Review Article
Molecular mechanisms of left ventricular hypertrophy (LVH) in systemic hypertension (SH)—possible therapeutic perspectives

https://doi.org/10.1016/j.jash.2011.08.006Get rights and content

Abstract

Left ventricular hypertrophy (LVH) induced by systemic hypertension (SH) represents a maladaptive response to the increased overload. It is known that the LV pathological remodeling is associated with an increased risk of cardiovascular morbidity and mortality. Secretion and production of vasoactive peptides, such as angiotensin II, endothelin-1, norepinephrine, and Rho and Ras proteins, are increased during the process and play critical roles in the hypertrophic response to systemic hypertension. Oxidative stress, heat shock proteins, calcineurin, and some kinases are also involved in the hypertrophic process. Usually, antihypertensive treatments are able to reduce elevated blood pressure levels, but are not always useful to slow or prevent LVH. Experimental studies performed in animal models demonstrate that some humoral factors, by suppressing the biochemical hypertrophic responses, could prevent their cardiac complications independently of their possible anti-hypertensive effects. Cyclosporine-A, scutellarin, and spironolactone are also included among these antihypertrophic substances. Thus, new drugs deriving from these molecules and humoral factors could be employed to antagonize LVH.

Introduction

Left ventricular hypertrophy (LVH) is an increase in myocardial muscle mass resulting from enlargement of myocytes. It is a compensatory mechanism to the increased peripheral pressure or volume load. The process consists of increasing the muscular, vascular, and collagenous components of the myocardium. There are both pathological and physiological forms of LVH. Pathological LVH is distinguished from physiological because myocardial adaptations are unable to satisfy the increased demands or when they are only able to meet increased demands at the expense of normal function. In pathological LVH, extracellular connective tissue increases relative to myocytes, but capillary growth does not keep pace with myocyte growth. A leading component in the development of pathological LVH is myocardial fibrosis that compromises cardiac function. Cardiac fibrosis is initially manifested by diastolic dysfunction, although systolic dysfunction occurs with progressive disease. On the contrary, the increase in extracellular matrix and microvessels in physiological LVH is proportional to the myocyte hypertrophy and there is not a deleterious effect on left ventricular function.1 In other words, physiological LVH represents the normal response to exercise and results in an increasing heart mass and pumping ability.

From a diagnostic point of view, it is known that either physiological or pathological LVH can be detected by electrocardiography, echocardiography, or magnetic resonance imaging (MRI).2, 3, 4, 5, 6 Electrocardiography is the cheapest and most readily available of the three methods, but it is not sensitive and thus cannot be used to rule out LVH. Echocardiography is the test of choice to assess for LVH. Cardiac MRI is the current gold standard test for the diagnosis and is much more accurate than echocardiography. Its use, however, is severely restricted in clinical practice because of its high cost and limited availability.

LVH in systemic hypertension (SH) represents an independent risk factor for cardiovascular disease and increases cardiovascular morbility and mortality more than two-fold.7 A growing body of evidence indicates that LVH in SH depends on chronic hemodynamic overload, but is also induced by some neurohumoral substances secreted by the cardiac components in response to the pressure and volume overload.8 In the present report, we focus on pathological LVH induced by SH.

Local angiotensin II is responsible for the activation of protein kinases (ERKs) as well as the increase in protein synthesis in myocardial cells. On the other hand, the peptide acts on cardiac fibroblasts, increasing extracellular matrix proteins (such as collagen and fibronectin), inducing cardiac fibrosis. In addition, angiotensin II contributes to cardiac hypertrophy by the activation of G proteins and small G proteins (Rho proteins).9, 10, 11 It was recently reported that the substance does not have direct hypertrophic-promoting effects on cardiac myocytes, but evokes the hypertrophic responses by inducing endothelin-1 secretion from cardiac fibroblasts.12 This neurohumoral factor also acts by ERKs activation. On the contrary, an endothelin-1 receptor antagonist is able to suppress ERKs activation and stress-induced hypertrophy.

In addition to angiotensin II and endothelin-1, heat shock proteins 90 (HSP90), a group of proteins present in the cells (that increase when the cells are exposed to elevated temperatures or other stress) are also involved in the hypertrophic process. Recently Lee and colleagues provided evidence that HSP90 regulates angiotensin II–induced cardiac hypertrophy via stabilization of IKB kinase (IKK) complex.13

It is known that nuclear factor-κB (NF-κB) is a nuclear protein that controls the transcription of DNA. It is involved in cellular responses to some stimuli (eg, stress, cytokines, free radicals, cells growth).14 In an experimental study, Li et al demonstrated that NF-κB activation is increased in hypertrophic hearts induced by aortic banding in rats. In addition, specific inhibition of NF-κB activation by adenovirus-mediated gene or treatment with an antioxidant attenuates the development of myocyte hypertrophy.15 Normally, NF-κB dimers are sequestrated in the cytosol of unstimulated cells via a class of inhibitor proteins (IKK). Hypertrophic stimulus induces IKK phosphorylation, permitting NF-κB to translocate to the nucleus inducing the hypertrophic process. Freund et al also found that the inhibition of transcription factor NF-κB by cardiomyocyte-restricted expression of the NF-κB super-repressor IκBαΔN is sufficient to attenuate angiotensin II cardiomyocyte-hypertrophy.16 IκB sequestrates the NF-κB p65 subunit in the cytoplasm. If cells are stimulated by several factors, IKB phosphorylation leads to its degradation permitting NF-κB to translocate to the nucleus.17

Geldanamycin (GA), a specific Hsp90 inhibitor, is able to induce the IKK complex stability-maintenance. In addition, GA treatment causes a degradation of IKKα/β reducing angiotensin II hypertrophy via the ubiquitin-proteasome system (UPS).18

In addition, the angiotensin II type I receptor stimulation or the exposure to pressure overload provokes cardiac hypertrophy, by the activation of G proteins and small proteins (Rho and Ras proteins). Small G proteins (also called GTP-binding proteins) are monomeric proteins with a low molecular weight. Activation of small G proteins requires translocation from the cytoplasm to the cell membrane.19 Rho proteins are well-known substances acting in S phase of the cell cycle that play a role in cell proliferation, apoptosis, gene expression, and multiple other functions, such as cytoskeletal organization. Ras and Rho families stimulate hypertrophic growth of cardiac myocytes by phenylephrine.20, 21 Rho protein induces the organization of actin into striated (myofibrils) and nonstriated fibers (premyofibrils) by MAPK.22

Several studies have demonstrated that cardiomyocyte hypertrophy is associated with elevated levels of intracellular calcium or enhanced sensitivity to calcium. The calcium regulatory proteins coming in the hypertrophic process are calcineurin and calmodulin kinase II (CaMKII). Once activated, calcineurin binds to and dephosphorylates nuclear factor of activated T cells, transcription factors in the cytoplasm, permitting their translocation to the nucleus where they participate in hypertrophic gene expression.23

Integrins are a class of membrane receptors and are major players in transmitting the mechanical force across the plasma membrane and sensing the mechanical load in cardiomyocytes. These, together with a number of associated cytoskeletal proteins, connect the sarcomeric contractile apparatus to the extracellular matrix across the plasma membrane, and trigger intracellular signaling pathways activating the cardiomyocyte hypertrophy. Integrins also act by means of AKT, RAS, and MAPKs.24

Table 1 indicates reported the pathways and signaling molecules inducing LVH.

Cardiac hypertrophy is an initial adaptive response to increased blood pressure or afterload that subsequently becomes a maladaptive form. Excessive hypertrophy can result in coronary artery disease, arrhythmias, sudden death, dilated cardiomyopathy, and heart failure. Therefore, it represents a major cause of morbidity and mortality worldwide. Current treatments for cardiac hypertrophy by SH are limited to vasodilators or afterload reducers, with few if any therapies directed at the myocardial process (hypertrophy). Angiotensin-converting enzyme inhibitors and/or angiotensin-II receptor blockers (ARBs) are widely employed for reducing the blood pressure, abnormal peripheral vasoconstriction, and abnormal left ventricular hypertrophic response. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study provided evidence of a reduction of LVH in response to the ARB, losartan, independently of blood pressure lowering.25 Beta-blockers also act mainly by reducing peripheral blood pressure and minimally to antagonize LVH. Ca++ channel blockers affect the endothelin-1 in different ways. Diltiazem and nifedipine partially blocked the endothelin-1–induced response, whereas verapamil seems not influence this endothelin-1–induced effect.26 From all studies performed about the influence of the main antihypertensive drugs on LVH, it is evident that angiotensin-converting enzyme inhibitors are more potent than beta-blockers in the reduction of left ventricular mass index, whereas calcium channel blockers were somewhat in the intermediate range.27 Diuretics appear to reduce left ventricular mass through an effect on left ventricular internal diameters (by volume reduction).28 Contrary to this conclusion, Curry et al affirmed that indapamide mainly reduces wall thickness rather than internal left ventricular diameters.29 On the contrary, a recent report affirmed that hydrochlorothiazide does not significantly reduce left ventricular mass compared with the ARB, telmisartan.30 However, no drug has yet been found to act against cardiac hypertrophy without any effect on systemic blood pressure.

Antihypertensive and antihypertrophic effects of main drugs used for SH treatment are reported in Table 2.

Agents that reduce LVH without blood pressure lowering may be synthesized in the near future. It is known that secretion and production of vasoactive peptides, such as angiotensin II and endothelin-1, are often increased in SH and are involved in the induction of hypertrophic responses. An experimental study by Nozato et al demonstrated in vitro that G1 cyclins are involved in myocardial hypertrophy stimulating the cell cycle. Thus G1 cyclins play an important role in cardiac myocyte hypertrophy stimulated by angiotensin II.31 Therefore, G1 cyclin antagonists could be important to reduce LVH.

Geldanamycin, a HSP90 inhibitor, also is able to prevent angiotensin II–induced cardiac cell hypertrophy. It specifically binds HSP90 and significantly inhibits angiotensin II–induced cell hypertrophy and NF-κB activation.13, 32

Rho is a family of small GTP proteins that controls a wide variety of cellular processes including: cytoskeletal organization, cell growth, production of ROS, survival, and others.33 Recent evidence indicates that activated Rho/Rho-kinase pathway contributes to angiotensin II–induced cardiac hypertrophy and vascular remodeling. Fasudil, a Rho-kinase inhibitor, is able to antagonize angiotensin II–induced hypertrophy and myocardial interstitial fibrosis without changing blood pressure levels.34

Recently, Sheng et al demonstrated in animal models that a cross-talk exists between the calcineurin and the c-Jun NH2-terminal kinase pathways in controlling hypertension-induced cardiac hypertrophy. Inhibition of the calcineurin and c-Jun NH2-terminal kinase pathways, as cyclosporine, may be the basis of a reversal of cardiac hypertrophy by calcineurin blockers.35 Nevertheless, the toxic effects of cyclosporine, such as nausea, tremor, diarrhea, headache, and muscle weakness, must be also considered.

Jla et al evidenced that a newly developed angiotensin II type 1 receptor antagonist, CS866, is useful to promote regression of cardiac hypertrophy by reducing Integrin β1 expression.36 CS866 is an angiotensin II receptor blocker that has demonstrated effectiveness for lowering blood pressure in animal models of hypertension. It exerts protective properties particularly in the cases with nephropathy and atherosclerotic lesions.37

Previously, Takemoto et al found that the inhibitors of 3-hydroxy-3-methhylglutaryl-CoA reductase (statins) inhibit cardiac hypertrophy by blocking Rho isoprenylation.38 This demonstrates that statins prevent the development of cardiac hypertrophy in a cholesterol-independent manner and without reducing blood pressure. The antihypertrophic effect of statins could be due to decreases in angiotensin II type 1 receptor expression39 or myocardial converting enzyme activity.40 But, the primary action includes the rise in nitric oxide production that contributes to the antihypertrophic effect favoring cardiac metabolism.41 These pleiotropic effects suggest that statins may be beneficial in hypertensive patients with LVH even without disorders of lipid metabolism.42 To confirm the influence of statins on LVH, the REVIERTE (Left Ventricular Hypertrophy Reduction With Statins in Hypertensive Patients) study will be conducted at the Cardiovascular Unit Hospital on October 12 in Mexico City. Kang and Mehta demonstrated that rosuvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, attenuates angiotensin II–mediated cardiomyocyte growth, by inhibiting both lectin-like oxidized low-density lipoprotein receptor and angiotensin-II type 1 receptor expression and suppressing the heightened intracellular redox state.43

Scutellarin, a flavonoid extracted from a traditional Chinese herb, is broadly used in various cardiovascular diseases. The flavonoid significantly reduces infarction size both in myocardial and cerebral ischemia.44 Recently Wei-Pan and coworkers found that Scutellarin also exerts an antihypertrophic effect, via suppressing the Ca++-mediated calcineurin and CaMKII pathways.45 This finding supports the perspective that scutellarin could be an effective candidate against cardiac hypertrophy. But scutellarin also induces neo-angiogenesis, which plays a pivotal role in physiologic and pathologic processes46 and is involved in such disorders as ischemic heart disease, diabetes, chronic inflammation, and cancer.47

It is known that aldosterone is also able to induce cardiac fibrosis in experimental animal models. Matsumura et al demonstrated that aldosterone may induce LVH in human beings as well as in experimental animals.48 The mechanism of aldosterone-induced fibrosis is unclear, but the neurohormone has been shown to increase collagen I synthesis in cardiac fibroblasts. It may also increase the number of endothelin receptors, which increases collagen synthesis. The growth of the left ventricle by aldosterone also seems to be associated with the nitric oxide pathway.49 A number of studies indicate that mineralocorticoid receptor activation exerts deleterious effects in cardiovascular system.50, 51, 52, 53 From a clinical viewpoint, the LIFE study showed that the ARB, losartan, blocking the renin-angiotensin-aldosterone system, greatly reduces LVH in hypertensive patients in comparison to the beta-blocker, atenolol. In this study, blood pressure was nearly identical in both treatment groups. In addition, analysis of regression lines comparing changes in LVH clearly show the pressure independence of LVH reduction.54, 55, 56 The effect of aldosterone on cardiac fibrosis development was blocked by spironolactone, an aldosterone antagonist, that even at low doses, did not reverse SH.57 In support of this theory is the finding that eplerenone (a new aldosterone-antagonist) treatment resulted in a reduction in the collagen/elastin ratio.58

To confirm that total inhibition of aldosterone greatly reduces LVH, more recently Pouleur and coworkers for the ALLAY (Aliskiren in Left Ventricular Hypertrophy) study demonstrated that aliskiren (a direct renin inhibitor) alone or in combination with the angiotensin receptor blocker, losartan, was associated with greater reduction in plasma aldosterone compared with losartan alone in hypertensive patients. This reduction was associated with regression of left ventricular wall thickness and left ventricular myocardial index reduction induced by aliskiren more than losartan (for a direct renin inhibition).59 This study further confirms that aldosterone inhibition significantly reduces LVH in SH.

Section snippets

Conclusion

LVH induced by SH, despite its initial adaptive nature, subsequently is associated with an increased risk of cardiovascular morbidity and mortality that raises by more than two-fold. Data indicate that left ventricular mass regression improves survival in hypertensive patients. Some antihypertensive treatments are able to decrease the rates of adverse cardiovascular events independent of how much the blood pressure is lowered for the regression of LVH.5, 60 It is known that LVH does not always

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