Left Ventricular Hypertrophy and Coronary Artery Calcifications: A Dangerous Duet?

Hypertension is a leading risk factor for premature morbidity and mortality in developed and developing countries.1 It is a common cause of cerebrovascular disease and a major contributor to the global burden of ischemic heart disease and heart failure.1 Several cardiac alterations may be present in hypertensive patients, which include cardiac structural and functional changes (increased left ventricular [LV] mass, LV systolic and diastolic dysfunction, and impairment of coronary reserve), arrhythmias, and enlargement of left atrial and aortic root.2 Within the array of such abnormalities, considerable attention has been paid to LV hypertrophy for its negative association with major cardiovascular events and survival.3,4 LV hypertrophy, either diagnosed by ECG or echocardiography,5,6 reflects a dangerous vicious circle characterized by endothelial dysfunction, intrinsic myocyte impairment, ischemia, myocardial fibrosis, and apoptosis. A growing number of studies linked LV hypertrophy to ischemic heart disease: experimental and epidemiological data have shown that the reduction in coronary reserve associated with LV hypertrophy makes the heart more susceptible to ischemia when the demand increases or when the perfusion pressure drops.3,7,8 Furthermore, several factors including insulin and insulin-like growth factors, angiotensin II, cathecholamines, endothelin, and altered plasma viscosity may accelerate the progression of coronary artery disease in hypertensive patients.3,7 Ischemic heart disease events are numerically the most common cardiovascular event among hypertensive patients and the presence of LV hypertrophy significantly increases the probability of these complications.9,10 In an observational context, the Dallas Heart Study11 showed an association between some markers of concentric ventricular hypertrophy and the burden of atherosclerosis assessed by coronary artery calcifications (CACs). In the current issue of the Journal, Grossman and coworkers12 add further data which need to be reconciled with the extensive previous literature in this intriguing area. Briefly, in this post-hoc analysis of the International Nifedipine Study Intervention as Goal for Hypertension Therapy (INSIGHT), echocardiography and computed tomography were used to assess LV hypertrophy and CAC, respectively.12 Specifically, the Authors tried to assess the interaction between LV hypertrophy and CAC in asymptomatic hypertensive patients. The primary endpoint of the study was the first cardiovascular event. During follow up (mean 13.3 ± 2.6 years), 89 patients experienced the primary endpoint: the event rate was higher in those with CAC (43.4%) than in those without CAC (21.5%; P < 0.001). Similarly, the event rate was higher in those with LV hypertrophy (44.4%) than in those with normal LV mass (31.6%; P < 0.01).12 Interestingly, LV hypertrophy did not show any association with cardiovascular events in the absence of CAC. Conversely, LV hypertrophy affected long-term CV events in subjects with CAC. In other words, the excess risk associated with LV hypertrophy occurred only in the presence of coronary artery disease. Specifically, compared to those who have no CAC and no LV hypertrophy, the unadjusted hazard ratio was 0.79 (95% confidence interval: 0.29 to 2.17) in those without CAC and with LV hypertrophy and 3.57 (95% confidence interval: 1.90 to 6.72) in those with CAC and LV hypertrophy.12 Although intriguing, these findings are open to discussion and should be interpreted with caution. First, the study population was a small subgroup of 544 subjects enrolled in 1995 to the calcification arm of the INSIGHT and this was a not prespecified analysis.12 Moreover, survival models were not adjusted for randomized treatment and did not consider the possible effects of serial changes in LV geometry. The INSIGHT trial compared the effect of the calcium antagonist Nifedipine vs. a thiazide diuretic.12 In this context, published data suggest that (i) treatment with calcium-channel- blockers results in significant regression of LV hypertrophy, perhaps greater than that seen with diuretics13,14 and that (ii) regression of LV hypertrophy results in improved survival.4,15 Second, in their analysis, Grossman and coworkers12 found an interaction between CAC and LV hypertrophy with a significant hazard ratio of 2.85 (95% confidence interval: 1.62 to 5.001; P < 0.001). Nevertheless, it seems that the effect of such statistical interaction in survival analyses using Cox proportional hazard regression models has not been fully considered. In detail, the Authors compared the prognosis of 4 different subgroups of patients, as identified by LV hypertrophy (absent, present) and CAC (absent, present). When exploring the effect of LV hypertrophy in multivariable models, age, gender, hypercholesterolemia, proteinuria, and estimated glomerular filtration rate were included as potential confounders.12 Of note, when the effects of two or more variables are synergic, the absence of an interaction effect in the multivariable model could lead to bias and misinterpretation of results.16 Since the analysis by Grossman and coworkers recognized a significant statistical interaction between LV hypertrophy and CAC, the main point that should be put into the context is the evidence of a synergistic effect on survival of LV hypertrophy and myocardial perfusion abnormalities due to CAC even in the absence of symptomatic coronary artery disease. Such finding is not surprising. Myocardial ischemia may result from LV hypertrophy itself because of an associated increase in coronary vascular resistance, a reduction in the number of capillaries per gram of muscle tissue, a rise in coronary vascular resistance, and impaired coronary reserve even due to arteriolar rarefaction, medial wall thickening of arterioles, perivascular fibrosis, endothelial dysfunction, and myocyte hypertrophy.7 Thus, the coexistence of LV hypertrophy and coronary calcifications may further reduce coronary blood flow, increase myocardial oxygen demand, and predisposes to severe ischemia of the subendocardial myocardium and myocardial infarction.17 To this purpose, ECG may not be able to identify underlying coronary artery disease in patients with LV hypertrophy.18,19 Moreover, the diagnostic accuracy of the ST segment response in patients with baseline ECG abnormalities due to LV hypertrophy is quite poor.18,19 ST-segment changes at rest may condition a reduced specificity of exercise test in hypertensive patients with chest pain, while the sensitivity is only marginally affected.18,19 In conclusion, the analysis by Grossman and coworkers12 supports a new perception of hypertensive heart disease beyond the mere numerical values of LV mass and blood pressure. Increased LV mass should be broadly considered as a marker of cardiovascular risk (Figure 1) by reflecting and integrating the long-term activity of several factors which are potentially active in promoting progression of atherosclerotic lesions.3 The present analysis of the INSIGHT Study,12 albeit interesting and provocative, cannot conclusively clarify to what extent the knowledge of CAC may refine cardiovascular risk stratification in individual hypertensive patients.20 Data available are still limited and further studies in this area are urgently needed.20 The wide spectrum of hypertensive heart disease. At present, LV hypertrophy is considered a biomarker integrating the long-term exposure to both pressure overload and several nonhemodynamic factors which may promote progression of coronary atherosclerosis ultimately leading to adverse clinical events. Thus, its recognition by ECG or echocardiography is useful to improve the cardiovascular risk stratification of hypertensive patients. Abbreviations: CAD, coronary artery disease; ECG, electrocardiography; Echo, echocardiography; LVH, left ventricular hypertrophy. The authors declared no conflict of interest.