocardial ablation for hypertrophic obstructive cardiomyopathy. J Cardiovasc Comput Tomogr 2010;4(1):62-5. 65. Mitsutake R, Miura S, Sako H, et al. Usefulness of multi-detector row computed tomography for the management of percutaneous transluminal septal myocardial ablation in patient with hypertrophic obstructive cardiomyopathy. IntJCardiol 2008;129(2):e61-e63. 66. Lawrenz T, Borchert B, Leuner C, et al. Endocardial radiofrequency ablation for hypertrophic obstructive cardiomyopathy: acute results and 6 months' follow-up in 19 patients. JAmCollCardiol 2011;57(5):572-76. 67. Sreeram N, Emmel M, de Giovanni JV. Percutaneous radiofrequency septal reduction for hypertrophic obstructive cardiomyopathy in children. JAmCollCardiol 2011;58(24):2501-10. 68. Poon SS, Cooper RM, Gupta D. Endocardial radiofrequency septal ablation - A new option for non-surgical septal reduction in patients with hypertrophic obstructive cardiomyopathy (HOCM)?: A systematic review of clinical studies. Int J Cardiol 2016;222:772-4. 69. Cooper RM, Shahzad A, Hasleton J, et al. Radiofrequency ablation of the interventricular septum to treat outflow tract gradients in hypertrophic obstructive cardiomyopathy: a novel use of CARTOSound(R) technology to guide ablation. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 2016;18(1):11320. 70. Fifer MA. Controversies in cardiovascular medicine. Most fully informed patients choose septal ablation over septal myectomy. Circulation 2007;116(2):207-16. 71. Maron MS, Olivotto I, Maron BJ, et al. The case for myocardial ischemia in hypertrophic cardiomyopathy. Journal of the American College of Cardiology 2009;54(9):866-75. 72. Olivotto I, Cecchi F, Gistri R, et al. Relevance of coronary microvascular flow impairment to longterm remodeling and systolic dysfunction in hypertrophic cardiomyopathy. Journal of the American College of Cardiology 2006;47(5):1043-8. 73. Cecchi F, Olivotto I, Gistri R, et al. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. The New England journal of medicine 2003;349(11):1027-35. 74. Basso C, Thiene G, Corrado D, et al. Hypertrophic cardiomyopathy and sudden death in the young: pathologic evidence of myocardial ischemia. Human pathology 2000;31(8):988-98. 75. Petersen SE, Jerosch-Herold M, Hudsmith LE, et al. Evidence for microvascular dysfunction in hypertrophic cardiomyopathy: new insights from multiparametric magnetic resonance imaging. Circulation 2007;115(18):2418-25. 76. Camici P, Chiriatti G, Lorenzoni R, et al. Coronary vasodilation is impaired in both hypertrophied and nonhypertrophied myocardium of patients with hypertrophic cardiomyopathy: a study with nitrogen-13 ammonia and positron emission tomography. Journal of the American College of Cardiology 1991;17(4):879-86. 77. Raphael CE, Cooper R, Parker KH, et al. Mechanisms of Myocardial Ischemia in Hypertrophic Cardiomyopathy: Insights From Wave Intensity Analysis and Magnetic Resonance. Journal of the American College of Cardiology 2016;68(15):1651-60. 78. Maron BJ, Wolfson JK, Epstein SE, et al. Intramural ("small vessel") coronary artery disease in hypertrophic cardiomyopathy. Journal of the American College of Cardiology 1986;8(3):54557. 79. Yang EH, Yeo TC, Higano ST, et al. Coronary hemodynamics in patients with symptomatic hypertrophic cardiomyopathy. The American journal of cardiology 2004;94(5):685-7.
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80. Kyriakidis MK, Dernellis JM, Androulakis AE, et al. Changes in phasic coronary blood flow velocity profile and relative coronary flow reserve in patients with hypertrophic obstructive cardiomyopathy. Circulation 1997;96(3):834-41. 81. Plehn G, Vormbrock J, Meissner A, et al. Effects of exercise on the duration of diastole and on interventricular phase differences in patients with hypertrophic cardiomyopathy: relationship to cardiac output reserve. Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology 2009;16(2):233-43. 82. Timmer SA, Knaapen P, Germans T, et al. Effects of alcohol septal ablation on coronary microvascular function and myocardial energetics in hypertrophic obstructive cardiomyopathy. American journal of physiology Heart and circulatory physiology 2011;301(1):H129-37. 83. Jaber WA, Yang EH, Nishimura RA, et al. Immediate improvement in coronary flow reserve after alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy. Heart (British Cardiac Society) 2009;95(7):564-9. 84. de Resende MM, Kriegel AJ, Greene AS. Combined effects of low-dose spironolactone and captopril therapy in a rat model of genetic hypertrophic cardiomyopathy. Journal of cardiovascular pharmacology 2006;48(6):265-73. 85. Marian AJ. Experimental therapies in hypertrophic cardiomyopathy. J Cardiovasc Transl Res 2009;2(4):483-92. 86. Axelsson A, Iversen K, Vejlstrup N, et al. Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebocontrolled trial. Lancet Diabetes Endocrinol 2015;3(2):123-31. 87. Abozguia K, Elliott P, McKenna W, et al. Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation 2010;122(16):1562-9. 88. Coppini R, Ferrantini C, Yao L, et al. Late sodium current inhibition reverses electromechanical dysfunction in human hypertrophic cardiomyopathy. Circulation 2013;127(5):575-84. 89. Coppini R, Mazzoni L, Ferrantini C, et al. Ranolazine Prevents Phenotype Development in a Mouse Model of Hypertrophic Cardiomyopathy. Circulation Heart failure 2017;10(3). 90. Gentry JL, 3rd, Mentz RJ, Hurdle M, et al. Ranolazine for Treatment of Angina or Dyspnea in Hypertrophic Cardiomyopathy Patients (RHYME). Journal of the American College of Cardiology 2016;68(16):1815-17. 91. Olivotto I, Hellawell JL, Farzaneh-Far R, et al. Novel Approach Targeting the Complex Pathophysiology of Hypertrophic Cardiomyopathy: The Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) Trial. Circulation Heart failure 2016;9(3):e002764. 92. Green EM, Wakimoto H, Anderson RL, et al. A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science (New York, NY) 2016;351(6273):617-21. 93. Stern JA, Markova S, Ueda Y, et al. A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Left Ventricular Outflow Tract Obstruction in Feline Hypertrophic Cardiomyopathy. PloS one 2016;11(12):e0168407.
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Summary of new developments
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Septal reduction
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Echo remains the mainstay imaging evaluation and provides best characterization of physiologic abnormalities. Myocardial tissue abnormalities are best assessed with CMR using late Gadolinium enhancement (LGE) and T1 mapping. Diffusion tensor-CMR may provide an insight into the mechanistic myocardial abnormalities of HCM. LGE predicts SCD events and progression to heart failure. The risk of SCD in a general HCM population is low (0.5-1% p.a.). The HCM Risk-SCD risk model is the most accurate to date with some validation studies proving encouraging. This is not validated in those who have undergone septal reduction. Genetic analysis currently does not contribute significantly to risk assessment – this may change soon due to high output next generation sequencing. Effective removal of LVOT obstruction improves symptoms and potentially improves prognosis. Surgical and non-surgical septal reduction should be performed in centres of excellence with high volume of procedures. Surgical correction now often involves extended myectomy and correction of mitral valve abnormalities in addition to the traditional Morrow myectomy. Endocardial radiofrequency ablation of the septum is now a viable alternative in selected centres in those that cannot have surgery or alcohol ablation. The majority of HCM patients have perfusion assess by non-invasive methods. The presence of severe perfusion defects can predict adverse outcome. Perfusion defects result from increased metabolic demands and coronary flow abnormalities. Coronary flow abnormalities include extravascular compression of intramyocardial arterioles, impaired ventricular relaxation and a shorter period of diastole for coronary perfusion and transient obstruction to flow in the LVOT leading to deceleration of flow into the epicardial arteries. Despite encouraging early small trials the use of antifibrotic agents has not proven to be effective at preventing progression of fibrosis in HCM, as the INHERIT study. Calcium channel blockers may provide some benefit in offsetting disease progress in the early preclinical period of MYBPC3 mutation carriers, this was a very small number of patients. Perhexiline can improve exercise capacity in HCM patients. Ranolazine has shown some promise in HCM due to its effect on the surface sodium channels, a trial involving a more potent sodium channel inhibitor Eleclzine (LIBERTY- HCM) faces problems with recruitment. Molecular therapy aimed at inhibiting sarcomere power has shown great promise in early murine and feline studies.
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Table 1: Summary of recent advances in HCM
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S0828-282X(17)30371-9
DOI:
10.1016/j.cjca.2017.07.007
Reference:
CJCA 2477
To appear in:
Canadian Journal of Cardiology
Received Date: 21 May 2017 Revised Date:
4 July 2017
Accepted Date: 11 July 2017
Please cite this article as: Cooper RM, Raphael CE, Liebregts M, Anavekar NS, Veselka J, New developments in hypertrophic cardiomyopathy, Canadian Journal of Cardiology (2017), doi: 10.1016/ j.cjca.2017.07.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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New developments in hypertrophic cardiomyopathy
Robert M Cooper MBChB MRCP PhD
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Corresponding author [email protected] Department of Cardiology
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Liverpool Heart and Chest Hospital Thomas Drive
L14 3PE United Kingdom
Claire E Raphael MBBS MRCP PhD
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Department of Cardiovascular Diseases
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Liverpool
Mayo Clinic, Rochester, MN USA
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Max Liebregts MD Department of Cardiology
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St Antonius Ziekenhuis, Nieuwegein
Nandan S Anavekar MBBCh FACC Department of Cardiovascular Diseases Mayo Clinic, Rochester, MN USA
Josef Veselka MD PhD Department of Cardiology, Motol University Hospital and 2nd Medical School, Charles University, Prague
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We discuss new developments in the investigation and management of HCM. Imaging including novel cardiac MRI techniques and echocardiography are included, along with new insights into the mechanisms of abnormal perfusion. Innovative approaches to the management of LVOT obstruction are covered, both surgical and non-surgical. We examine the evidence for the use of risk stratification models for sudden cardiac death and consider the importance of AF. Novel medications targeting HCM related abnormalities are also reviewed.
Abstract
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Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden death in the young and an important cause of heart failure at any age. In this review we discuss advances in investigation and management of this heterogenous disease.
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Improved cardiac imaging has allowed us to detail many of the structural abnormalities while the use of new techniques, predominantly in cardiac MRI, has given us a greater insight in to tissue architecture, mechanism of contractile abnormalities and function. Risk stratification remains challenging due to the low event rate in clinical studies. Multi centre registries have improved risk stratification for sudden cardiac death and multiple models may be used to aid decision making for implantable defibrillator therapy.
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We discuss the current state of non-surgical septal reduction therapy and results of multi centre registries. New approaches to septal reduction therapy including refinement of alcohol ablation and non-coronary interventions such as radiofrequency ablation of the septum show great promise. Surgical myectomy remains a major part of treatment; a greater recognition of abnormalities of the mitral valve apparatus can allow improved surgical options. Myocardial perfusion abnormalities are known to predict adverse outcome in HCM and we discuss underlying mechanisms and relevance to management.
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The off-label use of currently licensed medicines such as ranolazine, perhexiline, calcium channel blockers and renin-angiotensin system antagonists are discussed. A novel approach to medical treatment of the underlying sarcomeric disorder has been investigated and shows great potential.
Disclosures: All authors – nothing to disclose
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Introduction:
Hypertrophic cardiomyopathy (HCM) is an inherited disease characterised by otherwise unexplained
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hypertrophy of the myocardium. HCM has an estimated phenotypic prevalence of 1 in 500 and
possible genotypic prevalence of 1 in 2001. The management of HCM has evolved since the first descriptions and early recognition and management can effectively treat symptoms in the majority of patients. Better risk stratification models borne out of multi-center registries also allow more
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accurate identification of patients suitable for implantable cardioverter defibrillators (ICDs) as
primary prevention for sudden cardiac death2. There has been increased interest in HCM recently with a significant rise in targeted research, including the development of multiple international
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registries2-4. Here we focus on some areas of interest and recent development in the understanding and management of HCM.
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Imaging;
Echocardiography has been and remains the mainstay of the imaging evaluation in HCM, as it is portable and provides the best characterization of the physiologic abnormalities related to diastolic and systolic function, intraventricular obstruction and valvular abnormalities. Cardiovascular
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magnetic resonance (CMR) allows detailed description of the morphologic abnormalities seen in HCM and its ability to characterize tissue changes provides further understanding of the disease
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pathobiology and may support risk stratification algorithms. The goals of the imaging evaluation are to delineate the cardiac anatomy, to assess the implications of the anatomic findings on cardiac function, to evaluate ischemia and to monitor the efficacy of therapy5. The anatomic considerations at initial diagnosis include qualification and quantification of hypertrophy, assessment of the mitral apparatus, assessment of location and severity of intraventricular obstruction and the assessment of tissue characteristics that may signify underlying fibrotic change. Pathologic hypertrophy is considered in the presence of unexplained wall thickness >15mm in any myocardial segment or asymmetric septal hypertrophy with a septal to posterior wall thickness ratio >1.3 in normotensive individuals or >1.5 in hypertensive individuals5. The use of a wall thickness ratio in those with wall thickness <15mm remains controversial in some arenas and is
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constraints of lateral resolution. In these instances, CMR may be considered as an alternative initial imaging investigation. Indeed, CMR is more sensitive than echocardiography in the detection of segmental wall abnormalities and apical HCM7.
Myocardial tissue abnormalities are best assessed using CMR. Myocardial fibrosis is common and
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found in up to two thirds of patients 8 9. Late gadolinium enhancement (LGE) allows assessment of abnormalities of the extracellular milieu and is assumed to represent replacement fibrosis9 10. The
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pattern of LGE is variable but is usually a patchy, mid myocardial distribution, particularly in areas of maximal hypertrophy and the right ventricular septal insertion sites. LGE is a strong independent predictor of adverse outcome6 11, both SCD events and progression to heart failure symptoms11 12. However, lack of an accepted methodologic standard in addition to the technical variability in LGE imaging means that LGE quantification is not routinely performed as part of standard practice. Although LGE is a good tool for detecting replacement myocardial fibrosis, detection of diffuse
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interstitial fibrosis remains challenging, since normal myocardium is required as a reference. A promising new CMR technique is T1 mapping, which unlike LGE does not rely upon nulling techniques and allows for fibrosis identification even in the absence of Gadolinium administration. Several investigators have begun to look at T1 mapping within HCM13 14. However, no clinical
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outcome studies with T1 mapping have been conducted yet.
Assessment of left ventricular ejection fraction in HCM may be misleading. Small cavity size can result in a normal or supranormal ejection fraction, even when systolic function is impaired. The supranormal ejection fraction may also be related to a proposed hypercontractility associated with HCM15, which contributes to poor diastolic function.
It may also predict the development of
ventricular hypertrophy in those with a sarcomeric mutation and normal cardiac dimensions16. Diastolic dysfunction can be assessed using tissue echocardiographic Doppler studies and myocardial tagging by CMR; these methods have described some of the abnormalities in left ventricular filling5 17
. Recent developments in diffusion tensor CMR (DT-CMR) have provided a new level of insight. DT-
CMR assesses the myocardial microstructure dynamics and has demonstrated abnormalities in the
ACCEPTED MANUSCRIPT behaviour of the sheetlets that underlie the laminar nature of the myocardium. In healthy hearts these move from a more wall-parallel orientation in diastole to a more wall-perpendicular orientation in systole, a process integral to radial wall thickening. In HCM sheetlets in diastole occupy a systolic –like alignment, exhibiting a failure of diastolic relaxation and relatively immobile sheetlets. This is in accord with the low strain indices seen on echocardiography and tagging
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sequences18. 3D printing has been used as an extension of imaging in many areas of cardiology19, particularly in the congenital heart disease population. Models are also in use in HCM clinics to describe structural abnormalities and principles of the diagnosis. Any high quality imaging can be used to create a
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model but CT and CMR are most commonly chosen. In addition to patient education, models are
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also in use to guide structural interventions, including myectomy20.
Arrhythmia:
Sudden cardiac death risk stratification:
The most feared complication of HCM is sudden cardiac death (SCD). Although the incidence of SCD
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in the entire HCM population is low (0.5 to 1% per year), there is a small subgroup of patients who are at an increased risk6 and timely identification of these individuals is vital but challenging. When a HCM patient survives an episode of ventricular fibrillation or sustained ventricular tachycardia, all HCM guidelines recommend prophylactic ICD implantation for secondary prevention6 21 22. However,
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determining indications for prophylactic ICD implantation in primary prevention remains a challenge. The 2003 ACCF/ESC guidelines used 5 conventional risk factors to estimate the risk for SCD: (1) a family history of SCD, (2) maximal left ventricular wall thickness (LVWT) ≥30mm, (3) unexplained
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syncope, (4) non-sustained ventricular tachycardia, and (5) abnormal blood pressure response to exercise. The expert opinion recommendation stated that the presence of multiple conventional risk factors justified prophylactic treatment with an ICD for primary prevention22. From 2011 the American and European HCM guidelines diverged in their approach to SCD risk stratification. The 2011 ACCF/AHA guidelines are similar to the 2003 ACC/ESC guidelines in using the conventional risk factors for SCD, with the modification that the individual risk factors of family history of SCD, maximal LVWT ≥30 mm, and unexplained syncope alone were also considered sufficient for an ICD recommendation21. In 2014, a novel approach was introduced by the HCM Outcomes Investigators. Their model (HCM Risk-SCD) was based on an initial systematic review, identifying risk factors independently associated with SCD in at least one published multivariable analysis. A subsequent
ACCEPTED MANUSCRIPT univariate Cox regression analysis on a population of 3675 consecutive HCM patients found seven out of the eight pre-specified risk factors to be associated with SCD at a 15% significance level: left ventricular outflow tract (LVOT) gradient, left atrial diameter, age (inverse correlation), and conventional risk factors 1-4 (above). Abnormal blood pressure response on exercise was not included as it had not been independently associated with SCD in previous multivariate survival
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analysis. These predictors and their respective statistical weights were used to build an equation that estimated the risk of SCD in 5 years for an individual patient with HCM. The model was internally validated using bootstrapping and incorporated in the 2014 ESC guidelines2 6. It is
accessible as an online calculator which directly produces the corresponding ESC recommendation (>6%/5 years: ICD should be considered; 4–6%/5 years: ICD may be considered; <4%/5 years: ICD
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generally not indicated).
The first external validation study comparing these prediction models was conducted by Vriesendorp
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et al. in 706 HCM patients23. They found the HCM Risk-SCD model (C-statistic 0.69) to perform better than the 2003 ACC/ESC guidelines (C-statistic 0.55) and 2011 ACCF/AHA guidelines (C-statistic 0.60). The number needed to treat (NNT) with ICD therapy to prevent one case of SCD in 5 years was 17, compared to a NNT of 16 in the original study2. The NNT when using the 2003 and 2011 guidelines were found to be 22 and 20, respectively. In contrast, a second validation study by Maron et al.
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found the HCM Risk-SCD model to perform poorly in a cohort of 1629 consecutive HCM patients, where only 11% of patients who experienced a SCD event, and only 26% of patients who received an appropriate ICD intervention, respectively, were found to have a high predicted risk (≥6%/5 years) consistent with an ICD recommendation24. However, no direct comparisons with SCD risk
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stratification according to the 2003 ACC/ESC and 2011 ACCF/AHA guidelines were made. A study in a South-American HCM population of 502 patients found the HCM Risk-SCD model to be a very good predictor of SCD with a C-statistic of 0.93, compared to 0.76 and 0.71 when using the 2003 and 2011
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models, respectively25. Finally, a small study of patients who had received a prophylactic ICD for primary prevention found the HCM Risk-SCD model to be the only independent predictor of appropriate ICD therapy26, while none of the 11 patients with estimated low risk using the HCM RiskSCD model experienced appropriate ICD therapy. In aggregate, the aforementioned validation studies suggest that the HCM Risk-SCD model performed better than previous models. The HCM Risk-SCD model has not been validated in patients with obstructive HCM before and after septal reduction therapy. Due to a high LVOT gradient, these patients often have a high calculated 5year SCD risk. Additional studies are warranted to investigate if the calculated risk in these patients is valid for use in decision-making regarding primary prevention after septal reduction therapy. For
ACCEPTED MANUSCRIPT all models, the recommendation is to use the estimated 5-year SCD risk to complement clinical reasoning by providing objective individualised prognostic information2 rather than to determine when to offer ICD implantation2. As our understanding of HCM progresses, it is conceivable that additional risk factors may be added to future models. The use of CMR with LGE for quantification of myocardial fibrosis was
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independently linked to SCD in a large multicenter study of 1293 HCM patients with a continuous relationship between the extent of LGE and risk of SCD (a 40% increase in SCD risk per 10% increase in LGE)27. A subsequent meta-analysis which included 5 additional studies confirmed a correlation between the presence of LGE and risk of SCD but not between the extent of LGE and SCD11.
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Genetic analysis also has the potential to enter SCD risk stratification. Currently, a single
heterozygous sarcomeric mutation should not be used to alter risk stratification. Patients with
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multiple sarcomeric gene mutations have been shown to be at an increased risk of end-stage progression and SCD28 29. With next-generation sequencing it will be possible to screen for a larger number of culprit genes, which may lead to identification of more mutations that can be useful for SCD risk stratification. The much anticipated HCMR study has completed enrolment of over 2700 patients this year and aims to examine the role of genetics, biomarkers and CMR indices such as T1
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mapping in the prediction of SCD.
The decision to implant an ICD for primary prevention is not straightforward and detailed discussions should be had with patients with regards to benefits and risks, especially in the circumstance that one risk model portends a higher risk than another. In general, as the SCD event rate is low in HCM
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models.
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patients, multicenter large scale collaborations are required to optimize future SCD risk prediction
Atrial fibrillation (AF)
The prevalence of AF within HCM populations is estimated to be 18-28%30-32. The age of onset of AF is younger within the HCM population, likely due to increased atrial pressures and remodelling as an adaptation to diastolic dynfunction, possible LVOT obstruction and atrial myopathy. The age at AF diagnosis is reported to be 45-5730 31. The risk of thromboebolism is exaggerated in HCM and aggressive anticoagulation is recommended in both European and American guidelines6 21. Warfarin is proposed to be the medication of choice.
ACCEPTED MANUSCRIPT The use of direct oral anticoagulants (DOAC) has expanded significantly since guidance was published, and the patient population in question are often still in employment. The monitoirng of INRs becomes a challenge and many HCM patients are started on a DOAC to aid compliance of anticoagulation. The CHADSVASC score does not predict risk of thormoboembolism in AF and should not be used33. Anticoaguation is indicated in any HCM patient with observed AF, providing the risk of
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bleeding is not excessive. Restoration of sinus rhythm should be targeted in recent onset AF. This poses more of a challenge than in the structurally normal heart. Amiodarone is recommended but carries risk of side effects with long term use. AF ablation has been attempted but success rates are lower than non-HCM
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patients, with 51.8% of patients free from atrial arrhythmia after multiple procedures (mean 1.4) at 1.8 years, and continued antiarrhythmic use in 42%34. Predictors of failure of treatment included left atrial dilatation, LVOT obstruction, and duration of AF34. Early and aggressive treatment in those with
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a structurally normal heart improves the chances of resoring and maintaining sinus rhythm.
Septal reduction
Left ventricular outflow tract obstruction in HCM is associated with greater morbidity and
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mortality35-39 Relief of obstruction is associated with improvement in symptoms and perhaps outcome3 40-44. The first step in treating obstruction is the introduction of negatively inotropic medications6 21. Severe and highly symptomatic LVOT obstruction despite maximal tolerated medical
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therapy is an indication for septal reduction therapy6 21. Surgical myectomy has been considered the gold standard therapy in septal reduction for decades.45
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Relief of LVOT obstruction was historically achieved by removing of 5–10 g of myocardium from the basal interventricular septum, the Morrow procedure46. A more extended myectomy resecting down to the mid-septum is now used in many expert centres47. Mitral valve (MV) abnormalities in HCM are common48 and often under-recognised on pre-operative imaging studies49. Abnormalities of the valve include leaflet elongation, chordal elongation, dysplasia and prolapse. Papillary muscle abnormalities are also well recognised and include hypertrophy or bifidity, and abnormal origins or insertion directly into the MV5. There is no trial data to guide MV interventions in HCM, however expert consensus is that surgical correction should be considered in patients referred for myectomy. Small series of surgical correction of such abnormalities have shown encouraging results. Cutting thickened secondary MV chordae alters the position of the valve, reducing systolic anterior motion of the MV and hence LVOT obstruction50. In the resection-plication-release method the anterior
ACCEPTED MANUSCRIPT mitral valve leaflet is shortened by plication and abnormal papillary muscle attachments are released51. The use of less invasive methods such as Mitraclip have been explored in those with mild LVH and long anterior MV leaflets contributing to systolic anterior motion and obstruction,52-54 but results are limited to small series. The use of minimally invasive approach for standard myectomy has also been demonstrated to be effective55. Procedural volumes are a strong predictor of
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outcome, with average 30-day mortality rates post-myectomy of 5.2% across the United States56 but <1% in centers with more experience44 47.
Alcohol septal ablation (ASA) was introduced as an alternative therapy to surgical myectomy in the mid 1990s57. The technique involves injection of a small amount (1–3 ml) of desiccated alcohol58 into
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an appropriate septal branch resulting in myocardial necrosis, scarring and subsequent septal shrinking40 43 57 59 60. The alcohol induced scar of the septum widens the LVOT, reduces systolic
anterior motion of the MV and thereby relieves obstruction. Removal of LVOT obstruction by ASA
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has been shown to effectively reduce symptoms40 43 59 60. Results from the largest multinational ASA registry to date showed a 30-day mortality of 1%, a decrease in LVOT gradient of 76%, and 89% of post-ASA patients in NYHA class ≤2 at long-term follow-up.60 Initial fears of the alcohol induced scar increasing the risk of SCD or late LV dysfunction have not been fulfilled, and several studies have shown that patients after ASA have a long-term survival comparable with the sex- and age-matched
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general population43 59 61. Persistent LVOT obstruction (>30mmHg) after ASA has recently been demonstrated to be associated with mortality events (mortality and ICD activation), and achieving a gradient <30mmHg is therefore an appropriate target of septal reduction therapy62. Improving the location of the alcohol induced ablation scar using novel imaging techniques (i.e. pre-procedural
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computed tomography guidance to map septal arteries in the target myocardium) may help to achieve this target in the future63-65. The results of case series in ASA are generally reported from high volume centres, this should be borne in mind when applying conclusions to interventional
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centres that do not perform a large volume of procedures or do not have access to a full heart team. Direct endocardial radiofrequency ablation of the interventricular septum may allow non-surgical septal reduction therapy in those that are unable to undergo myectomy or ASA66 67. The procedure is still in the early phases with less than 100 cases reported so far, but it shows great promise in medium term reduction of LVOT obstruction and associated symptoms68. The use of intracardiac echocardiography merged with electroanatomic mapping systems to accurately identify the SAMseptal contact area and conduction systems has provided important insights into the location and size of the target in non-surgical septal reduction therapy69. The freedom from septal arterial anatomy constraints is very attractive in this procedure, but the method of myocardial damage
ACCEPTED MANUSCRIPT appears to be different in the acute phase, with increased tissue oedema and potential for paradoxical increase in LVOT obstruction in the immediate days after ablation67 69. The decision to pursue septal reduction therapy must be made in an informed setting. Patients will usually prefer a percutaneous solution if it is available so the benefits of surgery must be explained in detail70. Therapeutic decision making should involve the Heart team, comprising the clinical
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cardiologist, imaging cardiologist, interventional cardiologist and cardiovascular surgeon6. This will ensure the correct diagnosis is made and subtle anatomical variations are identified pre-operatively. Procedures are best performed in centers with sufficient procedural volume to minimize
complications. There is a clear learning and safety curve associated with volume of procedures in all
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centres, the definition of this will vary internationally.
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forms of septal reduction, this suggests that these procedures should only be performed in expert
Ischaemia:
Myocardial ischaemia is a key component in the pathophysiology of HCM. It is associated with chest pain, clinical deterioration and diastolic dysfunction71-73. Recurrent bouts of ischaemia may lead to the development of myocardial fibrosis, adverse remodelling of the left ventricle and development
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of systolic dysfunction71 73. Interest in myocardial ischaemia in HCM began with the finding of coagulative necrosis and neutrophilic infiltrate on post mortem, suggesting acute myocardial ischemia74. The landmark study by Cecchi et al demonstrated that hyperaemic perfusion measured
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by positron emission tomography (PET) was a powerful independent predictor of outcome in HCM with a 10 fold increase in relative risk of death and a 20 fold increase in development of heart
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failure, cardiac transplantation and death in patients with severe perfusion abnormalities73. The majority of patients with HCM have abnormal perfusion as assessed using nuclear or other noninvasive techniques. Perfusion abnormalities are typically widespread, subendocardial 75 and present in both hypertrophied and non-hypertrophied segments of the ventricle76. Microvascular dysfunction is often seen in patients with mild or no symptoms and can precede clinical deterioration by several years73. Myocardial ischaemia results from an imbalance between the oxygen consumption of the myocytes and the oxygen supply to these myocytes. In HCM, this may result from increased metabolic demand, increased contractility and increased systolic wall tension. Recent work using wave intensity analysis and CMR describe three mechanisms resulting in reduced myocardial perfusion in
ACCEPTED MANUSCRIPT HCM. Extravascular compression and deformation of the intra-myocardial arterioles during ventricular systole results in high pressures within the microcirculation, decelerating blood flow in the epicardial coronary arteries. Impaired ventricular relaxation and a shorter duration of diastole further reduce coronary perfusion, while transient obstruction of flow in the LVOT can lead to deceleration of blood entering the coronary arteries during systole77.
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The intra-mural arterioles are themselves abnormal, with a thickened intimal and medial layer and reduced luminal area78. However, coronary resistance during diastole is actually lower than in
control patients77 79, suggesting compensatory vasodilatation of the microcirculation to normalize myocardial perfusion at rest at the expense of the coronary flow reserve. In severe disease,
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coronary flow reserve may be almost completely exhausted, with near maximal hyperaemia at rest, leading to symptoms on minimal exertion and frequent bouts of ischemia. Coronary flow abnormalities are common in HCM, with flow reversal often seen during systole and higher flow
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velocities during diastole80. Patients with LVOT obstruction are further disadvantaged by a prolonged systolic duration at the expense of the diastolic phase81, reducing time for coronary filling during diastole. During exercise, diastolic time will be further reduced as the heart rate increases.
Treatment with beta blockers and calcium channel blockers are likely to benefit myocardial perfusion, with increase in diastolic duration as well as reduction in LVOT gradients. Septal
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reduction therapies have been shown to improve myocardial perfusion82 and coronary flow reserve83. Reduction in LVOT gradients will reduce intra-cavity pressures and microvascular compression as well as reducing the proximally coronary flow deceleration resulting from LVOT
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obstruction. Although there is no data to suggest that treatment of perfusion defects will improve outcome or reduce progression to heart failure, examination of the underlying pathophysiology
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suggests this may be of benefit.
Novel approaches in medical therapy Beta blockers, calcium channel blockers and disopyramide all have a place in the treatment of symptomatic LVOT obstruction6 21. Asymptomatic patients without LVOT obstruction do not currently warrant medical therapy6 21. There are however emerging alternative options in HCM. Antifibrotic agents: Spironolactone appeared to be effective in modulating the pathogenesis of fibrosis in animal models but efficacy in human models is still to be elucidated84. The use of other drugs to affect the renin-
ACCEPTED MANUSCRIPT angiotensin-aldosterone system has also been explored85, with encouraging results in preclinical and small human trials. The randomised controlled trial INHERIT did not appear to show any difference in burden of fibrosis as assessed by LGE (along with many other clinical outcome measures) with the use of losartan86. Calcium channel blockers in the preclinical state:
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HCM can have a ‘preclinical’ period. A family member may be found to have a sarcomeric mutation but a structurally normal heart; this could provide an opportunity to modify disease progression. The use of diltiazem was explored in such a manner in a small group of young mutation carriers, where there was the suggestion that progression of the disease was affected in those with an MYBPC3
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mutation16. Metabolic modulators:
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Perhexiline is a metabolic modulator that promotes the use of carbohydrates as the substrate for myocardial energy by inhibiting carnitine-palmitoyltransferase (CPT-1). Sarcomeric mutations in HCM increase calcium sensitivity and ATPase activity and hence the energetic cost of contraction. Modulation of this pathway was proposed to improve the contraction-relaxation cycle in HCM and encouraging results were seen in non-obstructive patients with exercise restriction. An improvement in exercise capacity peakVO2 was observed in a randomised trial using perhexline, but its use is
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restricted somewhat by the narrow therapeutic index and risk of side effects87. Late sodium current appears to be abnormal in HCM, and maintenance of intracellcular sodium levels is critical in calcium metabolism. Inhibition of this sodium current has therefore become a focus for medical therapy. Ranolazine showed promise in this respect in cardiomyocytes isolated
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after myectomy88, murine89 and human models90. A subsequent trial (Gilead LIBERTY-HCM) to explore the utility of the stronger sodium current inhibitor eleclazine was designed to explore the
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effects on exercise capacity in HCM, but sadly has been halted due to adverse effects in a parallel trial in ischaemic cardiomyopathy patients. No reports of effects or risks in HCM patients have been published thus far. 91.
Molecular therapy:
With the recognition that HCM was a disease of the sarcomere that causes hypercontractility there has been some focus on trying to ameliorate the abnormalities at a molecular level15. MYK-461 is a small molecule inhibitor of sarcomere power. This medication has been shown to attenuate the development of some of the hallmark features of HCM such as LVH, hypercontractility (expressed as fractional shortening) and fibrosis when used early in the disease in murine models92. The same molecule was also shown to reduce LVOT obstruction when used in cats with obstructive HCM93. The
ACCEPTED MANUSCRIPT safety of this therapy is currently being explored in humans. This represents an exciting development in HCM but is in a very preliminary stage.
Conclusion:
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Significant progress has been made in many aspects of the understanding and treatment of HCM in the last decade (a summary is provided in Table 1.). This is translating to better care in dealing with the consequences of the disease process, such as LVOT obstruction and prediction and treatment of life threatening arrhythmia. This is in practice in the clinical arena today. There remains some
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regional variability in standard of care available, this may be addressed by creating international standards and centres of excellence to concentrate the complex care that is often required. Perhaps
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more exciting than the change in clinical practice when dealing with the complications of HCM is the prospect of a greater understanding of the underlying pathological mechanisms. These insights could enhance early detection of HCM and allow us the opportunity to treat before some of the advanced complications occur.
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Table 1:
Imaging
Summary of new developments
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Category
-
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Sudden cardiac death risk stratification
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Septal reduction
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Echo remains the mainstay imaging evaluation and provides best characterization of physiologic abnormalities. Myocardial tissue abnormalities are best assessed with CMR using late Gadolinium enhancement (LGE) and T1 mapping. Diffusion tensor-CMR may provide an insight into the mechanistic myocardial abnormalities of HCM. LGE predicts SCD events and progression to heart failure. The risk of SCD in a general HCM population is low (0.5-1% p.a.). The HCM Risk-SCD risk model is the most accurate to date with some validation studies proving encouraging. This is not validated in those who have undergone septal reduction. Genetic analysis currently does not contribute significantly to risk assessment – this may change soon due to high output next generation sequencing. Effective removal of LVOT obstruction improves symptoms and potentially improves prognosis. Surgical and non-surgical septal reduction should be performed in centres of excellence with high volume of procedures.
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Novel approaches in medical therapy
-
-
-
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-
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-
Ischaemia
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Surgical correction now often involves extended myectomy and correction of mitral valve abnormalities in addition to the traditional Morrow myectomy. Endocardial radiofrequency ablation of the septum is now a viable alternative in selected centres in those that cannot have surgery or alcohol ablation. The majority of HCM patients have perfusion assess by non-invasive methods. The presence of severe perfusion defects can predict adverse outcome. Perfusion defects result from increased metabolic demands and coronary flow abnormalities. Coronary flow abnormalities include extravascular compression of intramyocardial arterioles, impaired ventricular relaxation and a shorter period of diastole for coronary perfusion and transient obstruction to flow in the LVOT leading to deceleration of flow into the epicardial arteries. Despite encouraging early small trials the use of antifibrotic agents has not proven to be effective at preventing progression of fibrosis in HCM, as the INHERIT study. Calcium channel blockers may provide some benefit in offsetting disease progress in the early preclinical period of MYBPC3 mutation carriers, this was a very small number of patients. Perhexiline can improve exercise capacity in HCM patients. Ranolazine has shown some promise in HCM due to its effect on the surface sodium channels, a trial involving a more potent sodium channel inhibitor Eleclezine (LIBERTY- HCM) faces problems with recruitment. Molecular therapy aimed at inhibiting sarcomere power has shown great promise in early murine and feline studies.
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Table 1: Summary of recent advances in HCM
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Figure legends:
Figure 1: DTCMR images. Sheetlet orientation changes are from blue in diastole to red in systole in normal control subjects. HCM takes a healthy systolic conformation (wall perpendicular sheetlets) but an incomplete diastolic conformation (mix of wall parallel and wall perpendicular sheetlets). Figure 2: An example of a HCM 3D print used for patient education, Figure 3: Septal reduction. Panel A; typical septal hypertrophy with SAM of the MV. Panel B; the target for septal reduction. Panel C; result after septal reduction. Panel D; bSSFP cine of HCM in systole with SAM of the MV (matching panel A). Panel E; LGE image with high signal intensity (infarct of ASA) in the basal septum. Panel F; post-ASA bSSFP cine in systole with septal shrinking and widening of the LVOT, no SAM is seen.
ACCEPTED MANUSCRIPT Figure 4: Panel A; bifid posterior papillary muscle. Panel B; MV prolapse in HCM. Panel C; direct insertion of papillary muscle in to MV. Panel D: Heavily fractionated papillary muscles – one of the anterior muscle moves into the LVOT in systole causing obstruction.
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Figure 5: Mechanisms of perfusion abnormalities in HCM. There are four potential contributing mechanisms to development of myocardial ischemia in HCM. First pass myocardial perfusion imaging using CMR typically demonstrates a circumferential subendocardial perfusion defect following administration of intravenous adenosine (panel A). A negative CMR perfusion scan is shown in panel B for reference.
Acknowledgements:
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Many thanks to Pedro Ferreira and Dr Zohya Khalique from Royal Brompton Hospital for their help with diffusion tensor CMR images.
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63. Cooper RM, Binukrishnan SR, Shahzad A, et al. Computed Tomography angiography planning identifies the target vessel for optimum infarct location and improves clinical outcome in alcohol septal ablation for hypertrophic obstructive cardiomyopathy. EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 2016. 64. Okayama S, Uemura S, Soeda T, et al. Role of cardiac computed tomography in planning and evaluating percutaneous transluminal septal myocardial ablation for hypertrophic obstructive cardiomyopathy. J Cardiovasc Comput Tomogr 2010;4(1):62-5. 65. Mitsutake R, Miura S, Sako H, et al. Usefulness of multi-detector row computed tomography for the management of percutaneous transluminal septal myocardial ablation in patient with hypertrophic obstructive cardiomyopathy. IntJCardiol 2008;129(2):e61-e63. 66. Lawrenz T, Borchert B, Leuner C, et al. Endocardial radiofrequency ablation for hypertrophic obstructive cardiomyopathy: acute results and 6 months' follow-up in 19 patients. JAmCollCardiol 2011;57(5):572-76. 67. Sreeram N, Emmel M, de Giovanni JV. Percutaneous radiofrequency septal reduction for hypertrophic obstructive cardiomyopathy in children. JAmCollCardiol 2011;58(24):2501-10. 68. Poon SS, Cooper RM, Gupta D. Endocardial radiofrequency septal ablation - A new option for non-surgical septal reduction in patients with hypertrophic obstructive cardiomyopathy (HOCM)?: A systematic review of clinical studies. Int J Cardiol 2016;222:772-4. 69. Cooper RM, Shahzad A, Hasleton J, et al. Radiofrequency ablation of the interventricular septum to treat outflow tract gradients in hypertrophic obstructive cardiomyopathy: a novel use of CARTOSound(R) technology to guide ablation. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 2016;18(1):11320. 70. Fifer MA. Controversies in cardiovascular medicine. Most fully informed patients choose septal ablation over septal myectomy. Circulation 2007;116(2):207-16. 71. Maron MS, Olivotto I, Maron BJ, et al. The case for myocardial ischemia in hypertrophic cardiomyopathy. Journal of the American College of Cardiology 2009;54(9):866-75. 72. Olivotto I, Cecchi F, Gistri R, et al. Relevance of coronary microvascular flow impairment to longterm remodeling and systolic dysfunction in hypertrophic cardiomyopathy. Journal of the American College of Cardiology 2006;47(5):1043-8. 73. Cecchi F, Olivotto I, Gistri R, et al. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. The New England journal of medicine 2003;349(11):1027-35. 74. Basso C, Thiene G, Corrado D, et al. Hypertrophic cardiomyopathy and sudden death in the young: pathologic evidence of myocardial ischemia. Human pathology 2000;31(8):988-98. 75. Petersen SE, Jerosch-Herold M, Hudsmith LE, et al. Evidence for microvascular dysfunction in hypertrophic cardiomyopathy: new insights from multiparametric magnetic resonance imaging. Circulation 2007;115(18):2418-25. 76. Camici P, Chiriatti G, Lorenzoni R, et al. Coronary vasodilation is impaired in both hypertrophied and nonhypertrophied myocardium of patients with hypertrophic cardiomyopathy: a study with nitrogen-13 ammonia and positron emission tomography. Journal of the American College of Cardiology 1991;17(4):879-86. 77. Raphael CE, Cooper R, Parker KH, et al. Mechanisms of Myocardial Ischemia in Hypertrophic Cardiomyopathy: Insights From Wave Intensity Analysis and Magnetic Resonance. Journal of the American College of Cardiology 2016;68(15):1651-60. 78. Maron BJ, Wolfson JK, Epstein SE, et al. Intramural ("small vessel") coronary artery disease in hypertrophic cardiomyopathy. Journal of the American College of Cardiology 1986;8(3):54557. 79. Yang EH, Yeo TC, Higano ST, et al. Coronary hemodynamics in patients with symptomatic hypertrophic cardiomyopathy. The American journal of cardiology 2004;94(5):685-7.
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80. Kyriakidis MK, Dernellis JM, Androulakis AE, et al. Changes in phasic coronary blood flow velocity profile and relative coronary flow reserve in patients with hypertrophic obstructive cardiomyopathy. Circulation 1997;96(3):834-41. 81. Plehn G, Vormbrock J, Meissner A, et al. Effects of exercise on the duration of diastole and on interventricular phase differences in patients with hypertrophic cardiomyopathy: relationship to cardiac output reserve. Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology 2009;16(2):233-43. 82. Timmer SA, Knaapen P, Germans T, et al. Effects of alcohol septal ablation on coronary microvascular function and myocardial energetics in hypertrophic obstructive cardiomyopathy. American journal of physiology Heart and circulatory physiology 2011;301(1):H129-37. 83. Jaber WA, Yang EH, Nishimura RA, et al. Immediate improvement in coronary flow reserve after alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy. Heart (British Cardiac Society) 2009;95(7):564-9. 84. de Resende MM, Kriegel AJ, Greene AS. Combined effects of low-dose spironolactone and captopril therapy in a rat model of genetic hypertrophic cardiomyopathy. Journal of cardiovascular pharmacology 2006;48(6):265-73. 85. Marian AJ. Experimental therapies in hypertrophic cardiomyopathy. J Cardiovasc Transl Res 2009;2(4):483-92. 86. Axelsson A, Iversen K, Vejlstrup N, et al. Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebocontrolled trial. Lancet Diabetes Endocrinol 2015;3(2):123-31. 87. Abozguia K, Elliott P, McKenna W, et al. Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation 2010;122(16):1562-9. 88. Coppini R, Ferrantini C, Yao L, et al. Late sodium current inhibition reverses electromechanical dysfunction in human hypertrophic cardiomyopathy. Circulation 2013;127(5):575-84. 89. Coppini R, Mazzoni L, Ferrantini C, et al. Ranolazine Prevents Phenotype Development in a Mouse Model of Hypertrophic Cardiomyopathy. Circulation Heart failure 2017;10(3). 90. Gentry JL, 3rd, Mentz RJ, Hurdle M, et al. Ranolazine for Treatment of Angina or Dyspnea in Hypertrophic Cardiomyopathy Patients (RHYME). Journal of the American College of Cardiology 2016;68(16):1815-17. 91. Olivotto I, Hellawell JL, Farzaneh-Far R, et al. Novel Approach Targeting the Complex Pathophysiology of Hypertrophic Cardiomyopathy: The Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) Trial. Circulation Heart failure 2016;9(3):e002764. 92. Green EM, Wakimoto H, Anderson RL, et al. A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science (New York, NY) 2016;351(6273):617-21. 93. Stern JA, Markova S, Ueda Y, et al. A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Left Ventricular Outflow Tract Obstruction in Feline Hypertrophic Cardiomyopathy. PloS one 2016;11(12):e0168407.
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Echo remains the mainstay imaging evaluation and provides best characterization of physiologic abnormalities. Myocardial tissue abnormalities are best assessed with CMR using late Gadolinium enhancement (LGE) and T1 mapping. Diffusion tensor-CMR may provide an insight into the mechanistic myocardial abnormalities of HCM. LGE predicts SCD events and progression to heart failure. The risk of SCD in a general HCM population is low (0.5-1% p.a.). The HCM Risk-SCD risk model is the most accurate to date with some validation studies proving encouraging. This is not validated in those who have undergone septal reduction. Genetic analysis currently does not contribute significantly to risk assessment – this may change soon due to high output next generation sequencing. Effective removal of LVOT obstruction improves symptoms and potentially improves prognosis. Surgical and non-surgical septal reduction should be performed in centres of excellence with high volume of procedures. Surgical correction now often involves extended myectomy and correction of mitral valve abnormalities in addition to the traditional Morrow myectomy. Endocardial radiofrequency ablation of the septum is now a viable alternative in selected centres in those that cannot have surgery or alcohol ablation. The majority of HCM patients have perfusion assess by non-invasive methods. The presence of severe perfusion defects can predict adverse outcome. Perfusion defects result from increased metabolic demands and coronary flow abnormalities. Coronary flow abnormalities include extravascular compression of intramyocardial arterioles, impaired ventricular relaxation and a shorter period of diastole for coronary perfusion and transient obstruction to flow in the LVOT leading to deceleration of flow into the epicardial arteries. Despite encouraging early small trials the use of antifibrotic agents has not proven to be effective at preventing progression of fibrosis in HCM, as the INHERIT study. Calcium channel blockers may provide some benefit in offsetting disease progress in the early preclinical period of MYBPC3 mutation carriers, this was a very small number of patients. Perhexiline can improve exercise capacity in HCM patients. Ranolazine has shown some promise in HCM due to its effect on the surface sodium channels, a trial involving a more potent sodium channel inhibitor Eleclzine (LIBERTY- HCM) faces problems with recruitment. Molecular therapy aimed at inhibiting sarcomere power has shown great promise in early murine and feline studies.
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Table 1: Summary of recent advances in HCM
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