Mechanical dyssynchrony: another mechanism of left ventricular dysfunction in hypertension?

Epidemiological studies, such as the Framingham Heart Study, have demonstrated that hypertension is the most common etiological factor for congestive heart failure, and is present in 50% of cases [1]. Hypertension may result in heart failure as a consequence of underlying coronary artery disease and arrhythmias, such as atrial fibrillation, and/or due to structural alterations of left ventricular myocardium leading to hypertensive-related left ventricular hypertrophy (LVH). In this conceptual framework, LVH is currently considered to be a measure of preclinical cardiac disease that predisposes to left ventricular dysfunction and heart failure in the hypertensive patient [2]. In addition to subclinical diastolic dysfunction, latent systolic dysfunction can develop before the onset of obvious left ventricular dysfunction and failure in patients with LVH [3]. Left ventricular function is affected not only by a depressed contractile status of the myocardium, abnormal loading conditions or both, but also by a disturbed synchrony of the myocardial walls [4]. Left ventricular synchrony is a pivotal factor in modulating left ventricular function. Ventricular contraction normally occurs in a highly coordinated manner and is determined by the propagation of ventricular depolarization and the excitation–contraction coupling. Mechanical activation of the ventricles depends on the rapid spread of electric signals via specialized fibers (His-Purkinje system) that arborize throughout the right ventricular and left ventricular endocardia [5]. In the normal heart, the duration of ventricular electrical activation (range 80–100 ms) and mechanical activation (range 150–200 ms) are closely related. Activation occurs from the endocardium to the epicardium [6], as well as from the apex to the base [7], and is nearly coincident in all regions of the left ventricle. Delayed electrical activation and/or impaired excitation–contraction coupling result in a dispersion of regional mechanical activation known as intraventricular dyssynchrony For the most common pattern of left ventricular dyssynchrony, the septal region is stimulated first, followed by delayed activation of the lateral left ventricular free wall. The result is a late-systolic activation of the left ventricular lateral free wall that, in turn, stretches the anteroseptal region, competing with aortic ejection and reducing net cardiac output. Left ventricular dyssynchrony is associated with increased presystolic mitral valve regurgitation, decreased left ventricular diastolic filling time, and reduced left ventricular contractility [4]. In addition, left ventricular mechanical dyssynchrony has detrimental effects on regional myocardial perfusion, metabolism and electrophysiology [8]. Finally, left ventricular mechanical dyssynchrony also triggers a number of changes in the expression and activity of proteins involved in cardiomyocyte function (i.e. the mitogen-activated kinase 42/44ERK, the sarcoplasmic/endoplasmic reticulum calcium-adenosine triphosphatase 2a, phospholamban and the gap junction protein Cx43) [9]. Dyssynchrony generates pathobiologic changes at the tissue, cellular and molecular levels that conspire to worsen left ventricular myocardial performance, increase arrhythmia susceptibility, and further challenge the failing heart. Although the diagnosis of left ventricular dyssynchrony is made mainly in patients with heart failure and prolonged QRS duration (> 120 ms), there is an increased number of reports that have identified dyssynchrony in the absence of heart failure (i.e. patients with hypertrophic cardiomyopathy and normal ejection fraction) or prolonged QRS (i.e. patients with idiopathic dilated cardiomyopathy and no conduction abnormalities); thus, the prevalence of left ventricular dyssynchrony may be underestimated [4]. The assessment of left ventricular dyssynchrony has been gaining interest because resynchronization of ventricular contraction by pacing (i.e. the so-called cardiac resynchronization therapy) has been demonstrated unequivocally to improve functional status, quality of life and left ventricular performance and to reduce hospitalization and mortality in patients with heart failure and prolonged QRS duration [10]. In this issue of the journal, Tan et al. [11] provide data showing that left ventricular dyssynchrony is present in hypertensive patients without heart failure or conduction abnormalities. Tan et al. [11] used echocardiography with tissue Doppler imaging (TDI) to simultaneously assess regional myocardial contraction and mechanical delay in 30 healthy subjects and 115 patients with mild-to-moderate essential hypertension. None of the patients exhibited a clinical history of cardiac disease, and the mean ejection fraction and QRS duration were normal. Hypertensive patients were divided into two subgroups in accordance with the presence (n = 84) or absence (n = 31) of LVH, as defined by values of the left ventricular mass index above the standard reference values. Diastolic dysfunction as assessed by pulsed Doppler echocardiography and TDI was present in the two subgroups of patients, namely in those with LVH. Left ventricular synchrony was determined by measuring the maximal difference and the standard deviation of time to peak myocardial systolic and time to peak early diastolic velocity using a 12-segment model. Thus, the main findings of the study can be summarized. (i) The parameters assessing left ventricular synchrony were significantly altered in the two subgroups of hypertensive patients, namely in the subgroup with LVH. (ii) The pattern of left ventricular dyssynchrony in both subgroups of patients, mainly characterized by delayed mechanical activation of the free wall region was similar, although not identical, to the classical left ventricular dyssynchrony pattern of patients with systolic heart failure and left bundle branch block. (iii) The prevalence of left ventricular dyssynchrony was significantly higher in LVH patients than in non-LVH patients. (iv) Parameters assessing left ventricular synchrony were significantly correlated not just with left ventricular mass index, but also with parameters assessing diastolic function in all patients. These findings confirm recent TDI data from the same group [12] and other studies [13] showing that left ventricular mechanical dyssynchrony frequently coexists in patients with essential hypertension. In addition, the results from the study by Tan et al. [11] showing the association of left ventricular dyssynchrony with hypertensive-related LVH are in agreement with those obtained in other studies [14,15]. Finally, in accordance with previous findings [13,14,16] the results from the study by Tan et al. [11] add further evidence to the relationship of left ventricular dyssynchrony not only with frank diastolic heart failure but also with subclinical diastolic dysfunction in hypertensive patients. Although acknowledged in part by the authors, the study by Tan et al. [11] has several limitations. (i) The number of patients in the study was small, and there is the potential confounding factor of long-term medication use. (ii) Coronary heart disease can account for left ventricular dyssynchrony. Coronary angiography was not performed as a part of the study protocol. Therefore, the presence of coronary heart disease cannot be entirely excluded, although none of the patients showed positive findings on treadmill exercise test. (iii) Although TDI is an established method for the assessment of left ventricular dyssynchrony, its angle-dependency precludes evaluation of dyssynchrony through the left ventricle. Translation of the heart in conjunction with the tethering motion of adjacent segments affects the velocity-derived values of TDI and may influence the calculation of the parameters assessing synchrony. In addition, the echocardiographic studies could not have been blinded because the presence of LVH may have been visible on the echocardiogram in some patients. (iv) Recently, the variability in the TDI measurement of those parameters assessing left ventricular dyssynchony was shown to be high [17], and this aspect can represent a major limitation in studies performed in small samples, as in the one under discussion. (v) There are other ultrasound methods that have been used to identify left ventricular dyssynchrony in hypertensive patients [18]. In the study by Tan et al. [11], the authors did not examine these methods and therefore cannot address the reproducibility of their results. This can be of relevance when taking into account that Nagakura et al.[19] reported that hypertensive patients with LVH did not exhibited remarkable left ventricular dyssynchrony as assessed using two-dimensional ultrasound speckle tracking imaging. Despite these limitations, the study by Tan et al. [11] raises interesting considerations on the pathophysiological relevance of the interaction of left ventricular dyssynchrony with LVH and diastolic dysfunction in hypertension. Although the physiology of diastolic function is complex, left ventricular dyssynchrony has been included among the intrinsic factors contributing to diastolic disturbances in LVH [20]. The major determinant of early diastolic filling is the strength and coordination of the previous systole, which is the driver for ventricular suction. In addition, left ventricular dyssynchrony and prolonged systolic times will result in a reduced left ventricular filling time and an uncoordinated and prolonged isovolumic relaxation that will further impair diastolic function [21]. Clinical studies have shown that regional dyssynchrony of left ventricular contraction and relaxation is associated with regional ischemia as well as with myocardial fibrosis [22,23], thus providing the potential mechanistic links between hypertensive-related LVH and left ventricular dyssynchrony. Hypertensive-related LVH is associated with a profound impairment of coronary autoregulation [24]. In hypertensives with LVH, a shift of the pressure–flow autoregulatory relationship is evident, and coronary flow decreases progressively as coronary perfusion decreases below 90 mmHg whereas, in hypertensives without LVH and in normotensive individuals, coronary flow is maintained down to a perfusion pressure of 60 mmHg. In addition, hypertensive patients with LVH have frequently impaired coronary flow reserve (defined as the maximal increase in coronary flow above its resting level when the coronary vasculature is maximally dilated), even in the absence of LVH [25]. The decrease in coronary vasodilator response present in these patients is accounted for by several changes in myocardial structure (perivascular fibrosis) and function (increase in left wall tension and oxygen consumption), as well as by structural alterations of intramyocardial arteries and/or inadequate capillary angiogenesis, together with increased arteriolar tone, endothelial dysfunction and extravascular systolic compression. On the other hand, various studies performed in human heart postmortem specimens and endomyocardial human biopsy samples have shown that the fraction of myocardial volume occupied by collagen type I and type III fibers is significantly increased in hypertensive patients with LVH compared to that in a normotensive population [26]. A linkage between the exaggerated accumulation of collagen fibers within the interstitium and surrounding intramural coronary arteries and arterioles and left ventricular dysfunction may be established [27]. Initially, the accumulation of collagen fibers compromises the rate of relaxation, diastolic suction and passive stiffness, contributing to impaired diastolic function. Continued accumulation of fibrous tissue, accompanied by changes in the spatial orientation of collagen fibers, further impairs diastolic filling and compromises transduction of cardiomyocyte contraction into myocardial force development, thus impairing systolic performance. The study by Tan et al.[11] together with data by Wang et al.[13] point to left ventricular dyssynchrony as a possible independent mechanism involved in the decline of systolic function in hypertensive patients with LVH. Thus, it also highlights the usefulness of assessing left ventricular synchrony in the clinical evaluation of hypertensive patients with LVH, as well as on the possibility that dyssynchrony of left ventricle may be a target for pharmacological strategies aiming to interfere with the transition from LVH to heart failure in hypertensive patients. As stated by the recent 2007 Guidelines for the Management of Arterial Hypertension of the European Society of Hypertension and the European Society of Cardiology [28], useful information on left ventricular diastolic function can be derived from TDI examination of left ventricular filling in hypertensive patients. However, this echocardiographic technique provides an excellent temporal resolution, thus providing measurements of the time intervals between the onset of electrocardiogram-derived QRS and the peak and onset of myocardial systolic and diastolic velocities that help to evaluate left ventricular synchrony. Additionally, TDI assessment of left ventricular dyssynchrony has provided independent and incremental prognostic information on heart failure events and mortality in a number of major cardiac diseases [29]. Because TDI is readily available in most of the current echocardiographic systems, this information can now be applied toward the optimal clinical management for patients who are vulnerable to the development of cardiovascular events (i.e. hypertensive patients with LVH). Although evidence-based data are scarce with respect to guiding therapy for hypertensive patients with left ventricular dysssynchrony and without heart failure, some clinical studies have reported beneficial effects as a result of the acute administration of verapamil [30] or captopril [31] on left ventricular dyssynchrony in patients with ischemic heart disease and hypertrophic cardiomyopathy, respectively. Short-term (1–2 weeks) therapy with verapamil has been shown also to reduce left ventricular dyssynchrony in patients with hypertrophic cardiomyopathy [32,33]. However, it is not known whether chronic pharmacological therapy can influence left ventricular synchrony. Recently, left ventricular contractile function and dyssynchrony was shown to be improved in patients with idiopathic dilated cardiomyopathy and normal QRS after 6 months of treatment with carvedilol [34]. This is the first study to examine cardiac resynchronization by long-term medical therapy and opens up a new pathway to investigate whether chronic therapy with antihypertensive drugs may provide benefits in terms of correction of left ventricular dyssynchrony and its hypothetical effect on the progression of heart failure in hypertensive patients with LVH and dyssynchrony.