What Is Left Ventricular Hypertrophy and Is There a Reason to Regress Left Ventricular Hypertrophy?

Left ventricular hypertrophy (LVH) is associated with an increased incidence of congestive heart failure, ventricular arrhythmias, myocardial infarction, carotid arthrosclerosis, cerebrovascular events, and sudden cardiac death.1–5 Given these important epidemiologic relationships, what is it about an increase in left ventricular mass (LVM) that leads to so much associated cardiovascular morbidity and mortality? A better understanding about this question may assist in the development of rational strategies to reduce the associated cardiovascular event rate risk. There is some debate with regard to the primary etiology of LVM increase because there are likely both blood pressure (BP)–dependent and BP-independent mechanisms involved. What may be most important are the physiologic relationships between the left ventricle and both aortic and peripheral vascular beds. Ventricular vascular coupling is an important physiologic consideration that may explain cardiac enlargement. One must consider that the aorta is an extension of the left ventricle. With each systolic contraction of the left ventricle, the blood is delivered into the elastic conduit vessel, the aorta. The aorta distends and subsequently recoils, facilitating the movement of the blood into distal arterial and arteriolar beds. The damping effect of the aorta on the ejected blood reduces systolic BP and changes the flow of blood from pulsatile to a smoother more consistent flow. The greater the viscoelasticity of the aorta, the lower the systolic BP and the smoother the blood flow. However, with increasing age and the presence of comorbidities such as diabetes, the aorta stiffens as viscoelasticity declines.6 As a result, there is less of a cushioning effect of the aorta with each systolic contraction of the heart. Systolic BP rises, blood flow is more pulsatile, and the transmitted pulse wave velocity increases. In a young, less stiff circulation, the typical pulse wave velocity measured as carotid to femoral pulse wave travel may be 6 or 7 m/s. As the pulse wave moves distally from the central aortic circulation, it reflects off the many bifurcations, trifurcations, and narrower regions throughout the distal arterial and arteriolar circulation.7 As the pulse wave is reflected, it returns to the central circulation and, when arriving early in diastole, this assists in the delivery of blood to the coronary circulation (which has virtually no blood flow during each systolic contraction of the heart). This ventricular vascular coupling assists in maintaining coronary blood supply and limits the risk for ischemia. However, with aging of the circulation, loss of aortic viscoelasticity, pulse wave velocity increases and its consequent reflective wave returns much earlier, each during late systole.8–10 As a result, there is an augmentation of the central aortic systolic BP from the arrival of reflected pulse wave in late systole.11 This dramatically increases workload of the heart and may be one of the most important factors leading to ventricular hypertrophy. In addition, with the pulse wave returning much earlier, it no longer coincides with early diastole to facilitate coronary perfusion. Consequently, this series of events related to impaired ventricular vascular coupling can increase the risk for coronary ischemia.12 It is likely that factors which lead to loss of viscoelasticity of the aorta, and consequent ventricular vascular coupling impairment, may be among the most important issues leading to LVH. As such, therapeutic considerations that improve ventricular vascular coupling may be the ideal strategy to facilitate regression of LVH and perhaps also modify some of the associated cardiovascular risks associated with cardiac enlargement.13 Why is it that some observers note that LVH is associated with increased cardiovascular morbidity and mortality independent of hypertension (or coronary artery disease)? There are a number of reasons to consider with respect to these epidemiologic observations. When considering “hypertension” one has to be careful how one uses this term. Typically, we utilize brachial artery cuff measurements as a biomeasure of systemic BP. In fact, although this has proved to be useful for many decades as a predictor for cardiovascular morbidity and mortality, we now realize that brachial BP may not accurately reflect the ambient pressure within the central aortic circulation.14 The peripheral arterial and arteriolar vascular beds have a relatively high wall to lumen ratio relative to the aorta. As a consequence, loss of viscoelasticity in these beds is less likely to alter pressure and flow relationships compared with the magnitude of these stiffening changes that occur within the central aortic circulation.8,9,15,16 Thus, the peripheral cuff BP measurements are more likely to remain stable whereas those within the central circulation are more likely to change with age and vascular disease. As such, central aortic pulse pressure measurements (aortic systolic–aortic diastolic BP) may be a better way to evaluate risk for left ventricular enlargement as opposed to brachial artery cuff BP measurements. As we will discuss, the pharmacologic reduction of central aortic pulse BP measurement may also be helpful to identify therapeutic strategies to regress of LVH. The reported independence of LVH and the presence of coronary artery disease also needs some perspective. It depends, in large part, on the definition and the sophistication of the testing to assess the relationship between cardiac enlargement and coronary artery disease. There are also many confounding relationships such as lipids, age, diabetes, and unknown factors that affect this relationship. Impaired ventricular vascular coupling and cardiac enlargement also explains some of the observed relationships between kidney disease and cardiovascular disease. One has to consider that the coronary, carotid, and renal arteries all emanate from the central aortic circulation. It is therefore not surprising that central aortic pulse pressure may similarly affect all 3 circulations. For example, LVH is associated with a substantial risk for cerebrovascular disease.5 One has to wonder whether therapeutic strategies that reduce central aortic pulse pressure or facilitate viscoelasticity or “destiffening” of the aorta, may provide more opportunity for reducing cardiovascular morbidity and mortality. Pharmacologic reduction of brachial artery BP, weight loss, and modification of dietary sodium intake has been reported to facilitate reduction in LVM.17–19 Might these strategies also facilitate improvement in ventricular vascular coupling and reduce central aortic pulse pressure?6 Variation in dietary sodium or potassium content could affect neurohormonal responses and reactive oxygen species production with consequent effects on aortic viscoelasticity. Likewise, there may be similar effects of exercise and weight loss. More studies are needed! Medications that are used to lower brachial artery cuff BPs to a similar degree are not always equivalent in reducing LVM.17,19 In a meta-analysis of clinical data, LVM index appears to be more effectively reduced by drugs that block the renin-angiotensin system compared with other strategies.17,19 The presumed mechanism is thought to be related to inhibition of angiotensin II–induced myocyte cell growth and other possible pleiotropic factors. Others have suggested that aldosterone inhibition assists in reducing collagen content in the myocardium and reduces scarring and fibrosis. Perhaps an alternative mechanism of mineralocorticoid receptor blockade benefit is facilitation of aortic viscoelasticity and more effective reduction of central aortic pulse pressure? Calcium antagonists also appear to be effective in reducing LVM.17 Is this a central or peripheral BP-lowering phenomenon? Or might these medications be more effective in improving aortic viscoelasticity. Some clinical data from the Conduit Artery Function Evaluation (CAFÉ) substudy20 of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)21 indicates that calcium antagonists in conjunction with renin-angiotensin system blockers (angiotensin-converting enzyme [ACE] inhibitors) are more effective in reducing central aortic BP compared with a treatment regimen incorporating β-blockers and thiazide diuretics, despite the fact that similar levels of brachial artery BP measures were obtained during the course of the study. Might this observation explain the more substantial reduction in cardiovascular morbidity and mortality observed with the calcium antagonist/ACE inhibitor regimen in this study? Likewise, brachial artery BPs were nearly identical in the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) study,22 yet a calcium antagonist and renin-angiotensin system–blocking regimen proved to be more effective in reducing cardiovascular morbidity and mortality compared with the same ACE inhibitor coupled with a thiazide diuretic. Might there be differences in ventricular vascular coupling and central aortic pulse pressure between these regimens of medications? Also intriguing is the observation that β-blockers, despite comparable effects in reducing brachial artery BP, as other medications, are less effective in reducing LVH.16 Might this also indicate less effective reduction of central aortic pulse pressure?19 Could this explain why older patients treated with β-blockers despite gaining the negative chronotropic benefits of these drugs on risk for ischemic heart disease appear to be more susceptible to cerebral vascular disease events?22 Could this be the result of a less effective reduction in central aortic pulse pressure? In perspective, given the improved technology available in clinical practice for measuring central pulse aortic pressure and pulse wave velocity, more longitudinal studies are needed to correlate central BPs, brachial artery BPs, LVM, and the incidence of end organ events related to the 3 key central aortic pressure circulations: coronary, carotid, and renal. Ultimately, understanding more about these relationships may assist in the rational choice of not only more appropriate levels of BP (measured both centrally and peripherally), but perhaps also the use of diet, exercise, and traditional antihypertensive medications, as well as the development of novel agents, which may be more specifically targeted to improve viscoelasticity of the central aorta. Thus, there may be opportunity for specific strategies to reduce further cardiovascular morbidity and mortality, which we could correlate with changes in LVM.23