- Email: [email protected]
Left ventricular hypertrophy and hypertension
Journal Pre-proof Left ventricular hypertrophy and hypertension
Mehmet Yildiz, Ahmet Afşin Oktay, Merrill H. Stewart, Richard V. Milani, Hector O. Ventura, Carl J. Lavie PII:
S0033-0620(19)30143-4
DOI:
https://doi.org/10.1016/j.pcad.2019.11.009
Reference:
YPCAD 1017
To appear in:
Progress in Cardiovascular Diseases
Received date:
17 November 2019
Accepted date:
17 November 2019
Please cite this article as: M. Yildiz, A.A. Oktay, M.H. Stewart, et al., Left ventricular hypertrophy and hypertension, Progress in Cardiovascular Diseases(2019), https://doi.org/10.1016/j.pcad.2019.11.009
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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.
© 2019 Published by Elsevier.
Journal Pre-proof
Left Ventricular Hypertrophy and Hypertension Authors: Mehmet Yildiz1 , Ahmet Afşin Oktay2 , Merrill H. Stewart3 , Richard V. Milani3 , Hector O. Ventura3 , and Carl J. Lavie3
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Running title: Left ventricular hypertrophy and hypertension
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Affiliations: 1 Department of Medicine, Southern Ohio Medical Center, Portsmouth, OH; 2 Department of Medicine, Division of Cardiology, Wentworth-Douglass Hospital, Partners HealthCare, Dover, NH; 3 Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute; Ochsner Clinical School - The University of Queensland School of Medicine, New Orleans, LA.
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Key Words: Hypertension; left ventricular geometry; left ventricular hypertrophy; remodeling; antihypertension therapy
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Disclosures: No relevant disclosures
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Word count: 5718 words. Figures: 3. Tables: 2.
Address for correspondence:
Ahmet Afşin Oktay, MD Department of Medicine, Division of Cardiology Wentworth-Douglass Hospital Partners HealthCare 789 Central Ave, Dover, NH Phone: +1(603) 516-4265 Fax: +1(603) 740-2173 Email: [email protected]
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Journal Pre-proof Abbreviations
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Angiotensin converting enzyme American College of Cardiology Atrial fibrillation American Heart Association Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Angiotensin receptor blockers Atherosclerosis Risk in Communities American Society of Echocardiography Blood pressure Coronary artery disease Coronary artery calcium scoring Calcium channel blockers Chlorthalidone, indapamide, and potassium‐ sparing diuretic/hydrochlorothiazide Chronic kidney disease Concentric remodeling Cardiovascular disease Diabetes mellitus European Association of Cardiovascular Imaging Electrocardiography Ejection fraction European Society of Cardiology European Society of Hypertension Hypertrophic cardiomyopathy Heart failure Heart Outcomes Prevention Evaluation Hypertension or hypertensive Losartan Intervention for Endpoint Reduction Left ventricle Concentric left ventricular hypertrophy Eccentric left ventricular hypertrophy Left ventricular hypertrophy Multiethnic Study of Atherosclerosis Myocardial infarction Magnetic resonance imaging Renin-angiotensin-aldosterone system Randomized clinical trial Relative wall thickness Systolic blood pressure Sudden Cardiac Death Sodium-glucose cotransporter type2 Speckle tracking echocardiography Two-dimensional Three-dimensional
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ACE: ACC: AF: AHA: ALLHAT: ARBs: ARIC: ASE: BP: CAD: CACS: CCBs: CHIP: CKD: CR: CVD: DM: EACVI: ECG: EF: ESC: ESH: HCM: HF: HOPE: HTN: LIFE: LV: cLVH: eLVH: LVH: MESA: MI: MRI: RAAS: RCT: RWT: SBP: SCD: SGLT2: STE: 2D: 3D:
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Journal Pre-proof Abstract Hypertension (HTN) is a major modifiable risk factor for cardiovascular disease (CVD) morbidity and mortality. The left ventricle (LV) is a primary target for HTN end-organ damage. In addition to being a marker of HTN, LV geometrical changes: concentric remodeling, concentric or eccentric LV hypertrophy (LVH) are major independent risk factors for not only
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CVD morbidity and mortality but also for all-cause mortality and neurological pathologies. Blood pressure control with lifestyle changes and antihypertensive agents has been demonstrated
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to prevent and regress LVH. Herein, we provide a comprehensive review of literature on the
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relationship between HTN and LV geometry abnormalities with a focus on diagnosis, prognosis,
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pathophysiological mechanisms, and treatment approaches.
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Journal Pre-proof Hypertension (HTN) is a major modifiable risk factor for cardiovascular disease (CVD) morbidity and mortality.1,2 HTN frequently coexists with other CVD risk factors, such as obesity, hyperlipidemia, diabetes mellitus (DM), chronic kidney disease (CKD), and tobacco use.3 The 2017 American College of Cardiology (ACC)/American Heart Association (AHA)/AAPA/ABC/ ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults has redefined the classification
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of HTN and proposed novel treatment strategies. The guideline now defines HTN as a systolic
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BP (SBP) of ≥130 mm Hg or a diastolic BP of ≥80 mm Hg, which increases the prevalence of
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HTN among U.S. adults from 32% to 46%. In diagnosing HTN, the emphasis is placed on the
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importance of out-of-office BP measurements, which are better predictors of target organ damage compared to in-office measurement and further discriminates sustained HTN from
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white-coat or masked HTN. The guideline also recommends incorporation of the atherosclerotic
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CVD risk score in the decision making to initiate pharmacological treatment with the aim of a
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target BP of <130/80 mm Hg.4
The left ventricle (LV) is a primary target for HTN end-organ damage. HTN induced
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remodeling of the LV is often grouped into three different geometric patterns: concentric remodeling (CR), concentric LV hypertrophy (LVH; cLVH), and eccentric LVH (eLVH).5 Electrocardiography (ECG), echocardiography, and cardiac magnetic resonance imaging (MRI) are the primary diagnostic modalities for the assessment of LV geometric changes.6 In addition to being an end-organ response, LVH is also an independent risk factor for CVD morbidity and mortality.7 The 2017 ACC/AHA high BP guideline noted the positive and negative prognostic effects of LV geometric changes. However, the authors did not recommend the routine use of echocardiography or cardiac MRI for the assessment of LVH during the evaluation and
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Journal Pre-proof management of HTN due to a lack of data in cost-effectiveness.4 Numerous treatment strategies from well-established thiazide diuretics, renin-angiotensin-aldosterone system (RAAS) inhibitors and calcium channel blockers to future promising sodium-glucose cotransporter type-2 (SGLT2) inhibitors have been shown to regress LVH.8–11 Herein, we discuss the relationship between HTN and LV geometric changes with a focus
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on diagnosis, epidemiology, pathophysiology, prognosis, and treatment (Figure 1).
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Diagnosis
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Abnormalities of LV geometry can be evaluated by ECG, two-dimensional (2D) and
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three-dimensional (3D) echocardiography, speckle tracking echocardiography (STE), or cardiac MRI. The 2018 European Society of Hypertension (ESH)/European Society of Cardiology (ESC)
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clinical practice guideline for the management of arterial HTN defined LVH as a high-risk
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component in the Systematic Coronary Risk Evaluation system and accepted LVH as a representative of diastolic dysfunction. The guideline recommends (Grade IIB) 2D
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echocardiography to detect LVH if the results are likely to influence treatment decisions.12
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According to the 2017 ACC/AHA high BP guideline, LVH assessment “is most useful” in cases of young adults or adults with a history of secondary HTN or heart failure (HF) where the presence of end-organ damage reinforces aggressive treatment in otherwise healthy individuals.4 Electrocardiography The 2018 ESH/ESC guideline for the management of arterial HTN recognizes the most commonly used ECG criteria as: (1) S V1 +RV5 or RV6 (Sokolow-Lyon) >35 mm, (2) R wave in aVL ≥11 mm, (3) SV3 +RaVL (Cornell voltage) >28 mm for men and >20 mm for women, and (4) Cornell product (Cornell voltage x QRS duration) >2440 mm x ms.12 5
Journal Pre-proof Jiang et al. compared the diagnostic value of 18 different ECG criteria to diagnose LVH among middle-aged subjects with HTN. Criteria of SD+SV4 (a combination of the deepest S‐ wave amplitude and the S‐ wave amplitude of lead V4 ≥ 28 mm (male) and ≥23 mm (female) had the highest sensitivity (29%) followed by Cornell product (24%). 13 In a recent analysis from the MESA (Multi-Ethnic Study of Atherosclerosis) study, a new machine learning ECG
ability compared to other traditional ECG techniques. 14
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technique, the Bayesian Additive Regression Trees, showed superior diagnostic and prognostic
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Despite the low sensitivity and specificity in diagnosing LVH, electrocardiographic LVH
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has a well-established prognostic value in CVD. In the ALLHAT (Antihypertensive and Lipid-
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Lowering Treatment to Prevent Heart Attack) study, baseline LVH by Cornell voltage was
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independently associated with increased CVD morbidity and all-cause mortality during a fiveyear follow-up among treated HTN participants.15 In the LIFE (Losartan Intervention for
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Endpoint Reduction) study, persistence or new development of LVH by both Cornell product
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2D Echocardiography
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and Sokolow-Lyon was associated with markedly increased all-cause mortality.16
2D echocardiography remains the most commonly used imaging modality for evaluation of LV geometry and its primary variables: LV mass and relative wall thickness (RWT). Linear method and 2D based formulas are the two main 2D echocardiographic methods for quantification of LV mass. In linear method, LV mass is calculated as 0.8 x 1.04 x [(interventricular septum + LV internal diameter + posterior wall thickness)3 – LV internal diameter3 ] + 0.6g. The linear method is a widely used technique in clinical practice due to its ease of use and accuracy in normally shaped ventricles. However, the linear method relies on the assumption that the ventricle has a prolate ellipsoid shape, and it does not consider the regional 6
Journal Pre-proof variations in LV thickness. Therefore, the accuracy of the linear method is limited in the setting of asymmetric hypertrophy, dilated LV, or other abnormalities of regional thickness. In addition, even small measurement errors lead to an exaggeration of inaccuracy due to the cubing of the parameters. 2D based formulas (truncated ellipsoid and area-length methods) have the advantage of partial correction for shape distortions. Therefore, they are less dependent on geometric assumptions compared to linear methods. However, cumbersome methodology, high
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measurement variability, and requirement of good image quality make 2D based methods less
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attractive in routine clinical practice.17
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In addition to BP, LV mass correlates with several other variables such as body size, age,
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sex, ethnicity, and physical activity level.18–24 Therefore, it is difficult to define standard values
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for LV mass.17 LV mass indexing to body surface area allows comparison among people with different body sizes. However, in extremely obese individuals indexing to height is more
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advantageous compared to body surface area.17,25
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The 2015 American Society Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) chamber quantification document defines increased LV mass
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index by body surface area as >95 g/m2 in women and >115 g/m2 in men by linear methods; and >88 g/m2 in women and >102 g/m2 in men by 2D formulas. RWT is calculated as 2 x posterior wall thickness/LV end-diastolic diameter. According to LV mass and RWT, LV geometric patterns are classified into four different types as follows: 1) normal LV geometry (normal LV mass index and RWT ≤0.42); 2) cLVH (increased LV mass index and RWT >0.42); 3) eLVH (increased LV mass index and RWT ≤0.42); and 4) CR (normal LV mass index and RWT >0.42).26 (Figure 2 and 3)
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Journal Pre-proof 3D Echocardiography 3D echocardiography provides more accurate and reproducible measurements in LV volumes and mass compared to 2D echocardiography by not only relying on geometric modeling but also allowing for the measurement of the non-foreshortened imaging.27,28 Despite its strengths, 3D echocardiography can slightly underestimate LV mass as compared to cardiac
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MRI.29
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3D echocardiography technology is evolving rapidly. Several recent studies confirmed the validity of automated techniques using artificial intelligence for accurate quantification of
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chamber volumes.30–33 These automated techniques are expected to help with the practical use of
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3D echocardiography in routine clinical practice as the application by untrained personnel can
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take additional time.
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The 2015 ASE/EACVI document on cardiac chamber quantification has not reported the normal reference values of LV mass by 3D echocardiography due to limited available data.17
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Since the 2015 document, several studies have been published validating the accuracy of LV
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mass quantification by 3D echocardiography against cardiac MRI. These studies have provided normal reference values for 3D echocardiographic LV mass index in healthy subjects (Table 1).34–36 While these studies have been helpful, owing to their comparatively small size, further research is needed to determine normal reference values in 3D echocardiography. Speckle Tracking Echocardiography LVH can develop secondary to pathological responses to pressure or volume overload as in cLVH or eLVH, physiological responses to physical exercise as in athletes, genetic disorders as in hypertrophic cardiomyopathy (HCM), or storage disorders as in amyloidosis (Table 2). The 8
Journal Pre-proof use of STE technology helps substantially with understanding the etiology of LVH and provides important prognostic information in patients with LVH and preserved ejection fraction (EF). Speckle tracking is a non-doppler and angle-independent quantitative ultrasound technique which measures strain and strain rate by tracking the motion of speckles during a cardiac cycle on both 2D and 3D echocardiograms. STE expands the measurements in three spatial directions as longitudinal, radial, and circumferential. The STE technology can also
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evaluate twisting, untwisting, and torsion of the LV myocardium.37 Global longitudinal strain by
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STE is the most commonly used strain parameter in clinical practice and it is a more sensitive
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marker of LV dysfunction as compared to EF.38 Detection of subclinical systolic dysfunction by
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STE provides diagnostic and prognostic insights in HTN patients with preserved EF.39,40
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Several studies have confirmed the utility of 2D STE in the differentiation of an athlete’s heart from HCM.41,42 For instance, Richand et al. demonstrated that pathologic hypertrophic
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segments in patients with HCM have significantly lower longitudinal strain compared to those of
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an athlete’s heart.41 Galderisi et al. compared the strain patterns of professional athletes with young patients with HTN. They found that global longitudinal strain was significantly lower in
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HTN patients compared to that of professional athletes.43 The typical apical sparing pattern of longitudinal strain is a sensitive and specific STE finding for differentiation of cardiac amyloidosis from LVH due to other pathologies.44 Cardiac Magnetic Resonance Imaging Cardiac MRI is generally considered the gold standard for quantification and assessment of cardiac chambers.45,46 This technology does not rely on geometric assumptions and provides superior delineation of the endocardium and epicardium. 47 Through its ability to provide
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Journal Pre-proof reproducible and unrestricted views, cardiac MRI has been used in clinical trials to demonstrate subtle regression in LV mass after anti-HTN treatment, e.g., LIFE sub-study.48 Cardiac MRI is valuable in distinguishing different types of LVH, including HTN heart disease, HCM, infiltrative cardiomyopathies, and athletes’ heart. It can further detect and quantify myocardial fibrosis, of prognostic importance in these conditions, by late gadolinium enhancement with T1 weighted sequences.49–53 Currently, its availability, cost, and time-
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consuming nature limits the use of cardiac MRI.45
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Epidemiology
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LV remodeling occurs in response to numerous modifiable and non-modifiable risk factors, including age, gender, genetic factors, HTN, DM, CKD, obesity, metabolic syndrome,
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obstructive sleep apnea, sedentary lifestyle, and dietary salt intake. The reported prevalence of
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LV geometric patterns in HTN patients varies depending on the population studied, the imaging modalities utilized, and the way geometric patterns are defined. A meta-analysis of 30 studies
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involving a total of 37,700 participants demonstrated that echocardiographic LVH was present in
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36% to 41% of all HTN participants. This prevalence increased to 58% to 77% in high-risk HTN participants defined as those with severe or refractory HTN or with history of DM or CVD.54 A prospective cohort study (n=6,105) with a median follow up of 14-years revealed ~2.5 times higher odds of developing ECG-LVH in the presence of HTN. In this study, there was a 49% increase in the odds of ECG-LVH for every 19 mm Hg increase in SBP (p<0.001).55 Pre-HTN has also been linked to cardiac remodeling. A meta-analysis involving more than 73,000 subjects reported that patients with pre-HTN had an average LV mass and RWT higher than that of normotensive patients but smaller than those with history of HTN 10
Journal Pre-proof (p<0.001).56 A large cohort study among 52,111 Korean participants revealed a significant association between HTN categories and the risk of LV remodeling defined with increased RWT. They found a progressive increase in the odds ratio of LV remodeling in the following order of HTN categories (from lowest to highest): normotension, pre-HTN, controlled HTN, newly diagnosed HTN, and uncontrolled HTN (OR: 1.00, 1.65, 2.02, 2.85, 3.31, respectively).57 The recently published PAMELA (Pressioni Monitorate E Loro Associazion) study reported a
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similar pattern of progressive increase in the incidence of LVH from normotensive to pre-HTN
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and HTN groups (9%, 23.2%, and 36.5%, respectively).58 Patients who progressed from pre-
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HTN to sustained HTN over time had a significantly higher incidence of LVH compared to those
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who had persistent pre-HTN. These findings highlight the significance of early detection and
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proper management of HTN to prevent end-organ damage. Masked HTN is characterized by consistently elevated out-of-office BP readings despite
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normal office BP readings.4 Masked HTN carries a higher risk of CVD mortality compared to
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sustained HTN.59 A meta-analysis of 13 studies with a total of 4,884 untreated subjects revealed a significantly higher LV mass index in patients with masked HTN compared to normotensive
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individuals.60 Similarly, patients with white-coat HTN have been shown to have higher LV mass index than those with normotension.61 The presence of other comorbidities significantly contributes to the risk of LV remodeling in patients with HTN. For instance, Palmieri et al. reported a higher prevalence of LV geometric abnormalities among DM patients with HTN compared to non-DM patients with HTN.62 In a prospective study of 1,160 subjects, the presence of metabolic syndrome and CKD was shown to increase the risk of LVH by 2.4-fold among patients with HTN.63
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Journal Pre-proof Ambulatory BP measurements more closely correlate with LV geometry abnormalities compared to office BP measurements.64,65 Abdalla et al. reported a higher prevalence of LVH among blacks with a reverse dipping pattern defined as an increase in BP at night assessed by ambulatory BP measurement.66 White coat HTN has a comparable effect to ambulatory HTN as attended and unattended BP measurements correlate similarly with LV mass (r=0.205 and
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r=0.194, respectively).67
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Pathophysiology
LV remodeling in response to HTN involves a complex interaction of cardiomyocytes
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and cardiac non-myocytes, such as endothelial cells, fibroblasts, and the immune system.68 The mechanical stretch activates intracellular signaling cascades and leads to gene
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expression and synthesis of proteins (e.g., actin, myosin), which organize in the sarcomere. In
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general, LV wall stress is reduced by increasing the size of cardiomyocyte by addition of sarcomeres in parallel, in the case of pressure overload; whereas, in series, in the case of volume
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overload.26 This adaptive response is also mediated by several neurohumoral mechanisms
myocytes.68,69
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involving expression of catecholamines, angiotensin II, and growth factors from cardiac non-
The adaptive and innate immune systems play a vital role in the pathogenesis of HTN and HTN induced end-organ damage.70 In clinical trials, an imbalance of adaptive immunity and elevated levels of pro-inflammatory markers was shown to contribute to end-organ damage in subjects with HTN.71,72 Mechanical stretch and upregulation of inflammation can trigger fibroblasts to differentiate into myofibroblasts which build up myocardial fibrosis with increased production of collagen type I and type II fibers. Myocardial fibrosis contributes to a variety of 12
Journal Pre-proof clinical presentations in HTN heart disease including HF with preserved or reduced EF, reduced coronary flow reserve, and cardiac arrhythmias.73–75 Another important pathophysiologic link between HTN and cardiac remodeling is the upregulation of the sympathetic nervous system. This finding is supported by the fact that in spontaneously HTN rats models, sympathectomy leads to a reduction in BP and normalization in
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LV mass.76
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Prognosis
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LVH is not only an adaptive response to hemodynamic changes but also a significant risk
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factor for adverse CVD outcomes. Echocardiographic LVH was associated with CVD morbidity and mortality, and all-cause mortality in the Framingham Heart Study three decades ago.77
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Similarly, a recently published analysis on ALLHAT study participants (n=26,384) with treated
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HTN showed a significant association between electrocardiographic LVH and increased risk of
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myocardial infarction (MI), stroke, HF, and all-cause mortality.15 Prognostic impact of LVH has been reported in different ethnic groups. A sub-group
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analysis of the ARIC (Atherosclerosis Risk In Communities) prospective cohort study reported a significantly increased risk of CVD in African-American subjects with LVH .78 A prospective cohort study, The Northern Manhattan Study, confirmed a similar pattern among HispanicAmericans by showing a significant association between LV mass and CVD morbidity.79 Women, in general, have a lower incidence of CVD morbidity compared to men as in ischemic heart disease; however, the incidence of HF, atrial fibrillation (AF), or stroke were more commonly reported in women.80–82 A community-based prospective cohort study, including 12,329 subjects with HTN, investigated the impact of LVH on gender-specific CVD 13
Journal Pre-proof morbidity profile. In this study, LVH was more commonly reported in women than men (43.4% vs. 32.1%; p<0.001). The presence of obesity and diabetes put both men and women at risk for LVH; however, women had a higher risk of LVH. Lower risk for major CVD events (composite of acute coronary syndrome, stroke, decompensated HF, and incident AF) was seen in HTN women compared to men in the absence of LVH (HR: 0.65; 95% CI: 0.44 to 0.96; p=0.031). However, this gender difference was erased in the setting of LVH. Women with HTN had a
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comparable major CVD event risk compared to men in the presence of LVH (HR: 0.94; 95% CI:
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0.69 to 1.30; p=0.720).83
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Cardiovascular and All-cause Mortality
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In a large retrospective study on a clinical population (n=35,602) referred for
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echocardiography, Milani et al. found a significant association between CR or LVH (concentric or eccentric) and increased risk of all-cause mortality (RR: 1.99; 95% CI: 1.88 to 2.18; p<0.0001
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and RR: 2.13; 95% CI: 1.89 to 2.40; p<0.0001, respectively). Compared to the other geometric
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patterns, cLVH carried a higher mortality risk. They further showed that prognosis was dynamic
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in response to the changes in LV geometry, as the reversal of CR to a normal geometric pattern improved survival (RR: 0.64; 95% CI: 0.42 to 0.97; p=0.03).84 Several studies have indicated a link between abnormalities in LV geometry and the risk of sudden cardiac death (SCD). A report from Oregon Sudden Unexpected Death Study, a population-based case-control study, showed a significant association between abnormal LV geometric patterns by echocardiography and increased risk of SCD (OR: 3.20, 2.47, 1.76 for cLVH, eLVH, and CR; respectively).85 A prospective cohort study from Italy evaluated SCD risk factors in relatively young and untreated HTN patients (n=3,242) without established CVD over an average 10-year follow up. Despite an overall low SCD event rate (~0.1%) in the study 14
Journal Pre-proof population, electrocardiographic LVH almost tripled the risk of SCD even after adjustment for sex, age, DM, and 24-hour ambulatory BP (HR: 2.99; 95% CI: 1.47 to 6.09; p=0.002).86 Heart Failure To emphasize the progressive nature of HF and the importance of prevention, the 2013 ACC Foundation/AHA guideline for the management of heart failure considers HTN and LVH
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as stage A and stage B HF, respectively.87 This staging also highlights the importance of these
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risk factors in the pathophysiology of HF.
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Traditional models of HF include one whereby sustained pressure overload results in an
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increased LV mass and RWT with consequent impairment of LV compliance and elevates filling pressures. In contrast, sustained volume overload remodels the heart by dilation in the LV with a
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RWT in the normal range.88 However, a new line of evidence has challenged this understanding.
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Sustained BP overload can cause distinct LV remodeling patterns at different parts of the heart (e.g., cLVH in the septum and eLVH in the lateral wall).89 Further, some epidemiological studies
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reported a higher prevalence of eLVH compared with cLVH in patients with HTN and also
disease (CAD).90
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failed to show the transition from cLVH to HF reduced EF without evidence of coronary artery
The most recent ASE document on the evaluation of LV diastolic dysfunction considers LVH with HTN as an indicator of diastolic dysfunction.91 Moreover, LVH has also been associated with the risk of development of systolic dysfunction. 92 A retrospective study by Milani et al. found that 13% of HTN subjects with cLVH (n=1,024) developed systolic dysfunction after an average of 33 ± 24 months of follow- up. Variables associated with this progression were interval MI, prolonged QRS interval (>120 ms), and elevated arterial
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Journal Pre-proof impedance (>4.0 mm Hg/ml/m2 ).93 Similar results were observed in a retrospective study by Krishnamoorthy et al. In their study, progression from LVH to systolic dysfunction occurred in 20% patients (over ~7.5-year of follow-up), but noted that was particularly rare in the absence of interval MI.94 Detectable troponin-T or elevated N-terminal pro-B type natriuretic peptide have been shown to predict future risk of HF among subjects with LVH (20.6% vs. 5.8% for detectable vs.
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undetectable troponin-T; 20.2% vs. 6.5% for elevated vs. normal N-terminal pro-B).95
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Coronary Artery Disease
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The population-based Dallas Heart Study (n=2,633) investigated the relationship between LVH by cardiac MRI and coronary artery calcium score (CACS) by computerized tomography.
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In a multivariable linear regression analysis, LV mass remained significantly associated with the
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quantity of CACS (β 0.32; p<0.001).96 A recent small cohort study among 132 subjects with stable angina and non-obstructive CAD, who underwent myocardial contrast stress
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echocardiography to measure the extent of myocardial ischemia, reported a significant
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association between LVH and risk of myocardial ischemia (OR: 3.27; 95% CI: 1.11 to 9.60; p=0.031).97 Furthermore, LVH was associated with increased CVD mortality after percutaneous coronary interventions. This finding highlights the prognostic impact of LVH in patients with established CAD.98 A retrospective observational study involving patients with ST-segment elevation MI (n=481) managed with successful primary percutaneous coronary intervention investigated the effect of LVH on long-term prognosis. The investigators reported a significant association between LVH and increased risk of all-cause mortality (OR:2.37; 95% CI: 1.09 to 5.12; p=0.028). Furthermore, severe LVH (defined as ≥149 g/m2 in male and ≥122 g/m2 in female) was associated with an even higher risk of mortality. (OR: 5.11; 95% CI: 1.45 to 17.9; 16
Journal Pre-proof p=0.001).99 A sub-study of the DANAMI-3 (DANish Study of Optimal Acute Treatment of Patients With ST-elevation Myocardial Infarction) trial involving ST-segment elevation MI patients (n=764) managed with successful primary percutaneous coronary intervention reported that LVH by cardiac MRI was significantly associated with larger final infarct size, smaller final myocardial salvage index, and higher incidence of microvascular obstruction.100
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Arrhythmias
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LVH increases the risk of cardiac arrhythmias. In a retrospective study among subjects with untreated HTN (n=2,482), each standard deviation increase in LV mass was associated with
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a 20% increase in the risk of AF (95% CI; 1.07 to 1.34; p=0.001).101 Hypertensive LVH was
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also significantly associated with the progression of AF from paroxysmal to persistent and
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permanent (OR: 4.84; 95% CI: 1.70 to 13.78; p= 0.003).102 Fortunately, in a small prospective study by Hennersdorf et al., regression in LV mass with anti-HTN treatment led to a significant
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decrease in the prevalence of AF from 12.5% to 1.5% (p=0.05).103
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Other than AF, LVH has been associated with ventricular and supraventricular
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arrhythmias. A meta-analysis involving 27,141 subjects revealed a 2.8-fold higher odds of developing ventricular tachycardia or fibrillation and 3.4-fold higher odds of developing supraventricular tachycardia in the presence of LVH.104 Cerebrovascular Disease An analysis on Framingham Heart Study participants (n=1,230, age >58 years, ~8-year follow-up) found that subjects in the highest quartile of LV mass to height ratio had a 2.7 times higher risk of cerebrovascular disease when compared to those in lowest quartile after adjustment for other variables.105 A retrospective cohort study, which included young ischemic 17
Journal Pre-proof stroke survivors (< 60-year-old) reported abnormal LV geometry in 37% of study subjects (21% had CR, and 16% had LVH).106 Bluemke et al. examined the association between LV mass by cardiac MRI and the risk of future stroke risk in 5,098 subjects enrolled in the prospective MESA study. Their analysis revealed a significant association between LV mass index and stroke risk after adjustment for other variables (HR: 1.2; 95% CI: 1.0 to 1.4; p=0.01).107
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Dementia
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There exists a link between LVH and increased risk of impaired cognitive performance. In a population-based study of subjects age >74 years old, echocardiographic LVH was found to
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predict cognitive decline over a 5-year follow-up.108 In the ARIC study (n=12,665),
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electrocardiographic LVH was associated with a markedly higher risk of dementia during a
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median of 18-year follow-up (HR: 1.90; 95% CI: 1.47 to 2.44).109 Similarly, a report on 4,999 MESA study participants (median follow-up of 12-years) revealed that LV mass index and LV
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mass to volume ratio (indicator of cLVH) by cardiac MRI were independently associated with
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increased risk of dementia (HR: 1.01; 95% CI: 1.00 to 1.02 and HR: 2.37; 95% CI 1.25 to 4.43,
Treatment
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respectively).110
Impact of Treatment In the 1990s, an investigation on subjects from the Framingham Heart Study demonstrated significant improvement in CVD morbidity by the regression of electrocardiographic LVH over time (OR: 0.46; 95% CI: 0.26 to 0.84).111 Subsequent landmark trials in the early 2000s such as MRFIT (Multiple Risk-Factor Intervention Trial), HOPE (Heart Outcomes Prevention Evaluation), and LIFE confirmed the possibility of LV regression in 18
Journal Pre-proof response to anti-HTN therapy and related CVD prognostic benefits.8,9,112 A recent report from SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated that, compared to standard SBP control (<140 mmHg), intensive SBP control (<120 mmHg) was associated with a 46% lower risk of developing ECG-LVH in participants without baseline LVH and 66% higher likelihood of regression/improvement of LVH in participants with baseline LVH.113 The ratio of regression in LV mass with anti-HTN therapy varies significantly depending
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on the population studied.114 The predictors of persistent LVH and lack of LVH regression with
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anti-HTN therapy are older age, central obesity, higher body mass index, kidney disease,
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suboptimal BP control, and longer duration of HTN.115,116 Therefore, to avoid irreversible LVH,
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anti-HTN therapy should be started early with an appropriate BP goal and simultaneous
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management of related comorbidities such as obesity.
The 2018 ESH/ESC guideline for the management of arterial HTN recommend (Grade
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1A and Grade IIA) that all patients with HTN and LVH should be treated with RAAS inhibitors
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in addition to calcium channel blockers (CCBs) or diuretics with a target SBP goal of 120-130
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mm Hg.12 Non-Pharmacological
In the early 1980s, a small randomized clinical trial (RCT) which enrolled overweight participants with HTN, revealed a significant regression in LV mass (up to 24%) in response to weight reduction with lifestyle changes. This significant association between LV mass and weight reduction was independent of change in BP.117 Furthermore, in a meta-analysis of 1,022 obese subjects, bariatric procedures were associated with a significant decrease in LV mass, RWT, and left atrial diameter, with a corresponding improvement in diastolic dysfunction.118
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Journal Pre-proof Lifestyle changes can also decrease the future risk of incident LVH in patients with HTN. In a prospective study of HTN subjects (n=454) without baseline LVH, regular aerobic exercise was shown to improve BP and reduce the risk of LVH development during 8.3 years of followup (10.3% for sedentary; 1.7% for active; p<0.001).119 Landmark Studies All major anti-HTN drug classes, including diuretics, CCBs, β-blockers, angiotensin-
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converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) have been
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shown to regress LVH secondary to HTN.
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In the early 2000s, the HOPE trial showed that compared to placebo, treatment with
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ramipril led to regression or prevention of LVH and reduction of CVD mortality, MI, and stroke
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risks (12.3% vs. 15.8% for regression/prevention of LVH vs. development/persistence of LVH; p=0.006).8 Losartan was compared to atenolol in the randomized LIFE trial, which enrolled
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9,193 HTN participants with electrocardiographic LVH. Losartan reduced the severity of LVH
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and prevented adverse CVD outcomes better than did atenolol (HR: 0.87; 95% CI: 0.77 to 0.98; p=0.021). In addition, losartan use was associated with a 25% lower risk of new-onset DM (HR:
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0.75; 95% CI: 0.63 to 0.88; p=0.001).9 Subsequent analysis from the LIFE study by Okin et al. reported a 12.2% lower rate of new-onset AF proportional to electrocardiographic LVH regression (for every 1050 mm x msec (per 1-SD) lower Cornell product) independent for BP reduction or medication (HR: 0.88; 95% CI: 0.80 to 0.97; p=0.007).120 In the PRESERVE (Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement) trial, enalapril was compared to long-acting nifedipine among HTN participants with LVH (n=202). Treatment with enalapril led to a moderate regression in LV mass with no significant difference between the two drug classes (26 g vs. 32 g; p=0.36).121
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Journal Pre-proof Pitt et al. compared a selective aldosterone blocker, eplerenone, to enalapril in a doubleblind RCT among HTN patients with LVH and reported similar degrees of LVH regression with enalapril and eplerenone.122 They also found that compared to eplerenone alone, the combination of enalapril and eplerenone was more effective in reducing LV mass. Other trials have explored the idea of combination therapy; the ADVANCE (Action in Diabetes and Vascular Disease Study) trial showed that a fixed combination of long-acting ACE inhibitor -perindopril- and a
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thiazide-like diuretic -indapamide- had additive CVD morbidity and mortality benefits. An
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echocardiographic sub-study of the ADVANCE trial also showed a reduction in LV mass index
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by 2.7 g/m2 (95% CI: -5.0 to -0.1; p=0.04) among those treated with this fixed combination.123 The landmark ALLHAT trial and subsequent ALLHAT-HF validation study endorsed the
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superiority of chlorthalidone over amlodipine, lisinopril, or doxazosin in preventing HF.124,125
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Subsequent posthoc analysis of ALLHAT revealed that reduction in LVH along with a reduction
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in BP by chlorthalidone explained up to 13% of its HF prevention effect compared to other antiHTN drug classes in the study.126
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The landmark PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-
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Neprilysin Inhibitors with an ACE inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial showed a more substantial reduction in CVD morbidity and mortality for sacubitril/valsartan treatment compared to enalapril. 127 Vasodilation and antiproliferative effects of sacubitril might explain some aspects of superiority. Schmieder et al., in a double-blind, multicenter RCT involving participants with HTN, reported that sacubitril/valsartan provided a more significant reduction in LV mass compared to olmesartan which might contribute to the superiority of sacubitril in terms of its favorable outcomes. 128 Furthermore, a recently published meta-analysis of 20 studies (16 non-RCTs and 4 RCTs)
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Journal Pre-proof revealed a significant regression in LV mass with sacubitril/valsartan treatment compared to ACE inhibitors or ARBs among subjects with HF with reduced EF.129 Meta-Analyses A meta-analysis involving 80 double-blind RCTs, including all major drug classes and echocardiographic assessment of LV mass, showed a significant reduction in the LV mass index
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by 13% with ARBs, 11% with CCBs, 10% with ACE inhibitors, 8% with diuretics, and 6% with
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β-blockers. The pairwise comparison analysis reported ARBs, CCBs, and ACE inhibitors to be more effective compared with β-blockers; however, diuretics were not included in the pairwise
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comparison analysis.130 The design for the meta-analyses was criticized because each treatment
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arm of the included studies was considered as a separate observation despite the original
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comparative designs. Fagard et al. conducted a meta-analysis of 75 RCTs using a pooled pairwise comparison of each drug class versus other classes along with meta-regression analysis.
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In this analysis, β-blockers reduced LV mass significantly less than ARBs (9.8% vs. 12.5%;
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p=0.01) and were found to be a significant negative predictor of the regression (-3.6%; p<0.01).
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Overall, the inferiority of β-blockers was more prominent than the superiority of ARBs.114 The mechanism behind the marked decrease in LV mass by ARBs, ACE inhibitors, or CCBs might be explained by 1) activation of RAAS stimulates myocardial cells growth; 2) increase in plasma angiotensin II level is independently associated with LVH; and 3) sympathetic nerve activity is stimulated through N-type calcium channels.131–133 On the other hand, the minimal decrease by β-blockers might be explained by a smaller reduction in central aortic BP and a more significant reduction in heart rate. Both of these factors result in a relatively increased LV end-diastolic diameter with subsequently increased LV wall stress.134
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Journal Pre-proof A meta-analysis by Roush et al. which combined the data of diuretic arms in 38 RCTs compared the efficacy of hydrochlorothiazide and “CHIP” diuretics (CHlorthalidone, Indapamide, and Potassium‐ sparing diuretic/hydrochlorothiazide). Their results revealed that “CHIP” diuretics reduced LV mass 2-fold more than hydrochlorothiazide.135 Subsequent headto-head systematic review involving 12 double-blind RCTs reported that “CHIP” diuretics were better than RAAS inhibitors in the reduction of LV mass.136
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Future Directions
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DM is a major risk factor for cardiac remodeling and LVH. SGLT2 inhibitors are
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relatively novel anti-diabetic agents with added benefits of BP and weight reduction.137,138
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Landmark trials, EMPA-REG Outcomes (Empagliflozin, Cardiovascular Outcomes, and
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Mortality in Type 2 Diabetes) and CANVAS (The Canagliflozin Cardiovascular Assessment Study) demonstrated beneficial effects of empagliflozin and canagliflozin on CVD morbidity and
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mortality, respectively, especially HF.139,140 To assess whether regression of LV mass could
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explain the potential mechanism behind the benefit in CVD morbidity and mortality with SGLT2 inhibitors, various small trials are still in progress, such as DAPA-LVH, EMPATROPHY,
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EMPA-HEART, and NCT0295691.141 Potential mechanisms for LV mass reduction by SGLT2 inhibitors include 1) decrease in LV wall stress secondary to diuresis and natriuresis which translates into reduced LV wall stress; and 2) suppression of sodium-hydrogen exchange in cardiomyocytes which impacts cardiac remodeling.142,143 In a non-diabetic rodent model of HF with preserved EF, Empagliflozin was shown to reduce the LV mass without affecting BP, which led to improving diastolic dysfunction.11 Animal model studies have shown regression of LVH by xanthine oxidase inhibitors by reducing oxidative tissue stress, which mediates myocardial hypertrophy.144,145 RCTs showed 23
Journal Pre-proof that allopurinol, a xanthine oxidase inhibitor, contributed to significant regression in LVH without a change in BP in adult patients with CAD, CKD, or DM.146–148 Renal sympathetic denervation was an exciting innovation for the treatment of resistant HTN until the single-blind Symplicity HTN-3 RCT failed to show a significant reduction in BP in the therapeutic arm.149 However, a recent meta-analysis involving 12 observational, but no prior RCTs, reported a significant decrease in LV mass index by cardiac MRI with renal
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sympathetic denervation (-5.43 g/m2 ; 95% CI: -10.1 to -0.35 g/m2 ).150
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Conclusions
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LVH is a leading risk factor for CVD morbidity and mortality, stroke, cognitive impairment, and all-cause mortality. Elevated BP, at HTN and pre HTN stages, is a major
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contributor to LV remodeling, including CR, cLVH, and eLVH. ECG and 2D echocardiography
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are the primary diagnostic tools for the diagnosis and quantification of LVH. Evolving 3D echocardiography technologies provide more accurate and reproducible measurements but are
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still relatively new, and ongoing studies to determine standard reference values are underway.
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Cardiac MRI is not only superior to other techniques in the quantification of LVH, but also helpful with distinguishing different types of LVH, yet can be costly and time-consuming. BP control with lifestyle changes and anti-HTN agents can lead to the prevention or regression of LVH. RAAS inhibitors with CCBs or diuretics are the guideline-directed treatments with wellknown survival benefits through the regression of LVH. Multiple clinical trials are currently underway to understand the impact of SGLT2 inhibitors on LV mass in DM patients with or without HTN.
24
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Journal Pre-proof Figure Legends Figure: 1: Central Illustration. Overview of left ventricular hypertrophy. Figure 2: Left ventricular geometric patterns determined by relative wall thickness and left ventricular mass index based on linear measurements. LVH, left ventricular hypertrophy. Adapted from Konstam et. al.151
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Figure 3: Left ventricular geometric patterns determined by 2D echocardiography linear method.
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Legend: Parasternal long-axis view demonstrating end-diastolic linear measurements of left
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ventricular (LV) internal diameter (LVID), LV septal wall (SW) thickness, LV posterior wall
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(PW) thickness. * interventricular septum, ∞ LV cavity, & LV inferolateral wall. Normal Geometry: 23-year-old male, LVID of 5.31 cm, LV SW of 1.08 cm, LV PW of 1.01
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cm, LV mass index of 112 g/m2 , relative wall thickness (RWT): 0.38.
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Concentric Remodeling: 50 year-old male, LVID of 4.19 cm, LV SW of 1.19 cm, LV PW of
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1.26 cm, LV mass index of 88 g/m2 , RWT: 0.60.
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Concentric LV hypertrophy (LVH): 57-year-old male, LVID of 5.31 cm, LV SW of 1.08 cm, LV PW of 1.01 cm, LV mass index of 144 g/m2 , RWT: 0.64. Eccentric LVH: 40-year-old male, LVID of 7.48 cm, LV SW of 1.19 cm, LV PW of 1.21 cm, LV mass index of 222 g/m2 , RWT: 0.32.
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Journal Pre-proof Table 1: 3D Echocardiography Derived Normal Reference Values of Left Ventricular Mass Index
Fukuda et al. (2012) Japanese 410 (253/157)
The ethnicity of the study population Number of subjects (Male/Female)
Muraru et al. (2013)
Mizukoshi et al. (2016)
European white 226 (101/125)
Japanese 230 (121/109)
American 160 (78/82)
Mass index (g/m2 ) 64 ± 12
77 ± 10
69 ± 8
70 ± 9
Women (Mean ± SD)
56 ± 11
74 ± 8
61 ± 8
60 ± 7
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Men (Mean ± SD)
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Table 2:
Differential Diagnosis of Left Ventricular Hypertrophy Physiological left ventricular hypertrophy Athlete's heart
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Secondary left ventricular hypertrophy Hypertensive heart disease Aortic stenosis Systemic diseases Cardiac amyloidosis Mitochondrial myopathy Fabry disease Pompe disease Danon disease
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Pathological left ventricular hypertrophy Primary left ventricular hypertrophy Hypertrophic cardiomyopathy
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Journal Pre-proof
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Conflict of interest: None.
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Figure 1
Figure 2
Figure 3
Mehmet Yildiz, Ahmet Afşin Oktay, Merrill H. Stewart, Richard V. Milani, Hector O. Ventura, Carl J. Lavie PII:
S0033-0620(19)30143-4
DOI:
https://doi.org/10.1016/j.pcad.2019.11.009
Reference:
YPCAD 1017
To appear in:
Progress in Cardiovascular Diseases
Received date:
17 November 2019
Accepted date:
17 November 2019
Please cite this article as: M. Yildiz, A.A. Oktay, M.H. Stewart, et al., Left ventricular hypertrophy and hypertension, Progress in Cardiovascular Diseases(2019), https://doi.org/10.1016/j.pcad.2019.11.009
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© 2019 Published by Elsevier.
Journal Pre-proof
Left Ventricular Hypertrophy and Hypertension Authors: Mehmet Yildiz1 , Ahmet Afşin Oktay2 , Merrill H. Stewart3 , Richard V. Milani3 , Hector O. Ventura3 , and Carl J. Lavie3
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Running title: Left ventricular hypertrophy and hypertension
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Affiliations: 1 Department of Medicine, Southern Ohio Medical Center, Portsmouth, OH; 2 Department of Medicine, Division of Cardiology, Wentworth-Douglass Hospital, Partners HealthCare, Dover, NH; 3 Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute; Ochsner Clinical School - The University of Queensland School of Medicine, New Orleans, LA.
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Key Words: Hypertension; left ventricular geometry; left ventricular hypertrophy; remodeling; antihypertension therapy
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Disclosures: No relevant disclosures
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Word count: 5718 words. Figures: 3. Tables: 2.
Address for correspondence:
Ahmet Afşin Oktay, MD Department of Medicine, Division of Cardiology Wentworth-Douglass Hospital Partners HealthCare 789 Central Ave, Dover, NH Phone: +1(603) 516-4265 Fax: +1(603) 740-2173 Email: [email protected]
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Journal Pre-proof Abbreviations
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Angiotensin converting enzyme American College of Cardiology Atrial fibrillation American Heart Association Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Angiotensin receptor blockers Atherosclerosis Risk in Communities American Society of Echocardiography Blood pressure Coronary artery disease Coronary artery calcium scoring Calcium channel blockers Chlorthalidone, indapamide, and potassium‐ sparing diuretic/hydrochlorothiazide Chronic kidney disease Concentric remodeling Cardiovascular disease Diabetes mellitus European Association of Cardiovascular Imaging Electrocardiography Ejection fraction European Society of Cardiology European Society of Hypertension Hypertrophic cardiomyopathy Heart failure Heart Outcomes Prevention Evaluation Hypertension or hypertensive Losartan Intervention for Endpoint Reduction Left ventricle Concentric left ventricular hypertrophy Eccentric left ventricular hypertrophy Left ventricular hypertrophy Multiethnic Study of Atherosclerosis Myocardial infarction Magnetic resonance imaging Renin-angiotensin-aldosterone system Randomized clinical trial Relative wall thickness Systolic blood pressure Sudden Cardiac Death Sodium-glucose cotransporter type2 Speckle tracking echocardiography Two-dimensional Three-dimensional
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ACE: ACC: AF: AHA: ALLHAT: ARBs: ARIC: ASE: BP: CAD: CACS: CCBs: CHIP: CKD: CR: CVD: DM: EACVI: ECG: EF: ESC: ESH: HCM: HF: HOPE: HTN: LIFE: LV: cLVH: eLVH: LVH: MESA: MI: MRI: RAAS: RCT: RWT: SBP: SCD: SGLT2: STE: 2D: 3D:
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Journal Pre-proof Abstract Hypertension (HTN) is a major modifiable risk factor for cardiovascular disease (CVD) morbidity and mortality. The left ventricle (LV) is a primary target for HTN end-organ damage. In addition to being a marker of HTN, LV geometrical changes: concentric remodeling, concentric or eccentric LV hypertrophy (LVH) are major independent risk factors for not only
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CVD morbidity and mortality but also for all-cause mortality and neurological pathologies. Blood pressure control with lifestyle changes and antihypertensive agents has been demonstrated
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to prevent and regress LVH. Herein, we provide a comprehensive review of literature on the
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relationship between HTN and LV geometry abnormalities with a focus on diagnosis, prognosis,
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pathophysiological mechanisms, and treatment approaches.
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Journal Pre-proof Hypertension (HTN) is a major modifiable risk factor for cardiovascular disease (CVD) morbidity and mortality.1,2 HTN frequently coexists with other CVD risk factors, such as obesity, hyperlipidemia, diabetes mellitus (DM), chronic kidney disease (CKD), and tobacco use.3 The 2017 American College of Cardiology (ACC)/American Heart Association (AHA)/AAPA/ABC/ ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults has redefined the classification
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of HTN and proposed novel treatment strategies. The guideline now defines HTN as a systolic
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BP (SBP) of ≥130 mm Hg or a diastolic BP of ≥80 mm Hg, which increases the prevalence of
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HTN among U.S. adults from 32% to 46%. In diagnosing HTN, the emphasis is placed on the
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importance of out-of-office BP measurements, which are better predictors of target organ damage compared to in-office measurement and further discriminates sustained HTN from
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white-coat or masked HTN. The guideline also recommends incorporation of the atherosclerotic
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CVD risk score in the decision making to initiate pharmacological treatment with the aim of a
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target BP of <130/80 mm Hg.4
The left ventricle (LV) is a primary target for HTN end-organ damage. HTN induced
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remodeling of the LV is often grouped into three different geometric patterns: concentric remodeling (CR), concentric LV hypertrophy (LVH; cLVH), and eccentric LVH (eLVH).5 Electrocardiography (ECG), echocardiography, and cardiac magnetic resonance imaging (MRI) are the primary diagnostic modalities for the assessment of LV geometric changes.6 In addition to being an end-organ response, LVH is also an independent risk factor for CVD morbidity and mortality.7 The 2017 ACC/AHA high BP guideline noted the positive and negative prognostic effects of LV geometric changes. However, the authors did not recommend the routine use of echocardiography or cardiac MRI for the assessment of LVH during the evaluation and
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Journal Pre-proof management of HTN due to a lack of data in cost-effectiveness.4 Numerous treatment strategies from well-established thiazide diuretics, renin-angiotensin-aldosterone system (RAAS) inhibitors and calcium channel blockers to future promising sodium-glucose cotransporter type-2 (SGLT2) inhibitors have been shown to regress LVH.8–11 Herein, we discuss the relationship between HTN and LV geometric changes with a focus
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on diagnosis, epidemiology, pathophysiology, prognosis, and treatment (Figure 1).
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Diagnosis
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Abnormalities of LV geometry can be evaluated by ECG, two-dimensional (2D) and
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three-dimensional (3D) echocardiography, speckle tracking echocardiography (STE), or cardiac MRI. The 2018 European Society of Hypertension (ESH)/European Society of Cardiology (ESC)
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clinical practice guideline for the management of arterial HTN defined LVH as a high-risk
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component in the Systematic Coronary Risk Evaluation system and accepted LVH as a representative of diastolic dysfunction. The guideline recommends (Grade IIB) 2D
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echocardiography to detect LVH if the results are likely to influence treatment decisions.12
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According to the 2017 ACC/AHA high BP guideline, LVH assessment “is most useful” in cases of young adults or adults with a history of secondary HTN or heart failure (HF) where the presence of end-organ damage reinforces aggressive treatment in otherwise healthy individuals.4 Electrocardiography The 2018 ESH/ESC guideline for the management of arterial HTN recognizes the most commonly used ECG criteria as: (1) S V1 +RV5 or RV6 (Sokolow-Lyon) >35 mm, (2) R wave in aVL ≥11 mm, (3) SV3 +RaVL (Cornell voltage) >28 mm for men and >20 mm for women, and (4) Cornell product (Cornell voltage x QRS duration) >2440 mm x ms.12 5
Journal Pre-proof Jiang et al. compared the diagnostic value of 18 different ECG criteria to diagnose LVH among middle-aged subjects with HTN. Criteria of SD+SV4 (a combination of the deepest S‐ wave amplitude and the S‐ wave amplitude of lead V4 ≥ 28 mm (male) and ≥23 mm (female) had the highest sensitivity (29%) followed by Cornell product (24%). 13 In a recent analysis from the MESA (Multi-Ethnic Study of Atherosclerosis) study, a new machine learning ECG
ability compared to other traditional ECG techniques. 14
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technique, the Bayesian Additive Regression Trees, showed superior diagnostic and prognostic
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Despite the low sensitivity and specificity in diagnosing LVH, electrocardiographic LVH
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has a well-established prognostic value in CVD. In the ALLHAT (Antihypertensive and Lipid-
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Lowering Treatment to Prevent Heart Attack) study, baseline LVH by Cornell voltage was
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independently associated with increased CVD morbidity and all-cause mortality during a fiveyear follow-up among treated HTN participants.15 In the LIFE (Losartan Intervention for
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Endpoint Reduction) study, persistence or new development of LVH by both Cornell product
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2D Echocardiography
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and Sokolow-Lyon was associated with markedly increased all-cause mortality.16
2D echocardiography remains the most commonly used imaging modality for evaluation of LV geometry and its primary variables: LV mass and relative wall thickness (RWT). Linear method and 2D based formulas are the two main 2D echocardiographic methods for quantification of LV mass. In linear method, LV mass is calculated as 0.8 x 1.04 x [(interventricular septum + LV internal diameter + posterior wall thickness)3 – LV internal diameter3 ] + 0.6g. The linear method is a widely used technique in clinical practice due to its ease of use and accuracy in normally shaped ventricles. However, the linear method relies on the assumption that the ventricle has a prolate ellipsoid shape, and it does not consider the regional 6
Journal Pre-proof variations in LV thickness. Therefore, the accuracy of the linear method is limited in the setting of asymmetric hypertrophy, dilated LV, or other abnormalities of regional thickness. In addition, even small measurement errors lead to an exaggeration of inaccuracy due to the cubing of the parameters. 2D based formulas (truncated ellipsoid and area-length methods) have the advantage of partial correction for shape distortions. Therefore, they are less dependent on geometric assumptions compared to linear methods. However, cumbersome methodology, high
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measurement variability, and requirement of good image quality make 2D based methods less
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attractive in routine clinical practice.17
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In addition to BP, LV mass correlates with several other variables such as body size, age,
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sex, ethnicity, and physical activity level.18–24 Therefore, it is difficult to define standard values
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for LV mass.17 LV mass indexing to body surface area allows comparison among people with different body sizes. However, in extremely obese individuals indexing to height is more
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advantageous compared to body surface area.17,25
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The 2015 American Society Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) chamber quantification document defines increased LV mass
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index by body surface area as >95 g/m2 in women and >115 g/m2 in men by linear methods; and >88 g/m2 in women and >102 g/m2 in men by 2D formulas. RWT is calculated as 2 x posterior wall thickness/LV end-diastolic diameter. According to LV mass and RWT, LV geometric patterns are classified into four different types as follows: 1) normal LV geometry (normal LV mass index and RWT ≤0.42); 2) cLVH (increased LV mass index and RWT >0.42); 3) eLVH (increased LV mass index and RWT ≤0.42); and 4) CR (normal LV mass index and RWT >0.42).26 (Figure 2 and 3)
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Journal Pre-proof 3D Echocardiography 3D echocardiography provides more accurate and reproducible measurements in LV volumes and mass compared to 2D echocardiography by not only relying on geometric modeling but also allowing for the measurement of the non-foreshortened imaging.27,28 Despite its strengths, 3D echocardiography can slightly underestimate LV mass as compared to cardiac
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MRI.29
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3D echocardiography technology is evolving rapidly. Several recent studies confirmed the validity of automated techniques using artificial intelligence for accurate quantification of
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chamber volumes.30–33 These automated techniques are expected to help with the practical use of
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3D echocardiography in routine clinical practice as the application by untrained personnel can
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take additional time.
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The 2015 ASE/EACVI document on cardiac chamber quantification has not reported the normal reference values of LV mass by 3D echocardiography due to limited available data.17
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Since the 2015 document, several studies have been published validating the accuracy of LV
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mass quantification by 3D echocardiography against cardiac MRI. These studies have provided normal reference values for 3D echocardiographic LV mass index in healthy subjects (Table 1).34–36 While these studies have been helpful, owing to their comparatively small size, further research is needed to determine normal reference values in 3D echocardiography. Speckle Tracking Echocardiography LVH can develop secondary to pathological responses to pressure or volume overload as in cLVH or eLVH, physiological responses to physical exercise as in athletes, genetic disorders as in hypertrophic cardiomyopathy (HCM), or storage disorders as in amyloidosis (Table 2). The 8
Journal Pre-proof use of STE technology helps substantially with understanding the etiology of LVH and provides important prognostic information in patients with LVH and preserved ejection fraction (EF). Speckle tracking is a non-doppler and angle-independent quantitative ultrasound technique which measures strain and strain rate by tracking the motion of speckles during a cardiac cycle on both 2D and 3D echocardiograms. STE expands the measurements in three spatial directions as longitudinal, radial, and circumferential. The STE technology can also
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evaluate twisting, untwisting, and torsion of the LV myocardium.37 Global longitudinal strain by
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STE is the most commonly used strain parameter in clinical practice and it is a more sensitive
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marker of LV dysfunction as compared to EF.38 Detection of subclinical systolic dysfunction by
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STE provides diagnostic and prognostic insights in HTN patients with preserved EF.39,40
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Several studies have confirmed the utility of 2D STE in the differentiation of an athlete’s heart from HCM.41,42 For instance, Richand et al. demonstrated that pathologic hypertrophic
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segments in patients with HCM have significantly lower longitudinal strain compared to those of
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an athlete’s heart.41 Galderisi et al. compared the strain patterns of professional athletes with young patients with HTN. They found that global longitudinal strain was significantly lower in
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HTN patients compared to that of professional athletes.43 The typical apical sparing pattern of longitudinal strain is a sensitive and specific STE finding for differentiation of cardiac amyloidosis from LVH due to other pathologies.44 Cardiac Magnetic Resonance Imaging Cardiac MRI is generally considered the gold standard for quantification and assessment of cardiac chambers.45,46 This technology does not rely on geometric assumptions and provides superior delineation of the endocardium and epicardium. 47 Through its ability to provide
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Journal Pre-proof reproducible and unrestricted views, cardiac MRI has been used in clinical trials to demonstrate subtle regression in LV mass after anti-HTN treatment, e.g., LIFE sub-study.48 Cardiac MRI is valuable in distinguishing different types of LVH, including HTN heart disease, HCM, infiltrative cardiomyopathies, and athletes’ heart. It can further detect and quantify myocardial fibrosis, of prognostic importance in these conditions, by late gadolinium enhancement with T1 weighted sequences.49–53 Currently, its availability, cost, and time-
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consuming nature limits the use of cardiac MRI.45
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Epidemiology
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LV remodeling occurs in response to numerous modifiable and non-modifiable risk factors, including age, gender, genetic factors, HTN, DM, CKD, obesity, metabolic syndrome,
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obstructive sleep apnea, sedentary lifestyle, and dietary salt intake. The reported prevalence of
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LV geometric patterns in HTN patients varies depending on the population studied, the imaging modalities utilized, and the way geometric patterns are defined. A meta-analysis of 30 studies
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involving a total of 37,700 participants demonstrated that echocardiographic LVH was present in
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36% to 41% of all HTN participants. This prevalence increased to 58% to 77% in high-risk HTN participants defined as those with severe or refractory HTN or with history of DM or CVD.54 A prospective cohort study (n=6,105) with a median follow up of 14-years revealed ~2.5 times higher odds of developing ECG-LVH in the presence of HTN. In this study, there was a 49% increase in the odds of ECG-LVH for every 19 mm Hg increase in SBP (p<0.001).55 Pre-HTN has also been linked to cardiac remodeling. A meta-analysis involving more than 73,000 subjects reported that patients with pre-HTN had an average LV mass and RWT higher than that of normotensive patients but smaller than those with history of HTN 10
Journal Pre-proof (p<0.001).56 A large cohort study among 52,111 Korean participants revealed a significant association between HTN categories and the risk of LV remodeling defined with increased RWT. They found a progressive increase in the odds ratio of LV remodeling in the following order of HTN categories (from lowest to highest): normotension, pre-HTN, controlled HTN, newly diagnosed HTN, and uncontrolled HTN (OR: 1.00, 1.65, 2.02, 2.85, 3.31, respectively).57 The recently published PAMELA (Pressioni Monitorate E Loro Associazion) study reported a
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similar pattern of progressive increase in the incidence of LVH from normotensive to pre-HTN
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and HTN groups (9%, 23.2%, and 36.5%, respectively).58 Patients who progressed from pre-
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HTN to sustained HTN over time had a significantly higher incidence of LVH compared to those
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who had persistent pre-HTN. These findings highlight the significance of early detection and
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proper management of HTN to prevent end-organ damage. Masked HTN is characterized by consistently elevated out-of-office BP readings despite
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normal office BP readings.4 Masked HTN carries a higher risk of CVD mortality compared to
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sustained HTN.59 A meta-analysis of 13 studies with a total of 4,884 untreated subjects revealed a significantly higher LV mass index in patients with masked HTN compared to normotensive
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individuals.60 Similarly, patients with white-coat HTN have been shown to have higher LV mass index than those with normotension.61 The presence of other comorbidities significantly contributes to the risk of LV remodeling in patients with HTN. For instance, Palmieri et al. reported a higher prevalence of LV geometric abnormalities among DM patients with HTN compared to non-DM patients with HTN.62 In a prospective study of 1,160 subjects, the presence of metabolic syndrome and CKD was shown to increase the risk of LVH by 2.4-fold among patients with HTN.63
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Journal Pre-proof Ambulatory BP measurements more closely correlate with LV geometry abnormalities compared to office BP measurements.64,65 Abdalla et al. reported a higher prevalence of LVH among blacks with a reverse dipping pattern defined as an increase in BP at night assessed by ambulatory BP measurement.66 White coat HTN has a comparable effect to ambulatory HTN as attended and unattended BP measurements correlate similarly with LV mass (r=0.205 and
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r=0.194, respectively).67
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Pathophysiology
LV remodeling in response to HTN involves a complex interaction of cardiomyocytes
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and cardiac non-myocytes, such as endothelial cells, fibroblasts, and the immune system.68 The mechanical stretch activates intracellular signaling cascades and leads to gene
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expression and synthesis of proteins (e.g., actin, myosin), which organize in the sarcomere. In
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general, LV wall stress is reduced by increasing the size of cardiomyocyte by addition of sarcomeres in parallel, in the case of pressure overload; whereas, in series, in the case of volume
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overload.26 This adaptive response is also mediated by several neurohumoral mechanisms
myocytes.68,69
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involving expression of catecholamines, angiotensin II, and growth factors from cardiac non-
The adaptive and innate immune systems play a vital role in the pathogenesis of HTN and HTN induced end-organ damage.70 In clinical trials, an imbalance of adaptive immunity and elevated levels of pro-inflammatory markers was shown to contribute to end-organ damage in subjects with HTN.71,72 Mechanical stretch and upregulation of inflammation can trigger fibroblasts to differentiate into myofibroblasts which build up myocardial fibrosis with increased production of collagen type I and type II fibers. Myocardial fibrosis contributes to a variety of 12
Journal Pre-proof clinical presentations in HTN heart disease including HF with preserved or reduced EF, reduced coronary flow reserve, and cardiac arrhythmias.73–75 Another important pathophysiologic link between HTN and cardiac remodeling is the upregulation of the sympathetic nervous system. This finding is supported by the fact that in spontaneously HTN rats models, sympathectomy leads to a reduction in BP and normalization in
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LV mass.76
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Prognosis
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LVH is not only an adaptive response to hemodynamic changes but also a significant risk
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factor for adverse CVD outcomes. Echocardiographic LVH was associated with CVD morbidity and mortality, and all-cause mortality in the Framingham Heart Study three decades ago.77
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Similarly, a recently published analysis on ALLHAT study participants (n=26,384) with treated
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HTN showed a significant association between electrocardiographic LVH and increased risk of
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myocardial infarction (MI), stroke, HF, and all-cause mortality.15 Prognostic impact of LVH has been reported in different ethnic groups. A sub-group
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analysis of the ARIC (Atherosclerosis Risk In Communities) prospective cohort study reported a significantly increased risk of CVD in African-American subjects with LVH .78 A prospective cohort study, The Northern Manhattan Study, confirmed a similar pattern among HispanicAmericans by showing a significant association between LV mass and CVD morbidity.79 Women, in general, have a lower incidence of CVD morbidity compared to men as in ischemic heart disease; however, the incidence of HF, atrial fibrillation (AF), or stroke were more commonly reported in women.80–82 A community-based prospective cohort study, including 12,329 subjects with HTN, investigated the impact of LVH on gender-specific CVD 13
Journal Pre-proof morbidity profile. In this study, LVH was more commonly reported in women than men (43.4% vs. 32.1%; p<0.001). The presence of obesity and diabetes put both men and women at risk for LVH; however, women had a higher risk of LVH. Lower risk for major CVD events (composite of acute coronary syndrome, stroke, decompensated HF, and incident AF) was seen in HTN women compared to men in the absence of LVH (HR: 0.65; 95% CI: 0.44 to 0.96; p=0.031). However, this gender difference was erased in the setting of LVH. Women with HTN had a
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comparable major CVD event risk compared to men in the presence of LVH (HR: 0.94; 95% CI:
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0.69 to 1.30; p=0.720).83
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Cardiovascular and All-cause Mortality
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In a large retrospective study on a clinical population (n=35,602) referred for
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echocardiography, Milani et al. found a significant association between CR or LVH (concentric or eccentric) and increased risk of all-cause mortality (RR: 1.99; 95% CI: 1.88 to 2.18; p<0.0001
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and RR: 2.13; 95% CI: 1.89 to 2.40; p<0.0001, respectively). Compared to the other geometric
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patterns, cLVH carried a higher mortality risk. They further showed that prognosis was dynamic
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in response to the changes in LV geometry, as the reversal of CR to a normal geometric pattern improved survival (RR: 0.64; 95% CI: 0.42 to 0.97; p=0.03).84 Several studies have indicated a link between abnormalities in LV geometry and the risk of sudden cardiac death (SCD). A report from Oregon Sudden Unexpected Death Study, a population-based case-control study, showed a significant association between abnormal LV geometric patterns by echocardiography and increased risk of SCD (OR: 3.20, 2.47, 1.76 for cLVH, eLVH, and CR; respectively).85 A prospective cohort study from Italy evaluated SCD risk factors in relatively young and untreated HTN patients (n=3,242) without established CVD over an average 10-year follow up. Despite an overall low SCD event rate (~0.1%) in the study 14
Journal Pre-proof population, electrocardiographic LVH almost tripled the risk of SCD even after adjustment for sex, age, DM, and 24-hour ambulatory BP (HR: 2.99; 95% CI: 1.47 to 6.09; p=0.002).86 Heart Failure To emphasize the progressive nature of HF and the importance of prevention, the 2013 ACC Foundation/AHA guideline for the management of heart failure considers HTN and LVH
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as stage A and stage B HF, respectively.87 This staging also highlights the importance of these
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risk factors in the pathophysiology of HF.
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Traditional models of HF include one whereby sustained pressure overload results in an
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increased LV mass and RWT with consequent impairment of LV compliance and elevates filling pressures. In contrast, sustained volume overload remodels the heart by dilation in the LV with a
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RWT in the normal range.88 However, a new line of evidence has challenged this understanding.
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Sustained BP overload can cause distinct LV remodeling patterns at different parts of the heart (e.g., cLVH in the septum and eLVH in the lateral wall).89 Further, some epidemiological studies
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reported a higher prevalence of eLVH compared with cLVH in patients with HTN and also
disease (CAD).90
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failed to show the transition from cLVH to HF reduced EF without evidence of coronary artery
The most recent ASE document on the evaluation of LV diastolic dysfunction considers LVH with HTN as an indicator of diastolic dysfunction.91 Moreover, LVH has also been associated with the risk of development of systolic dysfunction. 92 A retrospective study by Milani et al. found that 13% of HTN subjects with cLVH (n=1,024) developed systolic dysfunction after an average of 33 ± 24 months of follow- up. Variables associated with this progression were interval MI, prolonged QRS interval (>120 ms), and elevated arterial
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Journal Pre-proof impedance (>4.0 mm Hg/ml/m2 ).93 Similar results were observed in a retrospective study by Krishnamoorthy et al. In their study, progression from LVH to systolic dysfunction occurred in 20% patients (over ~7.5-year of follow-up), but noted that was particularly rare in the absence of interval MI.94 Detectable troponin-T or elevated N-terminal pro-B type natriuretic peptide have been shown to predict future risk of HF among subjects with LVH (20.6% vs. 5.8% for detectable vs.
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undetectable troponin-T; 20.2% vs. 6.5% for elevated vs. normal N-terminal pro-B).95
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Coronary Artery Disease
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The population-based Dallas Heart Study (n=2,633) investigated the relationship between LVH by cardiac MRI and coronary artery calcium score (CACS) by computerized tomography.
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In a multivariable linear regression analysis, LV mass remained significantly associated with the
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quantity of CACS (β 0.32; p<0.001).96 A recent small cohort study among 132 subjects with stable angina and non-obstructive CAD, who underwent myocardial contrast stress
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echocardiography to measure the extent of myocardial ischemia, reported a significant
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association between LVH and risk of myocardial ischemia (OR: 3.27; 95% CI: 1.11 to 9.60; p=0.031).97 Furthermore, LVH was associated with increased CVD mortality after percutaneous coronary interventions. This finding highlights the prognostic impact of LVH in patients with established CAD.98 A retrospective observational study involving patients with ST-segment elevation MI (n=481) managed with successful primary percutaneous coronary intervention investigated the effect of LVH on long-term prognosis. The investigators reported a significant association between LVH and increased risk of all-cause mortality (OR:2.37; 95% CI: 1.09 to 5.12; p=0.028). Furthermore, severe LVH (defined as ≥149 g/m2 in male and ≥122 g/m2 in female) was associated with an even higher risk of mortality. (OR: 5.11; 95% CI: 1.45 to 17.9; 16
Journal Pre-proof p=0.001).99 A sub-study of the DANAMI-3 (DANish Study of Optimal Acute Treatment of Patients With ST-elevation Myocardial Infarction) trial involving ST-segment elevation MI patients (n=764) managed with successful primary percutaneous coronary intervention reported that LVH by cardiac MRI was significantly associated with larger final infarct size, smaller final myocardial salvage index, and higher incidence of microvascular obstruction.100
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Arrhythmias
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LVH increases the risk of cardiac arrhythmias. In a retrospective study among subjects with untreated HTN (n=2,482), each standard deviation increase in LV mass was associated with
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a 20% increase in the risk of AF (95% CI; 1.07 to 1.34; p=0.001).101 Hypertensive LVH was
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also significantly associated with the progression of AF from paroxysmal to persistent and
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permanent (OR: 4.84; 95% CI: 1.70 to 13.78; p= 0.003).102 Fortunately, in a small prospective study by Hennersdorf et al., regression in LV mass with anti-HTN treatment led to a significant
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decrease in the prevalence of AF from 12.5% to 1.5% (p=0.05).103
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Other than AF, LVH has been associated with ventricular and supraventricular
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arrhythmias. A meta-analysis involving 27,141 subjects revealed a 2.8-fold higher odds of developing ventricular tachycardia or fibrillation and 3.4-fold higher odds of developing supraventricular tachycardia in the presence of LVH.104 Cerebrovascular Disease An analysis on Framingham Heart Study participants (n=1,230, age >58 years, ~8-year follow-up) found that subjects in the highest quartile of LV mass to height ratio had a 2.7 times higher risk of cerebrovascular disease when compared to those in lowest quartile after adjustment for other variables.105 A retrospective cohort study, which included young ischemic 17
Journal Pre-proof stroke survivors (< 60-year-old) reported abnormal LV geometry in 37% of study subjects (21% had CR, and 16% had LVH).106 Bluemke et al. examined the association between LV mass by cardiac MRI and the risk of future stroke risk in 5,098 subjects enrolled in the prospective MESA study. Their analysis revealed a significant association between LV mass index and stroke risk after adjustment for other variables (HR: 1.2; 95% CI: 1.0 to 1.4; p=0.01).107
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Dementia
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There exists a link between LVH and increased risk of impaired cognitive performance. In a population-based study of subjects age >74 years old, echocardiographic LVH was found to
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predict cognitive decline over a 5-year follow-up.108 In the ARIC study (n=12,665),
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electrocardiographic LVH was associated with a markedly higher risk of dementia during a
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median of 18-year follow-up (HR: 1.90; 95% CI: 1.47 to 2.44).109 Similarly, a report on 4,999 MESA study participants (median follow-up of 12-years) revealed that LV mass index and LV
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mass to volume ratio (indicator of cLVH) by cardiac MRI were independently associated with
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increased risk of dementia (HR: 1.01; 95% CI: 1.00 to 1.02 and HR: 2.37; 95% CI 1.25 to 4.43,
Treatment
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respectively).110
Impact of Treatment In the 1990s, an investigation on subjects from the Framingham Heart Study demonstrated significant improvement in CVD morbidity by the regression of electrocardiographic LVH over time (OR: 0.46; 95% CI: 0.26 to 0.84).111 Subsequent landmark trials in the early 2000s such as MRFIT (Multiple Risk-Factor Intervention Trial), HOPE (Heart Outcomes Prevention Evaluation), and LIFE confirmed the possibility of LV regression in 18
Journal Pre-proof response to anti-HTN therapy and related CVD prognostic benefits.8,9,112 A recent report from SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated that, compared to standard SBP control (<140 mmHg), intensive SBP control (<120 mmHg) was associated with a 46% lower risk of developing ECG-LVH in participants without baseline LVH and 66% higher likelihood of regression/improvement of LVH in participants with baseline LVH.113 The ratio of regression in LV mass with anti-HTN therapy varies significantly depending
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on the population studied.114 The predictors of persistent LVH and lack of LVH regression with
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anti-HTN therapy are older age, central obesity, higher body mass index, kidney disease,
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suboptimal BP control, and longer duration of HTN.115,116 Therefore, to avoid irreversible LVH,
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anti-HTN therapy should be started early with an appropriate BP goal and simultaneous
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management of related comorbidities such as obesity.
The 2018 ESH/ESC guideline for the management of arterial HTN recommend (Grade
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1A and Grade IIA) that all patients with HTN and LVH should be treated with RAAS inhibitors
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in addition to calcium channel blockers (CCBs) or diuretics with a target SBP goal of 120-130
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mm Hg.12 Non-Pharmacological
In the early 1980s, a small randomized clinical trial (RCT) which enrolled overweight participants with HTN, revealed a significant regression in LV mass (up to 24%) in response to weight reduction with lifestyle changes. This significant association between LV mass and weight reduction was independent of change in BP.117 Furthermore, in a meta-analysis of 1,022 obese subjects, bariatric procedures were associated with a significant decrease in LV mass, RWT, and left atrial diameter, with a corresponding improvement in diastolic dysfunction.118
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Journal Pre-proof Lifestyle changes can also decrease the future risk of incident LVH in patients with HTN. In a prospective study of HTN subjects (n=454) without baseline LVH, regular aerobic exercise was shown to improve BP and reduce the risk of LVH development during 8.3 years of followup (10.3% for sedentary; 1.7% for active; p<0.001).119 Landmark Studies All major anti-HTN drug classes, including diuretics, CCBs, β-blockers, angiotensin-
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converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) have been
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shown to regress LVH secondary to HTN.
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In the early 2000s, the HOPE trial showed that compared to placebo, treatment with
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ramipril led to regression or prevention of LVH and reduction of CVD mortality, MI, and stroke
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risks (12.3% vs. 15.8% for regression/prevention of LVH vs. development/persistence of LVH; p=0.006).8 Losartan was compared to atenolol in the randomized LIFE trial, which enrolled
na
9,193 HTN participants with electrocardiographic LVH. Losartan reduced the severity of LVH
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and prevented adverse CVD outcomes better than did atenolol (HR: 0.87; 95% CI: 0.77 to 0.98; p=0.021). In addition, losartan use was associated with a 25% lower risk of new-onset DM (HR:
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0.75; 95% CI: 0.63 to 0.88; p=0.001).9 Subsequent analysis from the LIFE study by Okin et al. reported a 12.2% lower rate of new-onset AF proportional to electrocardiographic LVH regression (for every 1050 mm x msec (per 1-SD) lower Cornell product) independent for BP reduction or medication (HR: 0.88; 95% CI: 0.80 to 0.97; p=0.007).120 In the PRESERVE (Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement) trial, enalapril was compared to long-acting nifedipine among HTN participants with LVH (n=202). Treatment with enalapril led to a moderate regression in LV mass with no significant difference between the two drug classes (26 g vs. 32 g; p=0.36).121
20
Journal Pre-proof Pitt et al. compared a selective aldosterone blocker, eplerenone, to enalapril in a doubleblind RCT among HTN patients with LVH and reported similar degrees of LVH regression with enalapril and eplerenone.122 They also found that compared to eplerenone alone, the combination of enalapril and eplerenone was more effective in reducing LV mass. Other trials have explored the idea of combination therapy; the ADVANCE (Action in Diabetes and Vascular Disease Study) trial showed that a fixed combination of long-acting ACE inhibitor -perindopril- and a
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thiazide-like diuretic -indapamide- had additive CVD morbidity and mortality benefits. An
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echocardiographic sub-study of the ADVANCE trial also showed a reduction in LV mass index
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by 2.7 g/m2 (95% CI: -5.0 to -0.1; p=0.04) among those treated with this fixed combination.123 The landmark ALLHAT trial and subsequent ALLHAT-HF validation study endorsed the
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superiority of chlorthalidone over amlodipine, lisinopril, or doxazosin in preventing HF.124,125
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Subsequent posthoc analysis of ALLHAT revealed that reduction in LVH along with a reduction
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in BP by chlorthalidone explained up to 13% of its HF prevention effect compared to other antiHTN drug classes in the study.126
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The landmark PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-
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Neprilysin Inhibitors with an ACE inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial showed a more substantial reduction in CVD morbidity and mortality for sacubitril/valsartan treatment compared to enalapril. 127 Vasodilation and antiproliferative effects of sacubitril might explain some aspects of superiority. Schmieder et al., in a double-blind, multicenter RCT involving participants with HTN, reported that sacubitril/valsartan provided a more significant reduction in LV mass compared to olmesartan which might contribute to the superiority of sacubitril in terms of its favorable outcomes. 128 Furthermore, a recently published meta-analysis of 20 studies (16 non-RCTs and 4 RCTs)
21
Journal Pre-proof revealed a significant regression in LV mass with sacubitril/valsartan treatment compared to ACE inhibitors or ARBs among subjects with HF with reduced EF.129 Meta-Analyses A meta-analysis involving 80 double-blind RCTs, including all major drug classes and echocardiographic assessment of LV mass, showed a significant reduction in the LV mass index
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by 13% with ARBs, 11% with CCBs, 10% with ACE inhibitors, 8% with diuretics, and 6% with
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β-blockers. The pairwise comparison analysis reported ARBs, CCBs, and ACE inhibitors to be more effective compared with β-blockers; however, diuretics were not included in the pairwise
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comparison analysis.130 The design for the meta-analyses was criticized because each treatment
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arm of the included studies was considered as a separate observation despite the original
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comparative designs. Fagard et al. conducted a meta-analysis of 75 RCTs using a pooled pairwise comparison of each drug class versus other classes along with meta-regression analysis.
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In this analysis, β-blockers reduced LV mass significantly less than ARBs (9.8% vs. 12.5%;
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p=0.01) and were found to be a significant negative predictor of the regression (-3.6%; p<0.01).
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Overall, the inferiority of β-blockers was more prominent than the superiority of ARBs.114 The mechanism behind the marked decrease in LV mass by ARBs, ACE inhibitors, or CCBs might be explained by 1) activation of RAAS stimulates myocardial cells growth; 2) increase in plasma angiotensin II level is independently associated with LVH; and 3) sympathetic nerve activity is stimulated through N-type calcium channels.131–133 On the other hand, the minimal decrease by β-blockers might be explained by a smaller reduction in central aortic BP and a more significant reduction in heart rate. Both of these factors result in a relatively increased LV end-diastolic diameter with subsequently increased LV wall stress.134
22
Journal Pre-proof A meta-analysis by Roush et al. which combined the data of diuretic arms in 38 RCTs compared the efficacy of hydrochlorothiazide and “CHIP” diuretics (CHlorthalidone, Indapamide, and Potassium‐ sparing diuretic/hydrochlorothiazide). Their results revealed that “CHIP” diuretics reduced LV mass 2-fold more than hydrochlorothiazide.135 Subsequent headto-head systematic review involving 12 double-blind RCTs reported that “CHIP” diuretics were better than RAAS inhibitors in the reduction of LV mass.136
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Future Directions
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DM is a major risk factor for cardiac remodeling and LVH. SGLT2 inhibitors are
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relatively novel anti-diabetic agents with added benefits of BP and weight reduction.137,138
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Landmark trials, EMPA-REG Outcomes (Empagliflozin, Cardiovascular Outcomes, and
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Mortality in Type 2 Diabetes) and CANVAS (The Canagliflozin Cardiovascular Assessment Study) demonstrated beneficial effects of empagliflozin and canagliflozin on CVD morbidity and
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mortality, respectively, especially HF.139,140 To assess whether regression of LV mass could
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explain the potential mechanism behind the benefit in CVD morbidity and mortality with SGLT2 inhibitors, various small trials are still in progress, such as DAPA-LVH, EMPATROPHY,
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EMPA-HEART, and NCT0295691.141 Potential mechanisms for LV mass reduction by SGLT2 inhibitors include 1) decrease in LV wall stress secondary to diuresis and natriuresis which translates into reduced LV wall stress; and 2) suppression of sodium-hydrogen exchange in cardiomyocytes which impacts cardiac remodeling.142,143 In a non-diabetic rodent model of HF with preserved EF, Empagliflozin was shown to reduce the LV mass without affecting BP, which led to improving diastolic dysfunction.11 Animal model studies have shown regression of LVH by xanthine oxidase inhibitors by reducing oxidative tissue stress, which mediates myocardial hypertrophy.144,145 RCTs showed 23
Journal Pre-proof that allopurinol, a xanthine oxidase inhibitor, contributed to significant regression in LVH without a change in BP in adult patients with CAD, CKD, or DM.146–148 Renal sympathetic denervation was an exciting innovation for the treatment of resistant HTN until the single-blind Symplicity HTN-3 RCT failed to show a significant reduction in BP in the therapeutic arm.149 However, a recent meta-analysis involving 12 observational, but no prior RCTs, reported a significant decrease in LV mass index by cardiac MRI with renal
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sympathetic denervation (-5.43 g/m2 ; 95% CI: -10.1 to -0.35 g/m2 ).150
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Conclusions
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LVH is a leading risk factor for CVD morbidity and mortality, stroke, cognitive impairment, and all-cause mortality. Elevated BP, at HTN and pre HTN stages, is a major
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contributor to LV remodeling, including CR, cLVH, and eLVH. ECG and 2D echocardiography
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are the primary diagnostic tools for the diagnosis and quantification of LVH. Evolving 3D echocardiography technologies provide more accurate and reproducible measurements but are
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still relatively new, and ongoing studies to determine standard reference values are underway.
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Cardiac MRI is not only superior to other techniques in the quantification of LVH, but also helpful with distinguishing different types of LVH, yet can be costly and time-consuming. BP control with lifestyle changes and anti-HTN agents can lead to the prevention or regression of LVH. RAAS inhibitors with CCBs or diuretics are the guideline-directed treatments with wellknown survival benefits through the regression of LVH. Multiple clinical trials are currently underway to understand the impact of SGLT2 inhibitors on LV mass in DM patients with or without HTN.
24
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Journal Pre-proof Figure Legends Figure: 1: Central Illustration. Overview of left ventricular hypertrophy. Figure 2: Left ventricular geometric patterns determined by relative wall thickness and left ventricular mass index based on linear measurements. LVH, left ventricular hypertrophy. Adapted from Konstam et. al.151
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Figure 3: Left ventricular geometric patterns determined by 2D echocardiography linear method.
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Legend: Parasternal long-axis view demonstrating end-diastolic linear measurements of left
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ventricular (LV) internal diameter (LVID), LV septal wall (SW) thickness, LV posterior wall
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(PW) thickness. * interventricular septum, ∞ LV cavity, & LV inferolateral wall. Normal Geometry: 23-year-old male, LVID of 5.31 cm, LV SW of 1.08 cm, LV PW of 1.01
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cm, LV mass index of 112 g/m2 , relative wall thickness (RWT): 0.38.
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Concentric Remodeling: 50 year-old male, LVID of 4.19 cm, LV SW of 1.19 cm, LV PW of
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1.26 cm, LV mass index of 88 g/m2 , RWT: 0.60.
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Concentric LV hypertrophy (LVH): 57-year-old male, LVID of 5.31 cm, LV SW of 1.08 cm, LV PW of 1.01 cm, LV mass index of 144 g/m2 , RWT: 0.64. Eccentric LVH: 40-year-old male, LVID of 7.48 cm, LV SW of 1.19 cm, LV PW of 1.21 cm, LV mass index of 222 g/m2 , RWT: 0.32.
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Journal Pre-proof Table 1: 3D Echocardiography Derived Normal Reference Values of Left Ventricular Mass Index
Fukuda et al. (2012) Japanese 410 (253/157)
The ethnicity of the study population Number of subjects (Male/Female)
Muraru et al. (2013)
Mizukoshi et al. (2016)
European white 226 (101/125)
Japanese 230 (121/109)
American 160 (78/82)
Mass index (g/m2 ) 64 ± 12
77 ± 10
69 ± 8
70 ± 9
Women (Mean ± SD)
56 ± 11
74 ± 8
61 ± 8
60 ± 7
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Men (Mean ± SD)
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Table 2:
Differential Diagnosis of Left Ventricular Hypertrophy Physiological left ventricular hypertrophy Athlete's heart
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Secondary left ventricular hypertrophy Hypertensive heart disease Aortic stenosis Systemic diseases Cardiac amyloidosis Mitochondrial myopathy Fabry disease Pompe disease Danon disease
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Pathological left ventricular hypertrophy Primary left ventricular hypertrophy Hypertrophic cardiomyopathy
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Journal Pre-proof
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Conflict of interest: None.
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Figure 1
Figure 2
Figure 3