Hypertensive heart disease

Most of the biological adaptive reactions compensating certain malfunctions often do not translate into the normalization of prognosis. Left ventricular hypertrophy (LVH) in response to chronic high blood pressure increases left ventricular mass to allow greater pumping work without augmenting wall tension or energy consumption. However, hypertrophied heart differs from the normal in so many aspects that the clinical danger of serious cardiovascular events outweighs the initial pathophysiological benefits and forces one to reconsider the impact of the adaptive myocardial growth to hypertensive heart disease (HHD) [1,2]. This raises a principal question: what is the decisive alteration and potential therapeutic target behind the pathology of HHD? Although not unequivocally proven, structural rebuilding with increased amount and altered quality of fibrotic tissue seems to be a dominant feature in the transition of originally adaptive hypertrophy to the ‘pathological remodelling’ [3–5]. Two main and distinct cardiac compartments may be distinguished. Noncollagenous proteins of cardiac muscle cells that include proteins from the sarcoplasmic reticulum, mitochondria, regulatory and modulatory contractile proteins and an enzymatic pool [6]. On the contrary, highly organized interstitium is represented by a network of extracellular matrix structures consisting of different collagen proteins. More than a dozen collagens are recognized, which are encoded by more than 20 collagen genes. Major types of collagen present are collagen I and III [7–9]. Collagen I exerts extraordinary tensile strength, thus significantly enhancing the diastolic myocardial stiffness [5,7,10], whereas collagen III constitutes a fine network and is present especially during the early stages of cardiac development or in the early stages of cardiac hypertrophy [6]. There is a significant functional crosstalk between collagens and other extracellular matrix proteins such as glycoproteins, glycosaminoglycans, elastin, fibronectin, laminin or specific receptor of connective tissue matrix: integrins [6,9]. Mechanisms of LVH development have been investigated extensively. Growth of cardiomyocytes is more closely associated with the extent of hemodynamic burden than is the growth of the interstitium. In a sequence of events, increased wall stress enhances the intracellular calcium level, which in turn activates the phosphatase calcineurin stimulating the transcriptional factors in the cytoplasm and the nucleus. This results in stimulated expression of cardiomyocyte proteins depending on the type, intensity and duration of the overload and on the genotype of the particular individual [9,11]. Fibrosis, on the contrary, depends mainly on the mutual disbalance between neurohumoral proproliferative factors, such as angiotensin II, aldosterone, endothelin I, catecholamines, oxidative stress or growth factors, and substances with antiproliferative activity, involving nitric oxide and prostacyclin [7,12,13]. The renin–angiotensin system and transforming growth factor β1 (TGF-β1) seem to be decisive in the development of reactive and reparative fibrosis [14,15]. Fibroblasts are the principal regulators of collagen turnover under physiological conditions, and early on in HHD they are transformed into myofibroblasts by an increased surge in angiotensin II, aldosterone, endothelin I and TGF-β1. Myofibroblasts, besides their ability to migrate and contract, affect extracellular matrix turnover by increasing the ratio between metalloproteinases and their inhibitors resulting in collagen accumulation with ventricular pathology development [7,15]. Despite recent advances in the understanding of the role of fibrosis in functional and prognostic deterioration of heart diseases, the molecular and cellular mechanisms are still not well understood. The traditional view assumes that resident cardiac fibroblasts are activated by humoral mechanism, oxidative stress and inflammation to convert into myofibroblasts producing collagenous proteins into the intercellular space [15]. However, the discovery of the participation of bone marrow-derived fibrocytes in wound healing started a new era in fibrosis-related diseases [16]. Fibrocytes are unique spindle-shaped cells with pluripotent markers representing a connection between bone marrow, circulating blood and damaged or otherwise altered tissues of several organs including lung, heart, or kidney. These progenitor cells express leukocyte markers CD34, CD45, CD13 indicating their bone marrow origin [17]. However, the expression of mesenchymal markers including procollagen I and III, fibronectin and vimentin indicates their relation to mesenchym, and the expression of chemokine receptors CXCR4, CCR2 or CCR7 signals their ability to traffic from the blood stream to the extravascular compartment. Expression of chemokine CXCL12 in several tissues and the biological axis of CXCL12/CXCR4 is a prerequisite for attracting fibrocytes into a particular organ [17]. After penetrating into the extravascular space, an increased TGF-β1 level enhances α smooth muscle actin (SMA) expression indicating the differentiation of fibrocytes into myofibroblasts [18]. The study by Keeley et al.[19] in this issue of the Journal of Hypertension shows that circulating fibrocyte levels and activated (α SMA expressing) fibrocyte number were elevated in patients with HHD as assessed by magnetic resonance as compared to normotensives. Moreover, the number of fibrocytes and activated fibrocytes strongly correlated with the extent of the indexed left ventricular mass. Finally, a subset of fibrocytes expressing chemokine markers CXCR4, CCR2, CCR7 and coexpressing both CXCR4 and CCR2 was also elevated in patients with HHD [19]. This is the first human study showing that circulating fibrocytes and their activated forms could participate in the process of hypertensive heart remodelling. However, this study should be considered as a pilot study due to the small number of patients (12 with HHD and 19 controls). Several important limitations should be kept in mind when considering the clinical relevance of these results; the small number of middle-aged patients involved in the study does not allow extrapolating these results to the general population of hypertensives. Moreover, use of antihypertensive medications by about half of the hypertensive patients may have interfered with the number of fibrocytes. Additionally, the reported magnetic resonance data reflect only overall left ventricular mass and not the content, concentration or even quality of the fibrotic tissue [19]. This study may have significant scientific and clinical implications in spite of several shortcomings, and stimulate several considerations:FIGURE 1: Possible contributions of fibrocytes (Fbc) to heart fibrosis and potential treatment approaches. Fibrocytes residing in bone marrow express markers of leukocytes (CD34). The potential stimuli for bone marrow to release Fbc into the blood stream may involve either humoral factors contributing to myocardial fibrosis or the hemodynamic overload itself. Fbc entering the circulation are activated and express α smooth muscle actin (SMA) and cytokine receptors such as CXR4, CCR2 or CCR7. Interaction of CCR4 with CCL2 (expressed in the remodelled tissue) determines the trafficking of Fbc into the myocardial tissue. Here Fbc are transformed into myofibroblasts producing extracellular matrix proteins such as collagen I and III, elastin, fibronectin and laminin. Hypothetic therapeutic interventions may reside in interference with fibrocytes at the level of their bone marrow release, activation or trafficking into the myocardium. Is the increased level of circulating fibrocytes a predecessor of myocardial fibrosis? Magnetic resonance may in the future not only precisely estimate the left ventricular weight [3], but also the amount and quality of myocardial collagen. Then it will be exciting to investigate whether there is a correlation between the level of circulating fibrocytes and the level of fibrosis. If this correlation is significant, then circulating fibrocyte levels could serve as an easily accessible and reproducible noninvasive marker of myocardial fibrosis development, its modification by treatment, and even as a marker of prognosis. In fact, enhanced fibrosis was associated with a deterioration of prognosis in the RALES (Randomized Aldacton Evaluation Study) trial involving 260 patients with heart failure in whom an increased serum level of N-terminal aminopeptid procollagen type III was associated with deteriorated prognosis, and spironolactone treatment reduced fibrosis and improved survival [20]. Circulating fibrocytes have been shown to serve as a predictor of early mortality in patients with idiopathic pulmonary fibrosis [21]. Is myocardial fibrosis indeed the result of bone marrow activation? Although the causal relation between end organ damage and bone marrow is difficult to prove, a remarkable increase in the level of fibrocytes originating from bone marrow in hypertensive patients with LVH compared to controls suggests that bone marrow at least largely contributes to the development of myocardial fibrosis. If so, what molecular signals translate chronic afterload into bone marrow activation? In a mouse model of hypertension and LVH induced by angiotensin II infusion, the level of circulating fibrocytes increased along with myocardial fibrosis [22]. In the same model of fibrosis, angiotensin II-induced nonadaptive cardiac fibrosis required monocyte chemoattractant protein, which modulated the uptake and differentiation of a bone marrow-derived CD34/CD45 fibroblast population [23]. Recently, it was shown that bone marrow-derived fibrocytes (expressing hematopoietic marker CD133 and leukocyte marker ED1) are key effector cells in the initiation of angiotensin II-induced myocardial fibrosis [24]. Is angiotensin II and perhaps other recognized neurohumoral stimulators of heart fibrosis responsible also for the release of fibrocytes from the bone marrow and/or for their activation and cytokine expression on their surface enabling them to home into the myocardium? An exciting question is whether activated circulating fibrocytes may affect several organs simultaneously like the heart, lungs or the liver? It is believed that heart and lung fibrosis may have associated pathologies [25]. This assumption is supported by the finding in the rat that Nω-nitro-L-arginine methyl ester-induced hypertension leads to stimulation of deoxyribonucleic and ribonucleic acid concentration (reflecting increased proliferation and protein synthesis) not only in the left ventricle but also in the kidney, brain and aorta [26]. These considerations raise the hypothesis that hypertension may be a neurohumoral syndrome associated with generalized organ remodelling. We cannot exclude that two distinct processes of fibrosis may coexist: one with fibroblasts residing in the myocardial tissue being attracted into altered tissue by paracrine or endocrine mechanisms and activated into myofibroblasts, and a second one with bone marrow-derived fibrocytes being homed into the myocardium through the blood stream and converted into myofibroblasts. What implications for HHD treatment may arise from these considerations? Assuming that treatment in the early stages of the cardiovascular continuum brings higher benefits than intervention in later stages [27], targeting the activated fibrocyte population before it can trigger myocardial fibrosis is promising. This might be achieved by interfering with fibrocyte in the bone marrow, their release into the blood stream or by preventing their trafficking into the myocardium on the chemokine levels (Fig. 1). Bleomycin-g treatment-induced lung fibrosis in mouse and antibodies neutralizing the CXCL12 tissue ligand led to a reduction in lung fibrocyte homing and attenuation of collagen deposition [28]. Furthermore, in a mouse closed chest model of ischemia-reperfusion cardiomyopathy, administration of serum amyloid P attenuated fibrocytes accumulation in the myocardium and prevented fibrosis and ventricular dysfunction [29]. In the CCR2 knockout mouse (CCR2 is the chemokine fibrocyte receptor mediating the recruitment of fibrocytes to the heart) angiotensin II infusion failed to induce myocardial fibrosis [22]. Alternatively, an ability to expand fibrocytes ex vivo for therapeutic readministration may prove to be of benefit during the later periods of HHD regarding their ability to support angiogenesis [30]. The focus on bone marrow activation in HHD could deepen the insight into the pathogenesis of target organ damage and it may open new doors to novel treatment strategies. The recent article by Keeley et al.[19] encourages us to take the next step in this direction, that is, to establish a correlation between circulating fibrocyte levels and left ventricular fibrosis in a large cohort of HHD patients without antihypertensive medication. Such a study might provide the key evidence needed to bring the heart–bone marrow interaction into the spotlight of cardiovascular research. ACKNOWLEDGEMENTS This study was supported by the research grants VEGA of the Ministry of Education (No 1/0227/12, 2/00183/12 and 1/0831/11). Conflicts of interest There are no conflicts of interest. However, F.S. has given lectures on behalf of Pfizer, Sanofi-Aventis, MSD, Zentiva, Servier, and Glenmark.