Regression of left ventricular hypertrophy; what are appropriate therapeutic objectives?

Cardiac hypertrophy is a morphological adaptive increase in myocardial mass in response to chronic work overload and is a common clinical finding affecting 23% of men and 33% of women over the age of 59 years 1. Pressure or volume overload on the myocardium results in an increase in myocardial wall stress and hypertrophy may be seen as an attempt to normalise wall stress and oxygen demand. Although initially protective, the increased myocardial mass requires an increase in coronary blood flow to maintain function; indeed, ventricular hypertrophy may be associated with myocardial ischaemia even with angiographically normal coronary arteries 234. Left ventricular hypertrophy (LVH) significantly increases the risk of myocardial infarction, congestive heart failure and sudden cardiac death 567. It is also associated with a greater prevalence of cardiac arrhythmias 8 and is an important risk factor for cardiac morbidity and mortality 910. Understanding the potential mechanisms for these adverse effects has been the focus of much interest in recent years. Coronary reserve, defined as the difference between basal flow and maximal flow during infusion of agents such as adenosine is reduced in left ventricular hypertrophy due to hypertension 3, 11, aortic stenosis 2, 4, aortic regurgitation 12, supravalvar aortic stenosis and hypertrophic cardiomyopathy 13, 14, and in experimental models of LVH 15161718. This impairment is marked in subendocardial layers, with some evidence of an alteration in the normal subendocardial-subepicardial distribution of perfusion at rest 19. Available evidence suggests that several factors contribute to this impaired coronary reserve. Coronary vascular resistance measured during maximal vasodilatation (minimal coronary vascular resistance) is increased in cardiac hypertrophy 17. Since coronary resistance is minimal during maximal vasodilatation, increased resistance in hypertrophy is likely to reflect a reduction in the available luminal cross sectional area per unit volume of myocardium. Several studies have suggested a reduction in the number of resistance vessels in hypertrophied myocardium 20, 21 while others suggest a lag in vascularisation and that arteriolar density normalises later in hypertrophy 22, 23. Systolic impedance to coronary flow as a result of perivascular compression during systole is well known and experimental studies indicate that this is increased in hypertrophied hearts 15. The reduced coronary reserve limits the ability of hypertrophied hearts to meet blood flow and metabolic requirements when demand is increased. Thus despite normal myocardial oxygen consumption 24 and myocardial perfusion per unit mass at rest, the hypertrophied heart is more vulnerable to ischaemia 18, 25, 26. LVH is associated with an increased risk of sudden cardiac death as well as total cardiovascular mortality 7, 8. Electrocardiographic or echocardiographic evidence of LVH is associated with an increased prevalence of ventricular arrhythmias, independent of treatment (diuretic) induced hypokalaemia suggesting an independent arrhythmogenic effect of LVH 272829. The increased risk of sudden cardiac death and arrhythmias associated with LVH has focused renewed interest on the underlying electrophysiological disturbances in hypertrophy. Numerous studies have reported prolongation of ventricular action potential duration (APD) in hypertrophy. Possible mechanisms for this include changes in i L-type calcium channels, ii sodium-calcium exchange, iii the delayed rectifier current (IK ) and iv the transient outward current 30. Delayed conduction also occurs in hypertrophied myocardium and this is associated with an increased propensity to arrhythmias 31. This reduced conduction velocity appears to be due at least in part to increased intercellular electrical impedance 32, possibly related to a reduction in intracellular pH 33 and alterations in gap junction morphology, which may also reduce gap junction conductance 34. Thus delayed conduction and repolarisation as well as increased dispersion of repolarisation 35, 36 are important features of hypertrophy and are known to favour conditions suitable for the development of re-entry arrhythmias. Although antihypertensive therapy in clinical practice has been effective in reducing mortality from stroke and renal failure its effect on cardiac mortality appears to be less impressive 37, 38. A number of factors are likely to account for this; a) the slope of the association between stroke and blood pressure is greater than that for cardiac morbidity, thereby offering a potentially greater opportunity for stroke prevention with anti-hypertensive treatment. Anti-hypertensive studies to date have had greater statistical power for assessing effects on stroke prevention than on cardiac mortality 39; b) a review of available anti-hypertensive studies suggests that benefits of lowering blood pressure in terms of coronary heart disease prevention are less than expected from epidemiological observations 39; c) studies of cardiac morbidity have tended to focus on coronary heart disease, ignoring other important cardiac end points, notably hypertensive heart failure; d) improving cardiac morbidity is partly dependent on reversing or modifying chronic processes such as atheroma and left ventricular hypertrophy and this has focused attention on the ability of different classes of antihypertensive agents to do so. In this context regression of left ventricular mass has received most attention to date. Echocardiography has provided an excellent tool for the study of LV mass and regression of left ventricular hypertrophy has been widely reported to occur following treatment of hypertension with β-adrenoceptor antagonists 40, 41, α-adrenoceptor antagonists 42, calcium antagonists 43, 44, angiotensin converting enzyme (ACE) inhibitors 45, 46 and diuretics 47, as well as by lifestyle modification that included weight loss and reduction in salt and alcohol intake 48. Normalisation of LV mass has not been demonstrated after any medical treatments. Regression of LV hypertrophy does occur following aortic valve replacement 49 but may remain incomplete in 50% of such patients 50. A number of meta-analyses have compared the relative efficacy of various classes of anti-hypertensive agent in regressing LVH 515253. These have suggested that ACE inhibitors may be most effective but the results need to be considered with caution as some uncontrolled studies were included 51, 52 and even when trials were carefully selected for good design features, they were often of small size and involved short periods of treatment 53. These meta-analyses have usefully highlighted potentially important baseline characteristics which may influence response to treatment, particularly gender, ethnic mix and pre-treatment LV mass indices. For example the Treatment of Mild Hypertension Study (TOMHS) randomized patients to receive one of five different anti-hypertensive agents in addition to lifestyle modification. Patients who received diuretic treatment had the greatest regression of LV mass but also had the highest pre-treatment values 48. A more recent trial 54 compared monotherapy using six agents from different anti-hypertensive classes in regressing LVH in 587 hypertensive men of whom 45% had LVH at entry. After 1 year groups signed to ACE inhibitor or diuretic treatment had the greatest regression. This study was limited by the lack of females and low follow-up rate (only 21% of randomized patients had echocardiographic measurements at 1 year). Ideal design features for future trials have been discussed previously 55. Double-blind, randomized, comparative trials should include both males and females with appropriate ethnic mix and treatment should be maintained for at least 1 year. The striking increase in LVH with age underscores the importance of studying elderly patients in sufficient numbers. Anatomically validated measurements of LV mass should be made in a central laboratory by experienced staff blind to treatment and trial size should be appropriate for the variance of the methods used, approximately 150 to 200 per treatment arm in the case of echocardiography. The LIVE study is a randomized controlled international trial to compare the efficacy of 12 months’ treatment with an ACE inhibitor, enalapril, or a diuretic, indapamide, in regressing LVH in hypertensive patients with LVH using a central laboratory for blind measurement of LV mass 56. The PRESERVE trial will compare the efficacy of 12 months’ treatment with enalapril or nifedipine in reducing LV mass and patients will be followed for a further 3 years to assess longterm morbidity and mortality 57. The LIFE study will compare the efficacy of atenolol vs angiotensin II receptor antagonism with losartan in reducing LVH and cardiovascular mortality 58. These large prospective trials should help to clarify optimal methods for regressing LVH and its effects. Beyond documenting the extent of LVH regression future studies will also need to determine the impact this has on longterm outcome. Epidemiological and retrospective studies suggest that LVH regression does improve prognosis 59, 60. Documenting that pharmacologically induced LVH regression reduces the prevalence of heart failure and cardiac death in prospectively controlled clinical trials would be of great clinical importance. In contrast to the intense interest in regression of LV mass, few studies have examined whether this is accompanied by reversal of the pathophysiological effects of LVH and available studies are often small and results conflicting. Reduction in the size of epicardial coronary arteries has been demonstrated following aortic valve replacement 61. One study compared coronary sinus blood flow measurements in patients with aortic stenosis with those in a separate group following aortic valve replacement and observed lower resting flow measurements in the latter 62. No correlation between coronary flow reserve and LV mass could be demonstrated in that study. Improvement in coronary flow reserve has also been reported following treatment of hypertensive patients with verapamil 63, however in that study this effect was independent of changes in LV mass and the same study found no improvement in flow reserve following treatment with an ACE inhibitor, suggesting a direct effect of verapamil 63. Disturbances in LV diastolic function associated with LVH have been shown to improve with regression of LV mass following antihypertensive treatment in some 64 but not all studies 65. One study has also demonstrated improvement in QT dispersion with antihypertensive treatment 36. Experimental studies have reported that antihypertensive treatment of spontaneously hypertensive rats reduces blood pressure and LVH 666768, with improvements in LV compliance 67 and reduced vulnerability to ischaemia 69 although coronary reserve remained impaired 70. In contrast other studies have demonstrated some recovery in coronary vascular morphology 71, 72 and coronary reserve 73 with regression of experimental hypertrophy. There is also some evidence that regression of experimental hypertrophy may reduce arrhythmogenicity and allow some electrophysiological recovery. A better understanding of the factors which regulate myocardial growth is emerging from recent studies. The existence and functional significance of angiotensin-II (Ang-II) receptors and synthesis of RAS components in the heart have been demonstrated 74 and there is evidence that components of the cardiac RAS are upregulated in hypertrophy 75. ACE inhibitors are effective in regressing LV mass in clinical, and experimental hypertrophy. While this effect on LVH may be partly attributed to interference with the RAS resulting in reduced systemic blood pressure and afterload, recent evidence suggests that doses of ACE inhibitors with no effect on pressure responses to angiotensin 1 can regress LV mass in rats in the absence of reductions in afterload or plasma renin activity 76. There is also evidence that fibrosis/connective tissue deposition 77 and pathological growth signals in the heart can be mediated by locally produced Ang-II acting on cardiac fibroblasts and myocytes. Mechanical stretch induces Ang II secretion from cultured myocytes suggesting an important role for the RAS in stretch induced hypertrophy 78. In addition vascular hypertrophy has been induced by direct infusion of Ang-II 79 or by increased local expression of ACE using gene transfer 80. These findings suggest that the paracrine/autocrine action of Ang-II is an important growth factor in the development and maintenance of hypertrophy. Ang-II interacts with two pharmacologically and molecularly distinct receptor subtypes, AT1 and AT2. The AT1 receptor mediates most of the biological actions of Ang-II 81 including myocyte hypertrophy 82. AT2 receptors may have a developmental role 83 and while Ang-II stimulates fibroblast collagen synthesis by both AT1 and AT2 receptors, inhibition of collagenase activity is specifically mediated by the AT2 subtype 84. (i) There is ample evidence that at least partial regression of LVH can be achieved with antihypertensive treatment. Recent work has begun to shed light on the mechanisms involved in the development of hypertrophy and therefore provides potential targets for more focused treatments. Clinical trials with appropriate power and design are needed to clarify whether antihypertensive treatments which also target these mechanisms are more effective in achieving regression. (ii) At present the extent to which reversal of the pathophysiological effects of LVH accompanies reduction in LV mass remains unclear. The ability to measure LV mass simply and non-invasively using echocardiography was an important milestone in the study of LVH and its regression. However LV mass alone does not provide an adequate indication of the severity or nature of LVH. For example LV mass may be markedly increased in athletes with values well within the range of what would be regarded as pathological for hypertensive patients, yet available evidence suggests that their hearts function normally. Work is therefore needed to establish whether the recognised abnormalities in cardiac electrophysiology, coronary haemodynamics and contractile function associated with LVH can be reversed and to identify optimal treatments for doing so. (iii) The ultimate question which needs to be answered is whether regression of LVH and its pathophysiology improves long term prognosis. Epidemiological studies suggest that this is so: long term clinical trials are needed to examine the extent to which pharmacological induced regression may do so.