Regression of Left Ventricular Hypertrophy: Lodestar to Stroke Prevention in the Treatment of Hypertension?

Hypertension is a well-established risk factor for serious cardiovascular complications, but no adverse consequence of hypertension is as strongly associated with the disorder or as devastating in its potential effects as stroke. In clinical trials of antihypertensive treatment conducted at the close of the last century, stroke, rather than myocardial infarction, emerged as the most common complication of hypertension.¹ Stroke carries a substantial risk of death—as many as one quarter of individuals who experience a stroke are dead within a year.² No less important, stroke often imposes a heavy toll on survivors through loss of physical or cognitive function or both. Some 20% of stroke survivors require institutional care 3 months after onset, and up to 30% are permanently disabled.² That stroke represents an especially dreaded cardiovascular condition was established in a survey of at-risk individuals and survivors of minor strokes.³ When asked, hypothetically, how many years of life with a major hemiparetic stroke they would be willing to trade to live in good health, 45% responded that they would prefer death to this outcome. On average, respondents were prepared to give up 6.6 years of a 10-year life expectancy with such a stroke, and 7.4 years when the stroke also resulted in aphasia. Hence, to the best judge—the individual patient—stroke is a starkly undesirable outcome.

Present-day care of patients with stroke is hampered by the poor efficacy of available therapies. This emphasizes the primacy of effective strategies to prevent cerebrovascular events. Among risk factors for stroke, hypertension is paramount: with a prevalence of one-third of adults in the United States, and an associated three- to fivefold risk increase, high blood pressure (BP) has the highest population attributable risk of all known reversible stroke risk factors.⁴ Moreover, the risk begins at BP levels that have long been considered normal. Starting with a systolic BP of 115 mm Hg, every 20–mm Hg increase is associated with more than a doubling in fatal stroke risk.⁵

As the most prominent manifestation of hypertensive end-organ damage, left ventricular (LV) hypertrophy has received attention as a possible therapeutic target in preventing cardiovascular complications of hypertension. The interest in LV hypertrophy soared, however, with recognition of its powerful prognostic ability independent of established cardiovascular risk factors in a variety of settings. Notably this impressive predictive capacity of LV hypertrophy was not limited to cardiac endpoints but extended to cerebrovascular events as well.⁶

That reversal of LV hypertrophy can be achieved through specific interventions has been documented in experimental and clinical studies. Both therapeutic lifestyle modification⁷ and various antihypertensive agents⁸ have been demonstrated to reduce LV mass in clinical trials. Furthermore, systematic reviews suggested that certain drug classes, namely, antagonists of the renin–angiotensin system and calcium-channel blockers, could achieve more LV hypertrophy regression than others, specifically, thiazide diuretics and β-adrenergic blockers.⁹ Yet use of regression of LV hypertrophy as a therapeutic target in hypertension required evidence that such regression could translate to reductions in subsequent cardiovascular or cerebrovascular events independently of associated BP reduction.

Relevant data in this regard first emerged from the Framingham Heart Study, which reported that among participants with electrocardiographic LV hypertrophy, serial decline in Cornell voltage was associated with a decreased risk of cardiovascular events compared with no decline independently of atherosclerosis risk factors and serial change in systolic BP.¹⁰ Thereafter, analyses from the Heart Outcomes Prevention Evaluation (HOPE) study documented greater prevention or regression of electrocardiographic LV hypertrophy for ramipril versus placebo independently of BP changes among nearly 9000 participants with cardiovascular disease or diabetes plus one additional risk factor.¹¹ Moreover, prevention or regression of electrocardiographic LV hypertrophy was associated with reduction of the primary composite cardiovascular endpoint—but not of stroke individually—as compared with persistence or development of LV hypertrophy. Yet because many follow-up electrocardiograms were obtained after cardiovascular events had occurred, these analyses could not address the impact of antecedent electrocardiographic changes in LV hypertrophy on incident cardiovascular outcomes.

Stronger supportive evidence has since been produced by separate reports¹² from the Lostartan Intervention for Endpoint Reduction in hypertention (LIFE) study, a randomized comparison of losartan-based versus atenolol-based therapy for patients with moderate-to-severe hypertension and electrocardiographic LV hypertrophy. Analyses of annual electrocardiograms obtained serially throughout the trial in the entire cohort of nearly 9200 participants, or of annual echocardiograms in a subgroup of almost 1000 participants, revealed significant reductions in the composite cardiovascular endpoint in association with lower in-treatment LV mass, independent of changes in systolic and diastolic BP or treatment assignment. What is more, these findings extended to stroke in particular. After adjustment for baseline Framingham risk score, treatment allocation, and serial BP changes during the trial, every decrease of one standard deviation in the Cornell voltage–duration product (1050 mm · msec) was associated with a 10% relative reduction (95% confidence interval [CI] = 4% to 16%) in incident stroke, with a comparable effect for Sokolow-Lyon voltage.¹² Likewise, for every decrement in LV mass index of one standard deviation (25.3 g/m²), there was an accompanying reduction of 24% (95% CI = 4% to 40%) in the relative risk of stroke after adjustment for baseline LV mass index, assigned treatment, and in-treatment BP.¹³ The latter effect ceased to be significant, however, on adjustment for age, smoking, diabetes, and prior cardiovascular disease at baseline (relative risk reduction = 10%, 95% CI = 33% to −20%).¹³ These findings suggest, but do not prove, that a strategy of comparing baseline and follow-up assessments of LV hypertrophy might be used to guide intensification of therapy to prevent stroke and other cardiovascular events in hypertensive patients.

In this issue of the Journal, Verdecchia et al¹⁴ go a step further in documenting the relation between changes in LV mass and subsequent cerebrovascular events in hypertensive patients by taking into account not only office BP but also ambulatory BP. In a subgroup of 880 participants from a prospective hypertension registry in Italy (Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA)), who remained free of cardiovascular disease at follow-up a median of 3.5 years later, the investigators examined the relationship between changes in LV mass and incident stroke or transient ischemic attack (TIA). Participants underwent office and 24-h BP measurements, as well as electrocardiographic and echocardiographic assessments of LV mass at entry and follow-up. Most subjects had initially untreated hypertension; but at follow-up 70% were receiving antihypertensive drugs, with the balance undertaking lifestyle measures only. There were significant decreases in office and ambulatory systolic and diastolic BP as well as in LV mass, which correlated more closely with change in average 24-h systolic BP (r = 0.39) than in office systolic BP (r = 0.32). There was no significant relationship between continuous changes in either electrocardiographic or echocardiographic LV mass and incident cerebrovascular events. However, when changes in echocardiographic LV mass were categorized as persistence of baseline LV hypertrophy or development of new LV hypertrophy at follow-up versus resolution of LV hypertrophy at follow-up or persistence of normal LV mass, the investigators documented a significantly higher incidence of cerebrovascular events in the former group. This relationship was independent of age and average 24-h systolic BP at follow-up (hazard ratio = 2.8, 95% CI = 1.18 to 6.69); no other covariates entered the multivariable Cox model. By contrast, similar categorization for electrocardiographic LV hypertrophy was not significantly related to incident cerebral ischemia.

The findings of Verdecchia et al extend recent observations from the LIFE study regarding the implications of changes in echocardiographic LV mass for cerebrovascular events by examining a cohort with milder hypertension and lower prevalence and severity of LV hypertrophy. Moreover, demonstration that interval change in the presence of LV hypertrophy in treated hypertensive patients predicted subsequent cerebral ischemia irrespective of average 24-h systolic BP lends support to the independent prognostic significance of serial echocardiographic assessments of LV hypertrophy in this population.

Nonetheless, the analyses by Verdecchia et al are based on a small number of incident cerebrovascular events—including a substantial proportion of TIA—which limits the conclusiveness of the investigators’ findings. (In comparison to the 34 incident strokes and TIA in the present cohort, there were 541 incident strokes in the LIFE trial, of which 61 occurred in the echocardiographic substudy.) The modest number of outcomes in the PIUMA subgroup reduces the stability of results, and may have given the study insufficient power to detect an association between in-treatment electrocardiographic LV hypertrophy and cerebrovascular events. The constraint on power also applies to the ability of the study to account for baseline LV mass index and thereby examine the extent to which the categorical association is driven by individuals who started out at high-normal LV mass index and progressed to frank hypertrophy versus participants who had markedly elevated LV mass index at baseline and failed to regress. In addition, the few events may have resulted in exclusion of relevant confounders from multivariable models.

These limitations notwithstanding, the findings reported by Verdecchia et al do support a cerebrovascular benefit of regression of LV hypertrophy independent of the attained level of BP. The increased cardiovascular risk associated with LV hypertrophy remains incompletely explained, but is thought to reflect in part the status of LV hypertrophy as an integrated measure of the effects of atherosclerosis risk factors, the severity and duration of which are only imperfectly assessed by cross-sectional clinical assessments. The phenomenon of LV hypertrophy occurs in response to mechanical stretch from pressure and volume overload, as well as to neurohumoral triggers, the most important of which appears to be the renin–angiotensin–aldosterone system (RAAS). The presence of LV hypertrophy therefore correlates closely with widespread vascular effects of the RAAS activation characteristic of hypertension, including endothelial dysfunction, vascular remodeling and hypertrophy, rarefaction of arterial beds, atherosclerosis, increased coagulation, and decreased fibrinolysis.¹⁵

It is these vascular effects that help to explain the predominance of ischemic, as distinguished from hemorrhagic, strokes in hypertension. Development of atherosclerosis in large cerebral arteries or arteriosclerosis in penetrating arteries provides the substrate for thrombosis, vascular occlusion, and embolism. Vascular remodeling and endothelial dysfunction in turn lead to decreased arterial compliance and impaired cerebral autoregulation, thereby increasing vulnerability to changes in cerebral perfusion.¹⁵ Notably, generalized increases in arterial stiffness also compound direct neurohormonal hypertrophic effects on the ventricular myocardium by increasing the speed of reflection of the systolic arterial pressure wave.¹⁶ This leads to augmentation not only of aortic systolic pressure—the principal mechanical stimulus to LV hypertrophy—but also of systolic pressure in the carotid and coronary arterial beds.

Regression of LV hypertrophy in available studies likely mirrors regression of vascular hypertrophy and improvement in endothelial function, and in this way might be postulated to decrease cerebrovascular risk. In support of this mechanism, a substudy of LIFE documented greater reduction of carotid mass with losartan-based than atenolol-based therapy,¹⁷ paralleling the greater regression of LV hypertrophy documented with the former regimen. Although direct measurements of carotid atherosclerosis are not available in the study by Verdecchia et al, tandem arterial and LV changes might have contributed to the observed BP-independent reduction in cerebrovascular risk.

Apart from reflecting the state of the vasculature, LV hypertrophy is closely linked to systolic and diastolic dysfunction, and to an attendant elevation in filling pressure that eventuates in left atrial enlargement. The presence of LV hypertrophy also increases susceptibility to myocardial ischemia and infarction by augmenting myocardial oxygen demand. Myocardial infarction and worsening systolic dysfunction or associated valvular disease can also foster left atrial enlargement. Left atrial enlargement in turn promotes stasis and fosters the development of atrial tachyarrhythmias such as atrial fibrillation, both of which predispose to thromboembolism. Although clinically recognized atrial fibrillation and coronary heart disease appeared to play little or no role in incident cerebrovascular events in the Verdecchia et al study, the LIFE study showed an association between reduced electrocardiographic LV hypertrophy and decreased incidence of atrial fibrillation,¹⁸ which would translate into lower stroke risk.

Finally, the hypertrophied LV may be a particularly powerful pump capable of generating especially high arterial pressure and rate of rise of pressure (dP/dt) in early systole. These hemodynamic alterations could predispose to plaque ulceration in the cervicocephalic arteries or to mural rupture of cerebral penetrating arteries, leading to brain infarction or intracerebral hemorrhage.

Whatever the mechanisms, the study by Verdecchia et al adds to accumulating evidence that regression of LV hypertrophy may be an important target for monitoring the efficacy of antihypertensive treatment in addition to assessment of BP, even when determined on a 24-h basis. Ultimately, the true merits and cost-effectiveness of an approach that uses serial echocardiography or electrocardiography to guide therapeutic intervention in this setting can be established only by a clinical trial that compares such a strategy to one that monitors BP response only. In this way, LV hypertrophy may be demonstrated to be a guiding light toward realizing the full benefits of antihypertensive therapy in individuals with high BP.