The importance of myocardial fibrosis in hypertensive heart disease

The development of hypertensive heart disease is an early and important finding that may have direct pathophysiological implications in the progression from early hypertension to cardiovascular death [1–3]. There are several determinants of left ventricular hypertrophy (Figure 1) [2,4]. Hemodynamic factors including blood pressure, aortic stiffness and vascular structure, and volume load play an important role in the development of left ventricular hypertrophy. Also important are nonhemodynamic mechanisms, including trophic factors mediated by, for example the sympathetic nervous system, the renin–angiotensin–aldosterone system and insulin. An elevated blood pressure will cause structural vascular changes in the coronary resistance vessels and promote atherosclerosis, and thus the development of coronary artery disease. More important, however, is the contribution of hypertension to the development of left ventricular hypertrophy. An increased afterload, which is an elevated arterial blood pressure, will induce cardiomyocyte hypertrophy, stimulate fibroblasts and increase collagen formation, and cause remodelling of the myocardium with a disproportionate increase in fibrous tissue.FIGURE 1: Schematic illustration of hemodynamic, nonhemodynamic and other determinants for myocardial remodelling in hypertensive heart disease. Adapted from [2,4].A diagnosis of left ventricular hypertrophy can be made with high specificity by use of a standard ECG, although determination of left ventricular mass by echocardiography or MRI techniques provide superior sensitivity and potential additional information. The presence of left ventricular hypertrophy established by an ECG or by echocardiography is a strong and independent risk factor for cardiovascular morbidity and mortality, and of total mortality, in the general population, in hypertensive patients, and in patients with coronary artery disease. Cardiac hypertrophy can promote atrial fibrillation and ventricular arrhythmias, with potentially fatal consequences [5]. Hypertension is the major risk factor for chronic heart failure [6], and myocardial remodelling with left ventricular hypertrophy and myocardial fibrosis plays a pivotal role in the development of heart failure with preserved systolic function. Furthermore, antihypertensive treatment reduces left ventricular mass [7], and the reduction of left ventricular mass reduces the risk for future cardiovascular events [8]. Thus, it is important to identify patients with cardiac hypertrophy and to provide proper antihypertensive treatment. The complex and dynamic myocardial changes in hypertensive heart disease involving cardiomyocyte hypertrophy, fibroblasts and extracellular matrix causing inappropriate myocardial fibrosis, and perivascular changes, have more recently become better understood [4] (Figure 1). There are biomarkers in the circulation that reflect cardiomyocyte hypertrophy and apoptosis, such as cardiotrophin-1 and annexin A5 [9]. Cardiac extracellular matrix fibrillar collagen synthesis can be assessed by markers of collagen I or collagen III, for example the carboxyterminal propeptide of procollagen type I, and its degradation can be measured by collagen I telopeptide or by specific matrix metalloproteinases and their inhibitors [10]. Studies have suggested that hypertension-induced myocardial fibrosis is present also in patients with chronic mild-to-moderate hypertension and normal left ventricular mass [11]. Thus, hypertensive heart disease with myocardial fibrosis in response to an increased left ventricular pressure overload may precede the cardiomyocyte response with left ventricular remodelling and hypertrophy, which might be taken as a later phenotypic manifestation of hypertensive heart disease. Diastolic dysfunction is common in patients with hypertensive left ventricular hypertrophy. By tissue Doppler velocity echocardiography, which is more sensitive than conventional mitral-pulsed wave Doppler echocardiography to detect diastolic dysfunction, virtually all hypertensive patients with cardiac hypertrophy have signs of diastolic dysfunction [12]. Of note, echocardiographic indices of diastolic function seem to be inversely related to the degree of myocardial fibrosis, assessed by circulating collagen markers, and these findings occur also in hypertensive patients with normal left ventricular geometry and mass [11,13]. More recently, two-dimensional speckle tracking echocardiography revealed systolic and diastolic abnormalities already in borderline prehypertensive patients [14], and two-dimensional speckle tracking echocardiography demonstrated a delayed and reduced diastolic untwisting during the isovolumic relaxation period in patients with hypertensive left ventricular hypertrophy [15]. This suggests that recent improvements in echocardiographic methodology can provide useful tools to identify patients with signs of hypertensive heart disease, and, thus, an increased risk for future cardiovascular events, at an earlier stage in their disease progression. Postsystolic shortening of the myocardium along the left ventricular long axis is the delayed ejection motion after closure of the aortic valve. Experimental evidence suggests that postsystolic shortening may be a mechanism of abnormal left ventricular diastolic filling [16]. An increased postsystolic shortening has been shown in patients with hypertension, diabetes, and coronary artery disease [17,18]. The study in this issue of the Journal of Hypertension by Tsai et al.[19] investigated patients with untreated hypertension and normotensive control individuals by two-dimensional speckle tracking echocardiography and assessed postsystolic strain index as a measure of postsystolic longitudinal myocardial shortening. The carboxyterminal propeptide of procollagen type I was measured as a marker of myocardial fibrosis. Their major finding was that the postsystolic strain index was independently related to diastolic dysfunction in a multivariate analysis including age, blood pressure, left ventricular mass, and left ventricular ejection fraction. Increased postsystolic shortening was associated with a delayed diastolic lengthening. Moreover, the postsystolic strain index was independently related to the carboxyterminal propeptide of procollagen type I in a multivariate analysis including age, body weight, blood pressure, and heart rate, suggesting that myocardial fibrosis contributes to diastolic dysfunction. Whether the relation between carboxyterminal propeptide of procollagen type I, as a marker of myocardial fibrosis and diastolic dysfunction was due to an impaired systolic longitudinal function with delayed myocardial relaxation, or to a reduced myocardial compliance in diastole, remains to be clarified, although the observation of normal longitudinal strain may be taken to suggest that the latter mechanism is of importance. The findings of this study are of interest as they provide evidence in support of the negative impact of myocardial fibrosis on diastolic function. Furthermore, the results suggest that postsystolic strain index obtained from two-dimensional speckle tracking echocardiography can be of value to identify patients with hypertensive heart disease. There are some potential limitations to the study by Tsai et al.[19]. The study comprises relatively few participants and there were no invasive hemodynamic measurements performed. The use of circulating levels of carboxy-terminal propeptide of procollagen type I provided only an indirect assessment of myocardial fibrosis. It would have been interesting to see results from circulating biomarkers also reflecting the degradation of extracellular matrix. Such information may help us to better understand the dynamic changes in myocardial extracellular matrix composition. In conclusion, early identifications of patients with hypertensive heart disease is important, as antihypertensive treatment will markedly reduce the risk for future cardiovascular complications. This study by Tsai et al.[19] and other studies show that recent advances in echocardiographic methodology can provide better ways to identify asymptomatic high-risk hypertensive patients at an earlier stage of disease. In addition, circulating biomarkers that reflect myocardial remodelling of extracellular matrix composition and cardiomyocyte function are now available and may give important information and improve risk stratification of hypertensive patients [4]. The potential clinical benefit of an improved risk assessment and appropriate treatment of hypertensive patients by these advances may be considerable. ACKNOWLEDGEMENTS Source of funding: None. Conflicts of interest There are no conflicts of interest.