Left Ventricular Hypertrophy the Problem and Possible Solutions

The Journal of International Medical Research 2005; 33 (Suppl 1): 3A 11A Left Ventricular Hypertrophy the Problem and Possible Solutions P GOSSE Cardiology Service Arterial Hypertension, Hospital Saint-André, Bordeaux, France Left ventricular hypertrophy (LVH), which describes pathological changes in cardiac structure, is a powerful and reversible predictor of cardiovascular risk. There is a continuous relationship between left ventricular mass (LVM) and the likelihood of cardiovascular events, with no cut-off between the absence of such events and heightened risk. A correlation between LVH and blood pressure is well established. There is a paradox, however, that the structural changes to the heart as a result of increased workload due to high blood pressure appear to promote cardiovascular disease. This may be partially explained by the fact that ambulatory blood pressure measurements correlate more closely with LVH than resting blood pressure. Blood pressure variation throughout the day is also emerging as an important correlate of LVH, and a strong association has been identified between an early morning rise in blood pressure and increased LVM. Use of anti-hypertensive agents not only lowers blood pressure, but can also bring about LVH regression. The pathological role of angiotensin II in LVH and target-organ damage within the cardiovascular continuum suggest that agents targeting the renin angiotensin aldosterone system (RAAS), such as the angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, may prove particularly effective and may confer beneficial effects in addition to the lowering of blood pressure. The angiotensin II receptor blockers may be very appropriate treatment options because of their placebo-like tolerability and the possibility of more complete blockade of the RAAS. Within this class of anti-hypertensive agents, pharmacological differences may mean that some agents afford greater cardioprotection than others. KEY WORDS: LEFT VENTRICULAR HYPERTROPHY; LEFT VENTRICULAR MASS; PATHOPHYSIOLOGY; HYPERTENSION; TREATMENT; ANGIOTENSIN II RECEPTOR BLOCKERS Introduction Left ventricular hypertrophy (LVH) is, in simple terms, an adaptive response to chronic exposure of the heart to an increased workload, a common cause being systemic hypertension. At the cellular level, the cardiomyocytes expand in thickness and length, but with little or no increase in the number of cells, to compensate for the increased haemodynamic stress on the ventricular wall. 1 In addition, as distinct from the hypertrophy seen in growth and as a result of exercise and physical training, fibroblasts proliferate with abnormal accumulation of collagen, leading to fibrosis. 1 The overall 3A

effect of these histological changes is an increase in left ventricular mass (LVM). In LVH, normal cardiac function becomes compromised. 2 The accumulation of fibrillar collagen within the adventitia of the intramyocardial coronary arteries and interstitial spaces brings about ventricular stiffness and decreases coronary flow reserve. Increased ventricular stiffness can lead to abnormal diastolic function and heart failure, with preserved systolic function. 3 The decreased coronary flow reserve increases the risk of cardiac ischaemia, potentially lethal cardiac arrhythmias and myocardial infarction. 4 In addition, the fibrosis disrupts the electrical and mechanical behaviour of the hypertrophied myocardium. Reduced cardiac contractility may finally occur as a result of increased workload and myocardial ischaemia. Left ventricular hypertrophy is widely recognized as a powerful, but reversible, risk factor for cardiovascular morbidity and mortality. Indeed, after age, LVH is the single strongest predictor of cardiovascular events, cardiovascular death and total mortality. 5 Epidemiological studies have shown that LVH is an independent risk factor for cardiovascular morbidity and mortality and for all-cause mortality in the general population, 6 as well as in individuals already at higher risk, such as those with hypertension 7 or coronary artery disease. 8 The risk is magnified even in hypertensive individuals with increases in echocardiographically detected LVM too small to be defined as LVH. 9,10 Findings from the Bordeaux cohort who were initially untreated reinforce this correlation (Fig. 1) and confirm that very small increases 1.0 LVM/h 2.7 quintiles 5th = 77 4th = 60 3rd = 52 2nd = 44 1st = 35 Event-free survival ratio 0.9 0.8 0.7 0.6 0.5 0 100 200 Follow-up (months) FIGURE 1: Age-, sex-, and blood pressure-adjusted event-free survival curves for left ventricular mass (LVM) indexed to height to the power 2.7 in 520 patients of the Bordeaux cohort followed up over 102 ± 42 months with 56 cardiovascular events recorded 4A

in LVM still impact on cardiovascular risk, independently of other variables. 11 Screening for LVH Diagnosis of LVH is not a simple matter. LVH is undetectable on physical examination. 3 Using voltage criteria and QRS duration, electrocardiograms can identify LVH with high specificity, but poor sensitivity. 12 Repolarization abnormalities (ST changes) are frequent, but can be regarded as a witness of reduced perfusion of the internal layers of the myocardial wall rather than being a specific marker of LVH. 13 Echocardiography, which is about eight-fold more sensitive, 14 has become the reference method to detect LVH. It provides a safe and noninvasive method for evaluating cardiac anatomy and function, and has been extensively used in clinical trials. More recently, magnetic resonance imaging has been developed that allows high-resolution visualization of the entire heart and gives an accurate measurement of LVM, in a manner that is independent of shape or perfusion. 15 The technique, which provides interstudy reproducibility in normal, dilated and hypertrophic hearts and is superior to twodimensional echocardiography, 16 is now accepted as the method of choice for LVM determination in clinical investigations and for serial evaluation of selected patients. As yet, it is not routinely used for diagnosis. The definition of LVH depends on the method by which the LVM is indexed (i.e. height, body surface area or height to the power 2.7, which appears to be particularly sensitive). 17 The cut-off proposed in the literature displays important differences between one study and another, 17 and the definition of the cut-off from the analysis of normal populations may not provide the most useful criterion. In the light of large variability in LVM measurements provided by echocardiography even in normal subjects, the calculation of the 95th percentile usually leads to a high cut-off value. Consequently, LVH is better defined in terms of risk prediction, there being a strong link between increased LVM and increased incidence of cardiovascular complications. 6 LVH and hypertension Numerous studies have demonstrated a correlation between LVM and blood pressure. This is logical as increased LVM can be regarded as a response to greater workload associated with high blood pressure, and could be considered a useful adaptation to a chronic increase in myocardial strain. There is, however, a paradox that LVH appears to promote cardiovascular disease. Three possible explanations have been proposed. 18 One possibility is that, as a marker of cardiovascular risk, LVH integrates the effect of various factors the main one being blood pressure with these effects being integrated over time. Two arguments support this hypothesis: first, LVH is a risk factor for not only cardiac disease but also for other cardiovascular events, such as stroke; 19 secondly, ambulatory blood pressure measurements correlate more closely with LVH than resting blood pressure, as discussed later. The second hypothesis is that, although LVH is an adaptive process, it is limited. The initial advantages of lowering parietal stress may be gradually overridden by the stimulated myocyte growth and the consequent remodelling of the left ventricular chamber. 1 This hypothesis, however, is not supported by the observation that the correlation between LVM and cardiovascular risk is continuous, with no obvious threshold. 11 The third hypothesis is that there is a clear distinction between physiological and pathological LVH from the outset. The proliferation of interstitial tissue and 5A

accumulation of collagen is possibly stimulated by different mechanisms to those causing myocyte hypertrophy. 16 Systolic blood pressure is more closely related to LVM than diastolic blood pressure. Other haemodynamic factors that can contribute to LVH include increased arterial stiffness of the aorta 20 and increased blood viscosity, 21 both of which increase the workload of the heart, and thus stimulate hypertrophic changes. Other factors may contribute to LVH; for example, the prevalence of LVH correlates strongly and independently with alcohol consumption, obesity and age. 18 Increased LVM correlates even more closely with 24-h mean ambulatory blood pressure than with isolated clinic measurements (Table 1). 22 26 As a result, 24-h mean values of ambulatory blood pressure are now regarded as more sensitive predictors of LVH. 27 Furthermore, treatment-induced reductions in LVM are reflected in corresponding reductions in 24-h mean blood pressure, but correlation between 24-h mean blood pressure and LVM is still relatively weak. 26 Other parameters, such as blood pressure recorded during activity, the difference between daytime and night-time values, and blood pressure recorded when the subject arises in the morning, have been proposed as being of greater prognostic value. 28 Most people, including those with hypertension, display a circadian variation in blood pressure, with levels being highest during the day and lowest in the middle of the night. 28 At the time of awakening, there is a surge in blood pressure. 29 This rapid elevation in blood pressure is accompanied by an acceleration in cardiac rhythm, with no significant correlation between the two parameters. The increase in blood pressure on rising has been linked to the overall variability in blood pressure, but appears independent of the mean blood pressure over 24 h. 29 In previously untreated patients with hypertension, both LVM and left ventricular wall thickness correlate with systolic blood pressure on arising. Two other studies have found that in treated and untreated hypertensive patients with a morning surge in blood pressure, LVM indexes are significantly higher. 30,31 It is interesting to note that the time of the early morning surge in blood pressure coincides with the peak incidence of acute cardiovascular events, 32 thus providing further evidence for the link between early morning blood pressure surge TABLE 1: Studies examining the relationship between clinic and ambulatory systolic blood pressures (SBP) in hypertensive subjects and left ventricular mass Correlation coefficients Number Clinic Daytime Night-time 24-h mean studied SBP SBP SBP SBP Rowlands et al. 22 46 0.48 0.52 0.47 0.54 Devereux and Pickering 23 100 a 0.24 0.50 0.10 0.38 White et al. 24 30 0.13 0.39 0.42 0.54 Verdecchia et al. 25 137 0.33 0.38 0.51 0.51 Gosse et al. 26 355 0.35 0.41 0.41 0.45 a Hypertensive plus normal subjects. 6A

and LVH. More recently, it has been demonstrated that, in elderly Japanese subjects, those with the greatest morning blood pressure experience a significantly higher incidence of silent and overt cerebrovascular events. 33 Other aspects of blood pressure variability may impact on LVH. In patients with similar 24-h mean blood pressures, those who do not exhibit the normal circadian variation and display little or no night-time fall in blood pressure (i.e. non-dippers ) have higher LVM values compared with normal dippers. 34 It has been proposed that blunted reduction in nocturnal blood pressure, if it persists over a period of time, may play a pivotal role in the development of some expressions of targetorgan damage, such as LVH and intimamedia thickening, during the early phase of essential hypertension. 34 Whatever the mechanisms, LVH appears more and more as a surrogate endpoint for morbid events in hypertension and thus deserves special attention. It fulfils most of the conditions of a substitute criterion, 35 with lower LVM during anti-hypertensive treatment being associated with lower incidences of clinical endpoints. 36 LVH and the role of the renin angiotensin aldosterone system The Framingham Heart Study has shown that LVH is reversible and responds well to the lowering of blood pressure. 37 Increasing use of anti-hypertensive therapy over the period 1950 1989 was associated with a reduced prevalence of high blood pressure and a concomitant decline in LVH in the general population. In part, this is thought to explain the considerable decline in mortality from cardiovascular disease observed since the late 1960s. However, this is not cause for complacency. The renin angiotensin aldosterone system (RAAS) orchestrates many of the cellular, biochemical and pathological changes that initiate and perpetuate LVH, with angiotensin II playing a key role (Fig. 2). 38 Elevated levels of circulating angiotensin II and aldosterone have been shown to correlate positively with increased LVM and reduced left ventricular function. 39,40 Thus, pharmacological interruption of the RAAS offers a potent method of preventing hypertension and regressing LVH, as well as protecting other target organs from angiotensin-ii-induced damage. Recently, a meta-analysis was conducted on data from double-blind, randomized, controlled trials performed up until September 2002 that evaluated the effects of diuretics, β-blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) on echocardiographically evaluated LVM in essential hypertension. 41 The meta-analysis revealed that treatments targeting the RAAS resulted in the most substantial reductions in LVM. Clinical studies have consistently shown that treatment of mildly hypertensive patients with ACE inhibitors 42,43 or ARBs 3,44 brings about LVH regression through mechanisms that seem partially independent of their ability to reduce blood pressure. Angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers The mechanisms of action of ACE inhibitors and ARBs differ. Formation of angiotensin II from angiotensin I is prevented by ACE inhibitors; however, angiotensin II can be generated by alternative enzymatic pathways, such as chymase present in the heart, that 7A

Local Angiotensin Circulating Vasoconstriction Fibrosis Myocardial remodelling Hypertension Myocyte hypertrophy Left ventricular hypertrophy Increased ventricular stiffness Reduced cardiac contractility Decreased coronary flow reserve Abnormal diastolic function and congestive heart failure FIGURE 2: The role of angiotensin II in left ventricular hypertrophy and cardiac pathophysiology 38 are not susceptible to ACE inhibition. 45,46 In contrast, the ARBs prevent the binding of angiotensin II to the type 1 receptors present in various tissue; thus, the deleterious effects of angiotensin II are overcome irrespective of whether it is produced systemically or locally and by whatever mechanism. 47 Extensive data have shown that ARBs have an important role in LVH management. 48 In clinical studies, ARBs have been shown to bring about regression of LVM. 49 52 The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, for example, has demonstrated that treatment with losartan, plus hydrochlorothiazide and other medications when needed for blood pressure control, resulted in greater LVH regression in patients than did conventional atenolol-based treatment. 53 Conclusions If allowed to advance, LVH is a considerable cause of cardiovascular disease and death. LVH regression by aggressive control of blood pressure may make a valuable contribution to improving prognosis. In the light of the important role that angiotensin II plays within the cardiovascular continuum, pharmacological targeting of the RAAS may confer additional benefits in terms of LVH reversal and improved prognosis to that provided by effective blood pressure alone using other anti-hypertensive agents. The ARBs, a class of anti-hypertensive agents with well-established efficacy and a placebo-like safety profile, 54 may prove especially valuable, by providing more complete blockade of angiotensin II than 8A

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