Microcirculation and left-ventricular hypertrophy

Left-ventricular hypertrophy is an abnormal increase in the mass of the left-ventricular myocardium that can reflect a maladaptive response to chronic pressure overload [1]. Left-ventricular hypertrophy may be detected in about one-third of people with hypertension. When present, the risk of adverse cardiovascular events almost doubles [2,3]. In long-term epidemiological studies, left-ventricular hypertrophy increased the risk for diastolic heart failure, systolic heart failure, atrial fibrillation, and sudden death in patients with hypertension [2,3]. More than 20 years ago, the Framingham Heart Study proved that 35% of men and 20% of women died within 5 years of the appearance of left-ventricular hypertrophy at electrocardiography (ECG) [4]. Further analyses [5–7] have repeatedly confirmed that the prognostic impact of left-ventricular hypertrophy is independent of increased arterial pressure. In a coronary angiography study, left-ventricular hypertrophy increased the risk of death by two and four-fold, respectively, in the absence and presence of coronary artery stenoses [8]. Several mechanisms have been proposed to explain the risk associated with left-ventricular hypertrophy. At present, left-ventricular hypertrophy can be considered a bio-marker integrating the long-term exposure to both pressure overload and several nonhemodynamic factors which may promote progression and destabilization of atherosclerotic lesions ultimately leading to adverse clinical events. Indeed, a number of factors can increase left-ventricular mass and promote progression of atherosclerotic lesions. They include insulin and insulin-like growth factors, angiotensin II, cathecholamines, endothelin and altered plasma viscosity [2]. A basic mechanism of the cardiac risk associated with left-ventricular hypertrophy may also reflect a network whose functional and structural elements are impaired coronary hemodynamics with reduced coronary blood flow and reserve, myocardial interstitial adaptations and cardiomyocite changes [9]. Atherosclerosis of large arteries and increased resistance of muscular arterioles increase the afterload leading to hypertrophy of cardiomyocites [10]. Concurrently, collagen deposition promotes abnormal fibrosis within the myocardial interstitium. Ventricular fibrosis hinders the elasticity of myocardium and systolic function [11–13]. Additional mechanisms (Fig. 1) which may account for impaired coronary hemodynamics include: abnormal regulation of vasomotor tone with reduced coronary blood flow and flow reserve [14–16]; coronary arteriolar compression by the hypertrophied and stiffer left ventricle (LV) produced by ventricular fibrosis; inadequate sizing of coronary vessels [17]; increased arteriolar wall thickening and arteriolar wall-to-lumen diameter [18]; insufficient microvessel growth to prevent dilution because of the greater increase in other myocardial components with a consequent decrease of microvascular density [19,20]; increased left-ventricular chamber diameter reflecting myocite hypertrophy and collagen deposition [10].FIGURE 1: Effects on left ventricle of long-term exposure to chronic pressure overload.In this context, the experimental model proposed by Huo and Kassab [21] and published in the current issue of Journal of Hypertension shed new light on left-ventricular mass and coronary neovascularazitation. Huo and Kassab [21] determined the structural and hemodynamic remodeling in the entire left circumflex arterial tree in response to left-ventricular hypertrophy induced by supravalvular aortic stenosis in young porcine. They observed that the number of vessels and the length of the left circumflex main trunk significantly increased. In keeping with previous studies [22–24], the authors found that left-ventricular hypertrophy of young porcine was associated with a 25% increase of vascular density. Notably, controls and left-ventricular hypertrophy hearts showed similar myocardial blood flows and vascular resistance [21]. These findings are at variance with other experimental models and suggest that different age-related phenomena may be postulated in the hypertrophied myocardium [25–27]. Some differences from previous studies need to be highlighted. First, the experimental model proposed by Huo and Kassab induced a significant increase in systolic left-ventricular pressure as compared to controls (144 ± 21 vs. 106 ± 7 mmHg, P < 0.05) but failed to produce a marked increase in the diastolic left-ventricular pressure. These findings may denote that significant collagen deposition and fibrosis did not develop in left-ventricular myocardium. Moreover, duration of induced hypertension is quite different from previous studies. In Huo and Kassab's model structural and hemodynamic remodeling in the left circumflex arterial tree was analyzed after a short period – 5 weeks – of induced hypertension. In contrast, Breisch et al.[27] analyzed the effects of pressure overload hypertrophy in the left-ventricular myocardium of adult cats after 4, 7, 30, 120 and 248 days of 90% constriction of the ascending aorta. Analysis of the microvasculature at different times after constriction of the aorta showed that capillary density and coronary reserve decreased with increasing time of hypertrophy. The combination of such alterations in flow reserve and capillary density might play an important role in the transition from a compensated to a failing heart. Similarly, Tomanek et al.[28] analyzed the adverse effects on the coronary mirovasculature of late-onset hypertension in middle-aged and senescent rats with renal wrap hypertension of 3 months duration. Compared with control rats, wall-to-lumen ratios of arterioles with lumen diameters less than 25 microns were higher in the hypertensive groups by some 30%, whereas larger arterioles did not show consistent inter-group differences. Capillary numerical density was markedly reduced in the hypertensive animals of both age groups. The observed microvascular alterations occurred in the absence of an absolute increase in left-ventricular mass, but in presence of cardiocyte hypertrophy. Thus, decrements in capillary numerical density were not only due to inadequate growth but reflected an absolute reduction in the number of these vessels associated with cardiocyte loss. The authors concluded that late-onset hypertension in middle-aged and senescent rats is characterized by left-ventricular wall remodeling that includes microvascular alterations that would be expected to limit maximal myocardial flow and O2 supply to the cardiomyocyte. Targeting the microcirculation to prevent or reverse left-ventricular hypertrophy might play a role in the long-term management of hypertension. Several blood pressure (BP)-lowering agents seem to have additional actions on vessel and microcirculatory network other than on vasomotor tone [29–32]. Only a few studies analyzed the actions of beta-blockers and diuretics on microvessel structure. In general, diuretic and/or beta-blocker-based treatment was reported to have no significant effect on structural changes of microcirculation [33–35]. In contrast, calcium channel blockers (CCBs) have been shown to increase microvessel density in several experimental models [29,32]. In particular, CCBs stimulate the growth of coronary capillary network, increase capillary density, and reduce the wall-to-lumen ratio of LV arterioles [29,32]. These findings, together with the experimental evidence of a marked reduction in coronary capillary density observed in adult hearts [27], may support CCBs as the drug class of choice for the treatment of left-ventricular hypertrophy in elderly patients. Significant changes, including a decrease in coronary vascular resistance and improvement of coronary flow reserve, were demonstrated in spontaneously hypertensive rats treated with either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II (type 1) receptor (AT1) antagonist, or both [30,31]. These hemodynamic responses can be explained by coronary vasodilatation induced by inhibition of angiotensin II-mediated constriction exerted by ACE inhibition, further inhibition of additionally generated angiotensin II by intracardiac chymase, augmented bradykinin-induced vasodilatation, and the beneficial effect of locally produced nitric oxide [30,31]. A key component in the development of left-ventricular hypertrophy is myocardial fibrosis, which appears to be pathophysiologically linked to the renin–angiotensin–aldosterone system (RAAS). Angiotensin II has a pro-fibrotic effect on the myocardium of hypertensive patients [36]; this may explain why ACE inhibitors and angiotensin II receptor blockers (ARBs) are effective agents for treating left-ventricular hypertrophy [37]. Indirect comparative effectiveness of ‘new’ drug class (ACE inhibitors, ARBs and CCBs) as compared with ‘old’ drugs (diuretics, beta-blockers) on microcirculation of the myocardium comes from clinical studies on left-ventricular hypertrophy regression in humans. In this context, the meta-analysis by Klingbeil et al.[38] disclosed that among antihypertensive medications currently available for the treatment of hypertension, ARBs decreased the left-ventricular mass by 13%, followed by CCBs at 11%, ACE inhibitors at 10%, diuretics at 8%, and beta-blockers at 6%. Pair-wise comparison showed that ARBs, CCBs and ACE inhibitors were all significantly more effective in reducing the left-ventricular mass than beta-blockers [38]. Both earlier recognition and improved understanding of cardiac hypertrophy may lead to more effective therapeutic strategies for this cardiovascular risk factor. In particular, a measure of the effect of antihypertensive treatment on microcirculation may be valuable in clinical practice. The histopathological proof by direct biopsy of myocardium is the best method to assess myocardial fibrosis or microcirculatory dysfunction, but it is almost impossible, and likely un-ethical, to perform routinely in clinical practice. Some other noninvasive techniques are available to investigate different aspects of the microcirculation in human myocardium [39]. Positron emission tomography (PET) may be used to measure regional myocardial blood flow and coronary flow. It carries very low radiation exposure and shows high repeatability and reproducibility [39]. Echocardiography, when combined with the injection of an ultrasound contrast agent, can be used to investigate myocardial perfusion. Modern ultrasound contrast agents consist of microbubbles containing nondiffusible gas. When a contrast agent is administered intravenously, myocardial contrast echocardiography enables tissue perfusion to be evaluated at the capillary level in which oxygen and nutrient transfer occurs [39]. Magnetic resonance imaging (MRI) allows the three-dimensional visualization of intravascular blood flow and tissue perfusion over time. In particular, MRI is capable of obtaining data about microvascular flow, regional myocardial wall motion, and viability in one single examination [39]. More traditional instrumental approaches are, however, also suitable to indirectly detect the compromise of coronary hemodynamics and left-ventricular microcirculation in patients with hypertension. In particular, some ECG and echocardiographic findings produced by ventricular fibrosis (Fig. 2) should be considered. The compressed coronary arterioles in the hypertrophied and fibrotic myocardium could mimic ECG signs of ischemia (typical strain pattern) even in the absence of occlusive atherosclerotic epicardial coronary arterial disease (Fig. 2, upper panel). In addition, ventricular fibrosis may be also associated with diastolic dysfunction (impaired relaxation abnormality) that can be recognized by echocardiography [40]. Left-ventricular diastolic dysfunction (Fig. 2, lower panel) is usually evaluated through standard Doppler imaging (peak E area, peak A area, peak E/A area ratio, E velocity, A velocity, E/A velocity ratio). Tissue Doppler imaging (TDI), a relatively recent application of the Doppler principle, is increasingly used to investigate diastolic function. TDI-derived parameters of diastolic function are relatively unaffected by preload and heart rate and hence more valued to distinguish normal from abnormal and pseudonormal filling as compared with traditional Doppler parameters [40].FIGURE 2: Traditional instrumental approach to indirectly detect impaired coronary hemodynamics and ventricular fibrosis. ECG, electrocardiography; LV, left ventricle; TDI, tissue Doppler imaging.ACKNOWLEDGEMENT The study was funded in part by the Fondazione Umbra Cuore e Ipertensione – ONLUS, Perugia, Italy. Conflicts of interest None of the authors of this study has financial or other reasons that could lead to a conflict of interest.