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Impact of peak provoked left ventricular outflow tract gradients on clinical outcomes in hypertrophic cardiomyopathy
International Journal of Cardiology 243 (2017) 290–295
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Impact of peak provoked left ventricular outflow tract gradients on clinical outcomes in hypertrophic cardiomyopathy Dai-Yin Lu a,b,c, Bereketeab Hailesealassie a,d, Ioannis Ventoulis a, Hongyun Liu a, Hsin-Yueh Liang a,e, Alexandra Nowbar a, Iraklis Pozios a, Marco Canepa a, Kenneth Cresswell a, Hong-Chang Luo a, M. Roselle Abraham a, Theodore P. Abraham a,⁎ a
Johns Hopkins Hypertrophic Cardiomyopathy Center of Excellence, Baltimore, MD, United States Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan c School of Medicine, National Yang-Ming University, Taipei, Taiwan d Division of Anesthesiology and Critical Care Medicine, Department of Anesthesiology, Johns Hopkins University, Baltimore, MD, United States e Division of Cardiology, Department of Medicine, China Medical University Hospital, Taichung, Taiwan b
a r t i c l e
i n f o
Article history: Received 5 February 2017 Received in revised form 23 March 2017 Accepted 10 April 2017 Keywords: Hypertrophic cardiomyopathy Left ventricle outflow tract obstruction Stress echocardiography Survival
a b s t r a c t Background: Hypertrophic cardiomyopathy (HCM) is traditionally classified based on a left ventricular outflow tract (LVOT) pressure gradient of 30 mmHg at rest or with provocation. There are no data on whether 30 mmHg is the most informative cut-off value and whether provoked gradients offer any information regarding outcomes. Methods: Resting and provoked peak LVOT pressure gradients were measured by Doppler echocardiography in patients fulfilling guidelines criteria for HCM. A composite clinical outcome including new onset atrial fibrillation, ventricular tachycardia/fibrillation, heart failure, transplantation, and death was examined over a median followup period of 2.1 years. Results: Among 536 patients, 131 patients had resting LVOT gradients greater than 30 mmHg. Subjects with higher resting gradients were older with more cardiovascular events. For provoked gradients, a bi-modal risk distribution was found. Patients with provoked gradients N 90 mmHg (HR 3.92, 95% CI 1.97–7.79) or b30 mmHg (HR 2.15, 95% CI 1.08–4.29) have more events compared to those with gradients between 30 and 89 mmHg in multivariable analysis. The introduction of two cut-off points for provoked gradients allowed HCM to be reclassified into four groups: patients with “benign” latent HCM (provoked gradient 30–89 mmHg) had the best prognosis, whereas those with persistent obstructive HCM had the worst outcome. Conclusions: Provoked LVOT pressure gradients offer additional information regarding clinical outcomes in HCM. Applying cut-off points at 30 and 90 mmHg to provoked LVOT pressure gradients further classifies HCM patients into low-, intermediate- and high-risk groups. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease presenting with exercise intolerance, heart failure and cardiac arrhythmias including sudden death [1]. About two-thirds of HCM patients demonstrate dynamic left ventricular outflow tract (LVOT) gradients at rest or with provocation [2,3], and elevated gradients are thought to be a major contributor to symptoms and complications. A resting LVOT gradient ≥ 30 mmHg is a strong, independent predictor for progression of heart failure and death [4,5]. Accordingly, current AHA/ACC/ESC guidelines classify HCM patients based on their ⁎ Corresponding author at: Johns Hopkins HCM Center of Excellence, 600 N. Wolfe Street, Carnegie 568, Baltimore, MD 21287, United States. E-mail address: [email protected] (T.P. Abraham).
http://dx.doi.org/10.1016/j.ijcard.2017.04.039 0167-5273/© 2017 Elsevier B.V. All rights reserved.
LVOT gradients into obstructive (resting and provoked gradients ≥ 30 mmHg), latent obstructive (resting b 30 and provoked ≥ 30 mmHg), and non-obstructive (resting and provoked gradients b30 mmHg) [6,7]. Among the HCM patients with no resting LVOT obstruction, N 50% developed gradients N 30 mmHg immediately after exercise [2]. Marked gradients ≥50 mmHg, either at rest or with provocation, represent the conventional threshold for surgical or percutaneous intervention if symptoms cannot be controlled with medications [7]. Despite a plethora of data regarding the clinical impact of elevated resting LVOT gradients, there is a knowledge deficit regarding the potential clinical implications of provoked LVOT gradients in HCM. Additionally, there is a lack of data regarding LVOT gradient response to exercise in nonHCM subjects. We analyzed clinical outcomes in a large cohort of prospectively enrolled and extensively characterized HCM patients.
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2. Methods 2.1. Study population and data collection The study was approved by the institutional review board and consisted of patients followed in the Johns Hopkins HCM Center. Patients were prospectively enrolled in the Johns Hopkins HCM registry from 2005 to 2015 at their first visit if they met the standard diagnostic criteria for HCM, namely, unexplained LV hypertrophy with maximal wall thickness ≥ 15 mm, in the absence of other cardiac or systemic cause that would produce such magnitude of hypertrophy. Patients with a previous history of myectomy or alcohol septal ablation were excluded. Patients were censored at the time of last follow up or event occurrence or a day prior to septal reduction therapy. A cohort of apparently healthy subjects (no cardiac history, not on cardiac medications, no baseline or stress induced echocardiographic abnormalities) referred for stress echocardiography for non-cardiac indications were included as the normal cohort to help define the normal range of LVOT gradients during exercise. 2.2. Echocardiography 2.2.1. Conventional measurements Images were obtained using a GE Vivid 7 or E-9 ultrasound machine (GE Ultrasound, Milwaukee, WI) with a multi-frequency phased-array transducer, and standard clinical protocol was implemented before exercise. Analysis of conventional measurements included septum and posterior wall thickness and ejection fraction by modified Simpson's rule, according to previously published guidelines [8]. Doppler measurements consisted of mitral inflow early diastole (E) and atrial contraction (A) waves. LVOT pressure gradients were measured in the apical views by continuous-wave Doppler echocardiography under resting conditions and during provocative maneuvers including Valsalva, treadmill exercise, and/or amyl nitrite inhalation to elicit latent obstruction, as previously reported [9–11]. Care was also taken to ensure that the Doppler signal we measured was LVOT forward flow, not mitral regurgitation flow. The hemodynamic classification was determined based on the highest provoked pressure gradient. Tissue Doppler peak early diastolic wave (e′) was derived from the apical 4-chamber view at the basal level of the septal wall and was used to calculate E/e′ ratio [12]. 2.2.2. Exercise test Patients with no contraindication underwent treadmill exercise testing. Those with active angina, decompensated heart failure, unstable arrhythmias, hemodynamic instability, severe hypertension and inability to walk on treadmill were excluded. Standard Bruce protocol was implemented in all subjects except those with history of poor functional status, in which case we used a modified Bruce or Naughton protocol. All subjects were monitored for symptoms, heart rate, blood pressure and 12-lead electrocardiography. Exercise capacity was expressed as metabolic equivalents (METs) [10]. 2.3. Definition of cardiovascular events and follow-up A composite cardiovascular (CV) end-point was pre-specified as the primary outcome variable and consisted of new onset atrial fibrillation (AF), sustained ventricular tachycardia/fibrillation (VT/VF), new onset or worsening of heart failure (HF) (defined as worsening of New York Heart Association (NYHA) functional class to class III or IV which required hospitalization), transplantation for end-stage heart failure, as well as all-cause mortality. All enrolled study participants were followed at regular intervals (1–12 monthly) in our HCM center with recording of symptoms and clinical events. Relevant changes in clinical state recorded at other health facilities were uploaded to the same record. Arrhythmic outcomes including AF and sustained VT/VF were recorded by
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reviewing clinical visit documents, 24-h Holter, and ICD interrogation reports. The diagnosis of AF is defined as an irregular heart rhythm without distinct P-waves documented on ECG, Holter (if duration ≥30 s) or from device recordings in patients with ICD [13]. New onset or worsening of HF at NYHA class III or IV and heart transplantation had to be documented in out-patient visits or in-hospital charts. If an arrhythmic event was experienced prior to enrollment and recurred during follow-up, that recurred event was not considered as an outcome. All-cause mortality statistics for the study populations were obtained by linking our database to the Social Security Death Index with a follow-up duration of up to 5 years. 2.4. Statistical analysis Locally weighted scatterplot smoothing (LOWESS) analysis was used to identify gross changes in rate of CV events with increasing rest and provoked LVOT pressure gradient. These cut-off points for resting and provoked pressure gradient were confirmed by identification of inflection points on the receiver operating characteristic (ROC) curve. Once cutoffs for rest and provoked gradients were identified, stratified descriptive statistics were performed on patient demographics, hemodynamics, conventional echocardiographic parameters and outcomes. The prognostic differences between patients with provoked LVOT gradients 0–29, 30–89 and above 90 mmHg were analyzed by Kaplan-Meier survival curves and log-rank tests. Cox proportional hazards models were used to identify the predictors of CV events, and variables which were statistically significant in the univariable analysis were included in a multivariable model. A p value of b0.05 was considered statistically significant. The analyses were performed using the statistical package SPSS, version 18.0 (SPSS Inc.). 3. Results A total of 569 patients were screened initially. 13 patients were excluded due to previous myectomy, and 20 were excluded because only conventional transthoracic echocardiography was performed and LVOT pressure gradient at peak stress was unavailable. Finally, 536 patients (mean age 52 ± 15 years, 67% men) were included in the analysis, including 199 non-obstructive, 202 labile obstructive, and 135 persistent obstructive HCM (Supplementary Fig. 1). 493 (92%) patients performed complete exercise stress test, and the other 43 patients used Valsalva maneuver and amyl nitrate inhalation as provocation. 3.1. Threshold for resting LVOT pressure gradient There were 92 composite events during a median follow-up duration of 2.1 years, including 33 new onset AF, 16 new onset sustained VT/VF, 29 HF and 14 death. By ROC analysis, we identified the cut-off value for rest LVOT pressure gradient as 29.7 mmHg, which was close to current guideline-suggested 30 mmHg. We found that 131 (24%) subjects had resting LVOT pressure gradient ≥30 mmHg. Patients with resting pressure gradient ≥30 mmHg were older, with more advanced NYHA functional class, more calcium channel blocker usage and more likely to have family history of HCM (Table 1A). This group also had a larger LA diameter and higher E/e′ ratio. Compared to patients with resting gradient b30 mmHg, patients with gradient ≥30 mmHg had much more composite CV events (34% vs. 13%, p b 0001). In univariable analysis, patients with resting gradient ≥30 mmHg had a 3.7 fold risk of future adverse events compared with those with resting gradient b30 mmHg (Hazard ratio (HR) 3.70, 95% confidence interval (CI) 2.45–5.58, p b 0.001). 3.2. Threshold for provoked LVOT pressure gradient A total of 40 healthy subjects completed exercise echocardiography. The average of peak LVOT pressure gradient at exercise was 23 mmHg; 95% CI 20–27 mmHg (Supplementary Table 1). LOWESS analysis for CV
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Table 1A Baseline characteristics in patients with resting LVOT gradient b30 versus ≥30 mmHg.
Age, years Male sex, n (%) Body mass index, kg/m2 Symptoms NYHA class I, n (%) II, n (%) III, n (%) Angina, n (%) Syncope, n (%) Co-morbidity Atrial fibrillation, n (%) VT/VF, n (%) ICD implantation, n (%) Family history HCM, n (%) Sudden cardiac death, n (%) SCD risk factors, n (%) Medications Beta-blocker, n (%) Disopyramide, n (%) Calcium channel blocker, n (%) Echocardiography Maximal wall thickness, cm Left atrial diameter, cm LVEF, % E/A E/e′ Resting LVOT gradient, mmHg Provoked LVOT gradient, mmHg
0–29 mmHg n = 405
≥30 mmHg n = 131
p Value
50.7 ± 15.8 270 (66.7) 29.3 ± 6.2
57.0 ± 12.8 75 (57.3) 29.9 ± 6.6
b0.001 0.064 0.406
254 (62.7) 107 (26.4) 44 (10.9) 139 (34.4) 81 (20.0)
55 (42.0) 52 (39.7) 24 (18.3) 52 (39.7) 23 (17.6)
b0.001
67 (16.5) 12 (3.0) 39 (9.7)
14 (10.7) 3 (2.3) 8 (6.1)
0.137 0.916 0.285
91 (22.6) 105 (26.0) 1.0 ± 0.9
19 (13.7) 29 (22.1) 1.0 ± 0.9
0.040 0.442 0.895
277 (68.6) 6 (1.5) 103 (25.5)
101 (77.1) 4 (3.1) 47 (35.9)
0.079 0.435 0.029
2.1 ± 0.6 4.1 ± 0.7 65.1 ± 8.0 1.4 ± 0.8 16.4 ± 9.1 10.8 ± 6.5 41.9 ± 37.1
2.2 ± 0.5 4.4 ± 0.7 65.5 ± 10.0 1.3 ± 0.7 24.6 ± 14.2 65.3 ± 27.9 118.0 ± 41.5
0.032 b0.001 0.696 0.175 b0.001 b0.001 b0.001
0.321 0.618
E/A = ratio of early diastolic mitral flow velocity to the late diastolic mitral flow velocity; E/e′ = ratio of early diastolic mitral flow velocity to the early diastolic mitral septal annulus motion velocity; HCM = hypertrophic cardiomyopathy; ICD = implantable cardioverter defibrillator; LVEF = left ventricle ejection fraction; LVOT = left ventricle outflow tract; NYHA = New York Heart Association functional class; SCD = sudden cardiac death; VT/VF = ventricular tachycardia/fibrillation.
event and exercise LVOT pressure gradient demonstrated that there was a bi-modal distribution of risk. Therefore, patients were separated into 3 groups by applying two cut-off LVOT gradient values of 30 and 90 mmHg. The lower inflection point was determined at 30 mmHg based on the 95% CI of physiological response in normal subjects. The upper inflection point was set at 90 mmHg, based on the ROC analysis for provoked LVOT pressure gradient versus CV events. Patients with provoked gradient ≥90 mmHg were older, with larger LA diameter and higher E/e′ ratio, whereas patients with provoked gradient b30 mmHg were most likely to have history of VT/VF, intra-cardiac defibrillator (ICD) implantation and family history of HCM (Table 1B). The cumulative incidence rates for composite outcome were 18, 8, and 27% in patients with provoked gradient b30 mmHg, 30–89 mmHg, and ≧90 mmHg, respectively. Subjects with provoked gradients between 30 and 89 mmHg had the best clinical outcome, in contrast to the other two groups (logrank p b 0.001) (Fig. 1A). In Cox survival analysis when those with provoked gradients 30–89 mmHg were taken as reference, provoked pressure gradients ≥90 mmHg and b 30 mmHg were independent predictors of CV events compared to gradients between 30 and 89 mmHg, after adjusting for age and sex (HR and 95% CI were 4.03, 2.21–7.33, and 2.03, 1.11–3.70, respectively) (Table 2, model 2). With additional adjustments for left atrial diameter, E/A and E/e′ ratio, which were also significantly associated with CV events in univariable analysis (Supplementary Table 2), the specified ranges of provoked LVOT gradient remained independently predictive of clinical outcomes (Table 2, model 3). 3.3. Proposed HCM classification based on rest and provoked LVOT gradients Based on the two inflection points in provoked gradients, 30 and 90 mmHg as described above, we further divided the previous latent
obstruction into two sub-groups: the “benign latent” sub-group: rest LVOT pressure gradient b30 mmHg and provoked gradient between 30 and 89 mmHg; and the “adverse latent” sub-group: rest LVOT pressure gradient b30 mmHg provoked gradient ≥90 mmHg. The “benign latent” HCM had the best event-free survival among the overall four categories, followed by the “adverse latent” and non-obstructive groups. In contrast, the prognosis of obstructive HCM (rest gradient ≥30 mmHg) remained the worst. Based on our data, we revised the HCM classification based on LVOT gradients into four groups (rather than three groups) by parsing the original latent obstructive HCM group into two sub-groups: the “benign” latent (provoked LVOT gradient between 30 and 89 mmHg); and the “adverse” latent group (provoked LVOT gradient ≥90 mmHg) (log-rank p b 0.001) (Fig. 1B). 4. Discussion In a relatively large HCM cohort we find several novel and clinically important observations concerning provoked LVOT gradients. Overall, provoked LVOT gradients identify high-risk and low risk sub-groups of HCM patients. First, we examined LVOT gradient response to exercise stress in those without cardiac pathology. These ranges have not been previously reported. Next, by parsing the latent obstructive HCM patients based on provoked gradient cut-offs at 30 and 90 mmHg we were able to identify a truly low risk group of HCM patients. Patients with “benign” latent obstructive HCM had the best prognosis (provoked gradients 30–89 mmHg), while those with the “adverse” latent (provoked gradients ≥90 mmHg) and non-obstructive HCM were associated with intermediate risk for CV events. Finally, patients with obstructive HCM had consistently higher risks than the other 2 groups, a finding that is highly concordant with previously published data. 4.1. Resting LVOT pressure gradient and clinical outcomes in HCM Clinical studies have established a consistent relationship between LVOT gradients at rest and unfavorable outcomes [2,5,14,15]. In a large HCM cohort, Maron et al. demonstrated a high correlation between resting peak LVOT pressure gradients ≥ 30 mmHg and symptoms of heart failure and cardiovascular death [4]. Interestingly, they found that values above this threshold of 30 mmHg did not increase the likelihood of complications or death. They proposed that the inability to stratify outcome with respect to magnitude of the gradient probably reflected the dynamic nature of outflow tract obstruction. In our current study, we corroborated that 30 mmHg remains the most efficient threshold value for prediction of complications. Moreover, we confirmed that using alternative cut-off values for resting gradients do not improve outcomes prediction. To date, there are sparse if any data examining the potential clinical implications of provoked gradients. 4.2. Physiologic stress LVOT pressure gradient Blood flow through the outflow tract is dynamic and may demonstrate significant variations in short periods of time. LVOT pressure gradient may be increased due to physiologic or structural factors, such as increased cardiac contractility, inadequate preload, tachycardia or concentric left ventricular hypertrophy. These variations in LVOT pressure gradient also occur in HCM [16]. Some of the factors influencing outflow tract gradients include volume status, physical position, sympathetic nervous system, diurnal variation, medications and exercise. The normal physiologic LVOT pressure gradient response to exercise stress has not been previously examined. In adjudicating normal versus abnormal it would be highly informative to establish the normal ranges. Accordingly, we examined 40 apparently normal subjects and found that 8 (20%) subjects had exercise LVOT pressure gradients N30 mmHg thus fulfilling the current definition of LVOT obstruction. These findings suggest that stress-induced LVOT pressure gradients need to be interpreted in context. Gradients N30 mmHg in the absence
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Table 1B Baseline characteristics based on provoked LVOT gradients.
Age, years Male gender, n (%) Body mass index, kg/m2 Symptoms NYHA class I, n (%) II, n (%) III, n (%) Angina, n (%) Syncope, n (%) Co-morbidity Atrial fibrillation, n (%) VT/VF, n (%) ICD implantation, n (%) Family history HCM, n (%) Sudden cardiac death, n (%) SCD risk factors, n (%) Medications Beta-blocker, n (%) Disopyramide, n (%) Calcium channel blocker, n (%) Echocardiography Maximal wall thickness, cm Left atrial diameter, cm LVEF, % E/A E/e′ Resting LVOT gradient, mmHg Provoked LVOT gradient, mmHg
0–29 mmHg n = 204
30–89 mmHg n = 181
≥90 mmHg n = 151
p Value
50.0 ± 15.7 127 (62.3%) 28.8 ± 5.4
51.2 ± 14.9 125 (69.1%) 30.2 ± 7.7
56.6 ± 14.5 93 (61.6%) 29.5 ± 5.6
b0.001 0.263 0.103
127 (62.3) 58 (28.4) 19 (9.3) 61 (30.0) 35 (17.2)
107 (59.1) 51 (28.2) 23 (12.7) 69 (38.1) 40 (22.1)
75 (49.7) 50 (33.1) 26 (17.2) 61 (40.4) 29 (19.2)
0.108
0.091 0.486
38 (18.6) 11 (5.4) 32 (15.8)
28 (15.5) 3 (1.7) 9 (5.0)
15 (9.9) 1 (0.7) 6 (4.0)
0.068 0.014 b0.001
61 (30.0) 52 (25.6) 1.03 ± 0.95
34 (18.9) 49 (27.1) 0.99 ± 0.97
14 (9.3) 33 (21.9) 0.99 ± 0.94
b0.001 0.530 0.910
143 (70.4) 2 (1.0) 47 (23.2)
129 (71.3) 6 (3.3) 58 (32.0)
106 (70.2) 2 (1.3) 45 (29.8)
0.974 0.224 0.130
2.1 ± 0.6 4.1 ± 0.8 64.9 ± 8.4 1.5 ± 0.9 16.1 ± 9.6 7.5 ± 3.5 16.8 ± 6.1
2.1 ± 0.6 4.1 ± 0.7 65.0 ± 7.6 1.3 ± 0.7 17.6 ± 10.4 18.7 ± 15.0 51.9 ± 16.2
2.2 ± 0.4 4.3 ± 0.7 65.9 ± 9.7 1.3 ± 0.7 22.2 ± 12.7 53.0 ± 34.8 129.8 ± 33.8
0.271 0.003 0.508 0.045 b0.001 b0.001 b0.001
E/A = ratio of early diastolic mitral flow velocity to the late diastolic mitral flow velocity; E/e′ = ratio of early diastolic mitral flow velocity to the early diastolic mitral septal annulus motion velocity; HCM = hypertrophic cardiomyopathy; ICD = implantable cardioverter defibrillator; LVEF = left ventricle ejection fraction; LVOT = left ventricle outflow tract; NYHA = New York Heart Association functional class; SCD = sudden cardiac death; VT/VF = ventricular tachycardia/fibrillation.
of key morphologic features of HCM and in the setting of an otherwise normal heart are most likely exaggerated physiologic response [17–19]. Conversely, low stress-induced LVOT gradients may not always be benign. We have previously demonstrated that non-obstructive hemodynamics is an independent predictor for ventricular tachycardia/fibrillation, and associated with more extensive fibrosis and microvascular ischemia [20]. 4.3. Proposed classification of HCM based on provoked LVOT gradients The current classification of HCM based on LVOT gradients uses a single threshold value of 30 mmHg for resting and provoked
gradients. Applying the resting cut-off value also to the provoked gradient is mostly empiric and based on expert consensus. To our knowledge, a systematic evaluation of provoked gradients has not been previously performed. Our data suggest that it may be more helpful to clinicians if there are a single resting threshold value and 2 threshold values for provoked-induced LVOT gradients. Applying this new algorithm, HCM would be classified into 4 groups: obstructive (resting and provoked gradients ≥ 30 mmHg), nonobstructive (resting and provoked gradients b 30 mmHg), benign latent-obstructive (resting b30 mmHg; provoked gradients ≥ 30 to b 90 mmHg) and adverse latent-obstructive (resting b30 mmHg; provoked gradients ≥ 90 mmHg) (Fig. 2).
Fig. 1. (A) Kaplan-Meier survival analysis based on provoked LVOT pressure gradients separated as follows: 0–29, 30–89, and ≥90 mmHg. (B) Kaplan-Meier survival analysis based on a proposed new classification of HCM patients into: non-obstructive (rest and provoked b30 mmHg), “benign latent” (rest b30 mmHg and provoked 30–89 mmHg), “adverse latent (rest b30 mmHg and provoked ≥90 mmHg), and obstructive (rest and provoked ≥30 mmHg).
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Table 2 Hazard ratios of provoked LVOT gradient for CV events during 5-year follow-up. Cases/events
Model 1 HR (95% CI)
Provoked LVOT stress gradient 30–89 mmHg 181/15 0–29 mmHg 204/37 ≥90 mmHg 151/40
Model 2 p Value
HR (95% CI)
b0.001 1 2.03 (1.17–3.71) 4.21 (2.32–7.62)
Model 3 p Value
HR (95% CI)
b0.001 1 2.03 (1.11–3.70) 4.03 (2.21–7.33)
p Value b0.001
1 2.15 (1.08–4.29) 3.92 (1.97–7.79)
Model 1: crude ratio. Model 2: adjusted for age and sex. Model 3: adjusted for age, sex, left atrial diameter, ratio of early diastolic mitral flow velocity to the late diastolic mitral flow velocity (E/A), ratio of early diastolic mitral flow velocity to the early diastolic mitral septal annulus motion velocity (E/e′). CI = confidence interval; HR = hazard ratio.
On the other hand, HCM patients with a persistent low resting and provoked pressure gradient may reflect intrinsic myocardial pathology, such as cardiac fibrosis [21], myocardial ischemia with reduced contractility [22,23], or dyssynchrony [24]. 4.4. Implications for clinical practice Our analysis indicates that modifying the current hemodynamic classification of HCM by LVOT gradients will offer incremental information regarding risk. Patients with rest gradients b30 mmHg and provoked gradients ≥30 but b 90 mmHg are a truly low risk group of HCM patients. Patients with obstructive HCM have consistently higher clinical risk than all other sub-groups and may warrant more aggressive treatment strategies including septal reduction therapy. 4.5. Study limitations Patients are from a single tertiary referral center introducing a potential referral bias. However, this cohort is no different than those reported in a majority of HCM-related publications. Nonetheless, caution may be exercised in extrapolating our results to the general HCM population. Secondly, we acknowledge that LVOT obstruction is dynamic and
like almost all HCM publications, attempted to obtain the highest pressure gradient at peak stress [2,25]. Moreover, multiple provocations were implemented including Valsalva maneuver and amyl nitrate stimulation in order to maximize the chances that we will record the highest pressure. This itself does not address the variability in LVOT gradients but in our experience in repeated studies, we find substantial consistency in provoked gradients in the same patient even when recorded months apart. So while there can be wide variability, in our experience, this is not confounding enough to reduce the reliability of our testing protocol. Thirdly, we used a composite endpoint similar to a majority of papers examining clinical outcomes in HCM since individual endpoints such as death, ventricular tachycardia/ventricular fibrillation and heart failure occur infrequently [21,26,27]. Finally, we excluded patients who underwent septal reduction prior to index clinic visit. Septal reduction procedures have been previously proved to give superior clinical outcomes in symptomatic, obstructive HCM and therefore would confound our results [28–30]. While our data suggested that benign labile-obstructive HCM patients have low rates of complications and superior clinical outcomes compared to the other sub-groups, these patients should be appropriately considered for surgical intervention, as determined by clinical symptoms and risk factors.
4.6. Conclusions Provoked LVOT gradients provide incremental information regarding clinical outcomes in HCM particularly in those without apparent resting LVOT obstruction. Provoked gradients b 30 mmHg or ≧90 mmHg are associated with higher risk of adverse outcomes when compared against those with provoked gradients between 30 mmHg and 89 mmHg, which denote a low risk group. A resting LVOT pressure gradient ≥ 30 mmHg was an independent predictor for long-term CV events. A combination of rest and provoked gradients may help better distinguish low, intermediate and high-risk cohorts within HCM with obvious clinical management implications. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2017.04.039.
Conflict of interest None.
Funding
Fig. 2. Proposed hemodynamic classification for hypertrophic cardiomyopathy.
This work was partially supported by the National Institutes of Health (grant number HL 98046). Dr. Lu was supported by the Taipei Veterans General Hospital-National Yang-Ming University Excellent Physician Scientists Cultivation Program, No. 104-V-A-005. Dr. Ventoulis and Dr. Pozios were supported by fellowship grants from Hellenic Cardiological Society (Grant number EKE 555/15-052015).
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Impact of peak provoked left ventricular outflow tract gradients on clinical outcomes in hypertrophic cardiomyopathy Dai-Yin Lu a,b,c, Bereketeab Hailesealassie a,d, Ioannis Ventoulis a, Hongyun Liu a, Hsin-Yueh Liang a,e, Alexandra Nowbar a, Iraklis Pozios a, Marco Canepa a, Kenneth Cresswell a, Hong-Chang Luo a, M. Roselle Abraham a, Theodore P. Abraham a,⁎ a
Johns Hopkins Hypertrophic Cardiomyopathy Center of Excellence, Baltimore, MD, United States Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan c School of Medicine, National Yang-Ming University, Taipei, Taiwan d Division of Anesthesiology and Critical Care Medicine, Department of Anesthesiology, Johns Hopkins University, Baltimore, MD, United States e Division of Cardiology, Department of Medicine, China Medical University Hospital, Taichung, Taiwan b
a r t i c l e
i n f o
Article history: Received 5 February 2017 Received in revised form 23 March 2017 Accepted 10 April 2017 Keywords: Hypertrophic cardiomyopathy Left ventricle outflow tract obstruction Stress echocardiography Survival
a b s t r a c t Background: Hypertrophic cardiomyopathy (HCM) is traditionally classified based on a left ventricular outflow tract (LVOT) pressure gradient of 30 mmHg at rest or with provocation. There are no data on whether 30 mmHg is the most informative cut-off value and whether provoked gradients offer any information regarding outcomes. Methods: Resting and provoked peak LVOT pressure gradients were measured by Doppler echocardiography in patients fulfilling guidelines criteria for HCM. A composite clinical outcome including new onset atrial fibrillation, ventricular tachycardia/fibrillation, heart failure, transplantation, and death was examined over a median followup period of 2.1 years. Results: Among 536 patients, 131 patients had resting LVOT gradients greater than 30 mmHg. Subjects with higher resting gradients were older with more cardiovascular events. For provoked gradients, a bi-modal risk distribution was found. Patients with provoked gradients N 90 mmHg (HR 3.92, 95% CI 1.97–7.79) or b30 mmHg (HR 2.15, 95% CI 1.08–4.29) have more events compared to those with gradients between 30 and 89 mmHg in multivariable analysis. The introduction of two cut-off points for provoked gradients allowed HCM to be reclassified into four groups: patients with “benign” latent HCM (provoked gradient 30–89 mmHg) had the best prognosis, whereas those with persistent obstructive HCM had the worst outcome. Conclusions: Provoked LVOT pressure gradients offer additional information regarding clinical outcomes in HCM. Applying cut-off points at 30 and 90 mmHg to provoked LVOT pressure gradients further classifies HCM patients into low-, intermediate- and high-risk groups. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease presenting with exercise intolerance, heart failure and cardiac arrhythmias including sudden death [1]. About two-thirds of HCM patients demonstrate dynamic left ventricular outflow tract (LVOT) gradients at rest or with provocation [2,3], and elevated gradients are thought to be a major contributor to symptoms and complications. A resting LVOT gradient ≥ 30 mmHg is a strong, independent predictor for progression of heart failure and death [4,5]. Accordingly, current AHA/ACC/ESC guidelines classify HCM patients based on their ⁎ Corresponding author at: Johns Hopkins HCM Center of Excellence, 600 N. Wolfe Street, Carnegie 568, Baltimore, MD 21287, United States. E-mail address: [email protected] (T.P. Abraham).
http://dx.doi.org/10.1016/j.ijcard.2017.04.039 0167-5273/© 2017 Elsevier B.V. All rights reserved.
LVOT gradients into obstructive (resting and provoked gradients ≥ 30 mmHg), latent obstructive (resting b 30 and provoked ≥ 30 mmHg), and non-obstructive (resting and provoked gradients b30 mmHg) [6,7]. Among the HCM patients with no resting LVOT obstruction, N 50% developed gradients N 30 mmHg immediately after exercise [2]. Marked gradients ≥50 mmHg, either at rest or with provocation, represent the conventional threshold for surgical or percutaneous intervention if symptoms cannot be controlled with medications [7]. Despite a plethora of data regarding the clinical impact of elevated resting LVOT gradients, there is a knowledge deficit regarding the potential clinical implications of provoked LVOT gradients in HCM. Additionally, there is a lack of data regarding LVOT gradient response to exercise in nonHCM subjects. We analyzed clinical outcomes in a large cohort of prospectively enrolled and extensively characterized HCM patients.
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2. Methods 2.1. Study population and data collection The study was approved by the institutional review board and consisted of patients followed in the Johns Hopkins HCM Center. Patients were prospectively enrolled in the Johns Hopkins HCM registry from 2005 to 2015 at their first visit if they met the standard diagnostic criteria for HCM, namely, unexplained LV hypertrophy with maximal wall thickness ≥ 15 mm, in the absence of other cardiac or systemic cause that would produce such magnitude of hypertrophy. Patients with a previous history of myectomy or alcohol septal ablation were excluded. Patients were censored at the time of last follow up or event occurrence or a day prior to septal reduction therapy. A cohort of apparently healthy subjects (no cardiac history, not on cardiac medications, no baseline or stress induced echocardiographic abnormalities) referred for stress echocardiography for non-cardiac indications were included as the normal cohort to help define the normal range of LVOT gradients during exercise. 2.2. Echocardiography 2.2.1. Conventional measurements Images were obtained using a GE Vivid 7 or E-9 ultrasound machine (GE Ultrasound, Milwaukee, WI) with a multi-frequency phased-array transducer, and standard clinical protocol was implemented before exercise. Analysis of conventional measurements included septum and posterior wall thickness and ejection fraction by modified Simpson's rule, according to previously published guidelines [8]. Doppler measurements consisted of mitral inflow early diastole (E) and atrial contraction (A) waves. LVOT pressure gradients were measured in the apical views by continuous-wave Doppler echocardiography under resting conditions and during provocative maneuvers including Valsalva, treadmill exercise, and/or amyl nitrite inhalation to elicit latent obstruction, as previously reported [9–11]. Care was also taken to ensure that the Doppler signal we measured was LVOT forward flow, not mitral regurgitation flow. The hemodynamic classification was determined based on the highest provoked pressure gradient. Tissue Doppler peak early diastolic wave (e′) was derived from the apical 4-chamber view at the basal level of the septal wall and was used to calculate E/e′ ratio [12]. 2.2.2. Exercise test Patients with no contraindication underwent treadmill exercise testing. Those with active angina, decompensated heart failure, unstable arrhythmias, hemodynamic instability, severe hypertension and inability to walk on treadmill were excluded. Standard Bruce protocol was implemented in all subjects except those with history of poor functional status, in which case we used a modified Bruce or Naughton protocol. All subjects were monitored for symptoms, heart rate, blood pressure and 12-lead electrocardiography. Exercise capacity was expressed as metabolic equivalents (METs) [10]. 2.3. Definition of cardiovascular events and follow-up A composite cardiovascular (CV) end-point was pre-specified as the primary outcome variable and consisted of new onset atrial fibrillation (AF), sustained ventricular tachycardia/fibrillation (VT/VF), new onset or worsening of heart failure (HF) (defined as worsening of New York Heart Association (NYHA) functional class to class III or IV which required hospitalization), transplantation for end-stage heart failure, as well as all-cause mortality. All enrolled study participants were followed at regular intervals (1–12 monthly) in our HCM center with recording of symptoms and clinical events. Relevant changes in clinical state recorded at other health facilities were uploaded to the same record. Arrhythmic outcomes including AF and sustained VT/VF were recorded by
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reviewing clinical visit documents, 24-h Holter, and ICD interrogation reports. The diagnosis of AF is defined as an irregular heart rhythm without distinct P-waves documented on ECG, Holter (if duration ≥30 s) or from device recordings in patients with ICD [13]. New onset or worsening of HF at NYHA class III or IV and heart transplantation had to be documented in out-patient visits or in-hospital charts. If an arrhythmic event was experienced prior to enrollment and recurred during follow-up, that recurred event was not considered as an outcome. All-cause mortality statistics for the study populations were obtained by linking our database to the Social Security Death Index with a follow-up duration of up to 5 years. 2.4. Statistical analysis Locally weighted scatterplot smoothing (LOWESS) analysis was used to identify gross changes in rate of CV events with increasing rest and provoked LVOT pressure gradient. These cut-off points for resting and provoked pressure gradient were confirmed by identification of inflection points on the receiver operating characteristic (ROC) curve. Once cutoffs for rest and provoked gradients were identified, stratified descriptive statistics were performed on patient demographics, hemodynamics, conventional echocardiographic parameters and outcomes. The prognostic differences between patients with provoked LVOT gradients 0–29, 30–89 and above 90 mmHg were analyzed by Kaplan-Meier survival curves and log-rank tests. Cox proportional hazards models were used to identify the predictors of CV events, and variables which were statistically significant in the univariable analysis were included in a multivariable model. A p value of b0.05 was considered statistically significant. The analyses were performed using the statistical package SPSS, version 18.0 (SPSS Inc.). 3. Results A total of 569 patients were screened initially. 13 patients were excluded due to previous myectomy, and 20 were excluded because only conventional transthoracic echocardiography was performed and LVOT pressure gradient at peak stress was unavailable. Finally, 536 patients (mean age 52 ± 15 years, 67% men) were included in the analysis, including 199 non-obstructive, 202 labile obstructive, and 135 persistent obstructive HCM (Supplementary Fig. 1). 493 (92%) patients performed complete exercise stress test, and the other 43 patients used Valsalva maneuver and amyl nitrate inhalation as provocation. 3.1. Threshold for resting LVOT pressure gradient There were 92 composite events during a median follow-up duration of 2.1 years, including 33 new onset AF, 16 new onset sustained VT/VF, 29 HF and 14 death. By ROC analysis, we identified the cut-off value for rest LVOT pressure gradient as 29.7 mmHg, which was close to current guideline-suggested 30 mmHg. We found that 131 (24%) subjects had resting LVOT pressure gradient ≥30 mmHg. Patients with resting pressure gradient ≥30 mmHg were older, with more advanced NYHA functional class, more calcium channel blocker usage and more likely to have family history of HCM (Table 1A). This group also had a larger LA diameter and higher E/e′ ratio. Compared to patients with resting gradient b30 mmHg, patients with gradient ≥30 mmHg had much more composite CV events (34% vs. 13%, p b 0001). In univariable analysis, patients with resting gradient ≥30 mmHg had a 3.7 fold risk of future adverse events compared with those with resting gradient b30 mmHg (Hazard ratio (HR) 3.70, 95% confidence interval (CI) 2.45–5.58, p b 0.001). 3.2. Threshold for provoked LVOT pressure gradient A total of 40 healthy subjects completed exercise echocardiography. The average of peak LVOT pressure gradient at exercise was 23 mmHg; 95% CI 20–27 mmHg (Supplementary Table 1). LOWESS analysis for CV
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Table 1A Baseline characteristics in patients with resting LVOT gradient b30 versus ≥30 mmHg.
Age, years Male sex, n (%) Body mass index, kg/m2 Symptoms NYHA class I, n (%) II, n (%) III, n (%) Angina, n (%) Syncope, n (%) Co-morbidity Atrial fibrillation, n (%) VT/VF, n (%) ICD implantation, n (%) Family history HCM, n (%) Sudden cardiac death, n (%) SCD risk factors, n (%) Medications Beta-blocker, n (%) Disopyramide, n (%) Calcium channel blocker, n (%) Echocardiography Maximal wall thickness, cm Left atrial diameter, cm LVEF, % E/A E/e′ Resting LVOT gradient, mmHg Provoked LVOT gradient, mmHg
0–29 mmHg n = 405
≥30 mmHg n = 131
p Value
50.7 ± 15.8 270 (66.7) 29.3 ± 6.2
57.0 ± 12.8 75 (57.3) 29.9 ± 6.6
b0.001 0.064 0.406
254 (62.7) 107 (26.4) 44 (10.9) 139 (34.4) 81 (20.0)
55 (42.0) 52 (39.7) 24 (18.3) 52 (39.7) 23 (17.6)
b0.001
67 (16.5) 12 (3.0) 39 (9.7)
14 (10.7) 3 (2.3) 8 (6.1)
0.137 0.916 0.285
91 (22.6) 105 (26.0) 1.0 ± 0.9
19 (13.7) 29 (22.1) 1.0 ± 0.9
0.040 0.442 0.895
277 (68.6) 6 (1.5) 103 (25.5)
101 (77.1) 4 (3.1) 47 (35.9)
0.079 0.435 0.029
2.1 ± 0.6 4.1 ± 0.7 65.1 ± 8.0 1.4 ± 0.8 16.4 ± 9.1 10.8 ± 6.5 41.9 ± 37.1
2.2 ± 0.5 4.4 ± 0.7 65.5 ± 10.0 1.3 ± 0.7 24.6 ± 14.2 65.3 ± 27.9 118.0 ± 41.5
0.032 b0.001 0.696 0.175 b0.001 b0.001 b0.001
0.321 0.618
E/A = ratio of early diastolic mitral flow velocity to the late diastolic mitral flow velocity; E/e′ = ratio of early diastolic mitral flow velocity to the early diastolic mitral septal annulus motion velocity; HCM = hypertrophic cardiomyopathy; ICD = implantable cardioverter defibrillator; LVEF = left ventricle ejection fraction; LVOT = left ventricle outflow tract; NYHA = New York Heart Association functional class; SCD = sudden cardiac death; VT/VF = ventricular tachycardia/fibrillation.
event and exercise LVOT pressure gradient demonstrated that there was a bi-modal distribution of risk. Therefore, patients were separated into 3 groups by applying two cut-off LVOT gradient values of 30 and 90 mmHg. The lower inflection point was determined at 30 mmHg based on the 95% CI of physiological response in normal subjects. The upper inflection point was set at 90 mmHg, based on the ROC analysis for provoked LVOT pressure gradient versus CV events. Patients with provoked gradient ≥90 mmHg were older, with larger LA diameter and higher E/e′ ratio, whereas patients with provoked gradient b30 mmHg were most likely to have history of VT/VF, intra-cardiac defibrillator (ICD) implantation and family history of HCM (Table 1B). The cumulative incidence rates for composite outcome were 18, 8, and 27% in patients with provoked gradient b30 mmHg, 30–89 mmHg, and ≧90 mmHg, respectively. Subjects with provoked gradients between 30 and 89 mmHg had the best clinical outcome, in contrast to the other two groups (logrank p b 0.001) (Fig. 1A). In Cox survival analysis when those with provoked gradients 30–89 mmHg were taken as reference, provoked pressure gradients ≥90 mmHg and b 30 mmHg were independent predictors of CV events compared to gradients between 30 and 89 mmHg, after adjusting for age and sex (HR and 95% CI were 4.03, 2.21–7.33, and 2.03, 1.11–3.70, respectively) (Table 2, model 2). With additional adjustments for left atrial diameter, E/A and E/e′ ratio, which were also significantly associated with CV events in univariable analysis (Supplementary Table 2), the specified ranges of provoked LVOT gradient remained independently predictive of clinical outcomes (Table 2, model 3). 3.3. Proposed HCM classification based on rest and provoked LVOT gradients Based on the two inflection points in provoked gradients, 30 and 90 mmHg as described above, we further divided the previous latent
obstruction into two sub-groups: the “benign latent” sub-group: rest LVOT pressure gradient b30 mmHg and provoked gradient between 30 and 89 mmHg; and the “adverse latent” sub-group: rest LVOT pressure gradient b30 mmHg provoked gradient ≥90 mmHg. The “benign latent” HCM had the best event-free survival among the overall four categories, followed by the “adverse latent” and non-obstructive groups. In contrast, the prognosis of obstructive HCM (rest gradient ≥30 mmHg) remained the worst. Based on our data, we revised the HCM classification based on LVOT gradients into four groups (rather than three groups) by parsing the original latent obstructive HCM group into two sub-groups: the “benign” latent (provoked LVOT gradient between 30 and 89 mmHg); and the “adverse” latent group (provoked LVOT gradient ≥90 mmHg) (log-rank p b 0.001) (Fig. 1B). 4. Discussion In a relatively large HCM cohort we find several novel and clinically important observations concerning provoked LVOT gradients. Overall, provoked LVOT gradients identify high-risk and low risk sub-groups of HCM patients. First, we examined LVOT gradient response to exercise stress in those without cardiac pathology. These ranges have not been previously reported. Next, by parsing the latent obstructive HCM patients based on provoked gradient cut-offs at 30 and 90 mmHg we were able to identify a truly low risk group of HCM patients. Patients with “benign” latent obstructive HCM had the best prognosis (provoked gradients 30–89 mmHg), while those with the “adverse” latent (provoked gradients ≥90 mmHg) and non-obstructive HCM were associated with intermediate risk for CV events. Finally, patients with obstructive HCM had consistently higher risks than the other 2 groups, a finding that is highly concordant with previously published data. 4.1. Resting LVOT pressure gradient and clinical outcomes in HCM Clinical studies have established a consistent relationship between LVOT gradients at rest and unfavorable outcomes [2,5,14,15]. In a large HCM cohort, Maron et al. demonstrated a high correlation between resting peak LVOT pressure gradients ≥ 30 mmHg and symptoms of heart failure and cardiovascular death [4]. Interestingly, they found that values above this threshold of 30 mmHg did not increase the likelihood of complications or death. They proposed that the inability to stratify outcome with respect to magnitude of the gradient probably reflected the dynamic nature of outflow tract obstruction. In our current study, we corroborated that 30 mmHg remains the most efficient threshold value for prediction of complications. Moreover, we confirmed that using alternative cut-off values for resting gradients do not improve outcomes prediction. To date, there are sparse if any data examining the potential clinical implications of provoked gradients. 4.2. Physiologic stress LVOT pressure gradient Blood flow through the outflow tract is dynamic and may demonstrate significant variations in short periods of time. LVOT pressure gradient may be increased due to physiologic or structural factors, such as increased cardiac contractility, inadequate preload, tachycardia or concentric left ventricular hypertrophy. These variations in LVOT pressure gradient also occur in HCM [16]. Some of the factors influencing outflow tract gradients include volume status, physical position, sympathetic nervous system, diurnal variation, medications and exercise. The normal physiologic LVOT pressure gradient response to exercise stress has not been previously examined. In adjudicating normal versus abnormal it would be highly informative to establish the normal ranges. Accordingly, we examined 40 apparently normal subjects and found that 8 (20%) subjects had exercise LVOT pressure gradients N30 mmHg thus fulfilling the current definition of LVOT obstruction. These findings suggest that stress-induced LVOT pressure gradients need to be interpreted in context. Gradients N30 mmHg in the absence
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Table 1B Baseline characteristics based on provoked LVOT gradients.
Age, years Male gender, n (%) Body mass index, kg/m2 Symptoms NYHA class I, n (%) II, n (%) III, n (%) Angina, n (%) Syncope, n (%) Co-morbidity Atrial fibrillation, n (%) VT/VF, n (%) ICD implantation, n (%) Family history HCM, n (%) Sudden cardiac death, n (%) SCD risk factors, n (%) Medications Beta-blocker, n (%) Disopyramide, n (%) Calcium channel blocker, n (%) Echocardiography Maximal wall thickness, cm Left atrial diameter, cm LVEF, % E/A E/e′ Resting LVOT gradient, mmHg Provoked LVOT gradient, mmHg
0–29 mmHg n = 204
30–89 mmHg n = 181
≥90 mmHg n = 151
p Value
50.0 ± 15.7 127 (62.3%) 28.8 ± 5.4
51.2 ± 14.9 125 (69.1%) 30.2 ± 7.7
56.6 ± 14.5 93 (61.6%) 29.5 ± 5.6
b0.001 0.263 0.103
127 (62.3) 58 (28.4) 19 (9.3) 61 (30.0) 35 (17.2)
107 (59.1) 51 (28.2) 23 (12.7) 69 (38.1) 40 (22.1)
75 (49.7) 50 (33.1) 26 (17.2) 61 (40.4) 29 (19.2)
0.108
0.091 0.486
38 (18.6) 11 (5.4) 32 (15.8)
28 (15.5) 3 (1.7) 9 (5.0)
15 (9.9) 1 (0.7) 6 (4.0)
0.068 0.014 b0.001
61 (30.0) 52 (25.6) 1.03 ± 0.95
34 (18.9) 49 (27.1) 0.99 ± 0.97
14 (9.3) 33 (21.9) 0.99 ± 0.94
b0.001 0.530 0.910
143 (70.4) 2 (1.0) 47 (23.2)
129 (71.3) 6 (3.3) 58 (32.0)
106 (70.2) 2 (1.3) 45 (29.8)
0.974 0.224 0.130
2.1 ± 0.6 4.1 ± 0.8 64.9 ± 8.4 1.5 ± 0.9 16.1 ± 9.6 7.5 ± 3.5 16.8 ± 6.1
2.1 ± 0.6 4.1 ± 0.7 65.0 ± 7.6 1.3 ± 0.7 17.6 ± 10.4 18.7 ± 15.0 51.9 ± 16.2
2.2 ± 0.4 4.3 ± 0.7 65.9 ± 9.7 1.3 ± 0.7 22.2 ± 12.7 53.0 ± 34.8 129.8 ± 33.8
0.271 0.003 0.508 0.045 b0.001 b0.001 b0.001
E/A = ratio of early diastolic mitral flow velocity to the late diastolic mitral flow velocity; E/e′ = ratio of early diastolic mitral flow velocity to the early diastolic mitral septal annulus motion velocity; HCM = hypertrophic cardiomyopathy; ICD = implantable cardioverter defibrillator; LVEF = left ventricle ejection fraction; LVOT = left ventricle outflow tract; NYHA = New York Heart Association functional class; SCD = sudden cardiac death; VT/VF = ventricular tachycardia/fibrillation.
of key morphologic features of HCM and in the setting of an otherwise normal heart are most likely exaggerated physiologic response [17–19]. Conversely, low stress-induced LVOT gradients may not always be benign. We have previously demonstrated that non-obstructive hemodynamics is an independent predictor for ventricular tachycardia/fibrillation, and associated with more extensive fibrosis and microvascular ischemia [20]. 4.3. Proposed classification of HCM based on provoked LVOT gradients The current classification of HCM based on LVOT gradients uses a single threshold value of 30 mmHg for resting and provoked
gradients. Applying the resting cut-off value also to the provoked gradient is mostly empiric and based on expert consensus. To our knowledge, a systematic evaluation of provoked gradients has not been previously performed. Our data suggest that it may be more helpful to clinicians if there are a single resting threshold value and 2 threshold values for provoked-induced LVOT gradients. Applying this new algorithm, HCM would be classified into 4 groups: obstructive (resting and provoked gradients ≥ 30 mmHg), nonobstructive (resting and provoked gradients b 30 mmHg), benign latent-obstructive (resting b30 mmHg; provoked gradients ≥ 30 to b 90 mmHg) and adverse latent-obstructive (resting b30 mmHg; provoked gradients ≥ 90 mmHg) (Fig. 2).
Fig. 1. (A) Kaplan-Meier survival analysis based on provoked LVOT pressure gradients separated as follows: 0–29, 30–89, and ≥90 mmHg. (B) Kaplan-Meier survival analysis based on a proposed new classification of HCM patients into: non-obstructive (rest and provoked b30 mmHg), “benign latent” (rest b30 mmHg and provoked 30–89 mmHg), “adverse latent (rest b30 mmHg and provoked ≥90 mmHg), and obstructive (rest and provoked ≥30 mmHg).
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Table 2 Hazard ratios of provoked LVOT gradient for CV events during 5-year follow-up. Cases/events
Model 1 HR (95% CI)
Provoked LVOT stress gradient 30–89 mmHg 181/15 0–29 mmHg 204/37 ≥90 mmHg 151/40
Model 2 p Value
HR (95% CI)
b0.001 1 2.03 (1.17–3.71) 4.21 (2.32–7.62)
Model 3 p Value
HR (95% CI)
b0.001 1 2.03 (1.11–3.70) 4.03 (2.21–7.33)
p Value b0.001
1 2.15 (1.08–4.29) 3.92 (1.97–7.79)
Model 1: crude ratio. Model 2: adjusted for age and sex. Model 3: adjusted for age, sex, left atrial diameter, ratio of early diastolic mitral flow velocity to the late diastolic mitral flow velocity (E/A), ratio of early diastolic mitral flow velocity to the early diastolic mitral septal annulus motion velocity (E/e′). CI = confidence interval; HR = hazard ratio.
On the other hand, HCM patients with a persistent low resting and provoked pressure gradient may reflect intrinsic myocardial pathology, such as cardiac fibrosis [21], myocardial ischemia with reduced contractility [22,23], or dyssynchrony [24]. 4.4. Implications for clinical practice Our analysis indicates that modifying the current hemodynamic classification of HCM by LVOT gradients will offer incremental information regarding risk. Patients with rest gradients b30 mmHg and provoked gradients ≥30 but b 90 mmHg are a truly low risk group of HCM patients. Patients with obstructive HCM have consistently higher clinical risk than all other sub-groups and may warrant more aggressive treatment strategies including septal reduction therapy. 4.5. Study limitations Patients are from a single tertiary referral center introducing a potential referral bias. However, this cohort is no different than those reported in a majority of HCM-related publications. Nonetheless, caution may be exercised in extrapolating our results to the general HCM population. Secondly, we acknowledge that LVOT obstruction is dynamic and
like almost all HCM publications, attempted to obtain the highest pressure gradient at peak stress [2,25]. Moreover, multiple provocations were implemented including Valsalva maneuver and amyl nitrate stimulation in order to maximize the chances that we will record the highest pressure. This itself does not address the variability in LVOT gradients but in our experience in repeated studies, we find substantial consistency in provoked gradients in the same patient even when recorded months apart. So while there can be wide variability, in our experience, this is not confounding enough to reduce the reliability of our testing protocol. Thirdly, we used a composite endpoint similar to a majority of papers examining clinical outcomes in HCM since individual endpoints such as death, ventricular tachycardia/ventricular fibrillation and heart failure occur infrequently [21,26,27]. Finally, we excluded patients who underwent septal reduction prior to index clinic visit. Septal reduction procedures have been previously proved to give superior clinical outcomes in symptomatic, obstructive HCM and therefore would confound our results [28–30]. While our data suggested that benign labile-obstructive HCM patients have low rates of complications and superior clinical outcomes compared to the other sub-groups, these patients should be appropriately considered for surgical intervention, as determined by clinical symptoms and risk factors.
4.6. Conclusions Provoked LVOT gradients provide incremental information regarding clinical outcomes in HCM particularly in those without apparent resting LVOT obstruction. Provoked gradients b 30 mmHg or ≧90 mmHg are associated with higher risk of adverse outcomes when compared against those with provoked gradients between 30 mmHg and 89 mmHg, which denote a low risk group. A resting LVOT pressure gradient ≥ 30 mmHg was an independent predictor for long-term CV events. A combination of rest and provoked gradients may help better distinguish low, intermediate and high-risk cohorts within HCM with obvious clinical management implications. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2017.04.039.
Conflict of interest None.
Funding
Fig. 2. Proposed hemodynamic classification for hypertrophic cardiomyopathy.
This work was partially supported by the National Institutes of Health (grant number HL 98046). Dr. Lu was supported by the Taipei Veterans General Hospital-National Yang-Ming University Excellent Physician Scientists Cultivation Program, No. 104-V-A-005. Dr. Ventoulis and Dr. Pozios were supported by fellowship grants from Hellenic Cardiological Society (Grant number EKE 555/15-052015).
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