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La tesis tratar de esclarecer el papel de la fibrosis miocárdica en pacientes con HTA desde estadíos tempranos de la enfermedad. Acorde con ello se pretende detectar aquellos pacientes con peor pronóstico clínico. Por otra parte, se analiza la posible interacción de la ERC en la progresión de fibrosis miocárdica y en la disfunción diastólica en pacientes hipertensos.

We investigated the effect of galectin-3 (Gal-3) inhibition with modified citrus pectin on markers of collagen metabolism in a proof-of-concept randomized placebo-controlled trial of participants with elevated Gal-3 levels and hypertension. Although higher Gal-3 levels were associated with female sex, diabetes, and reduced glomerular filtration rate in cross-sectional analyses, treatment with modified citrus pectin did not change collagen markers. The effect of Gal-3 inhibition among individuals with heart failure warrants further investigation. (C) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Background—Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and a potential substrate for arrhythmias and heart failure. Sarcomere mutations seem to induce profibrotic changes before left ventricular hypertrophy (LVH) develops. To further evaluate these processes, we used cardiac magnetic resonance with T1 measurements on a genotyped HCM population to quantify myocardial extracellular volume (ECV). Methods and Results—Sarcomere mutation carriers with LVH (G+/LVH+, n=37) and without LVH (G+/LVH−, n=29), patients with HCM without mutations (sarcomere-negative HCM, n=11), and healthy controls (n=11) underwent contrast cardiac magnetic resonance, measuring T1 times pre- and postgadolinium infusion. Concurrent echocardiography and serum biomarkers of collagen synthesis, hemodynamic stress, and myocardial injury were also available in a subset. Compared with controls, ECV was increased in patients with overt HCM, as well as G+/LVH− mutation carriers (ECV=0.36±0.01, 0.33±0.01, 0.27±0.01 in G+/LVH+, G+/LVH−, controls, respectively; P≤0.001 for all comparisons). ECV correlated with N-terminal probrain natriuretic peptide levels (r=0.58; P60% of overt patients with HCM but absent from G+/LVH− subjects. Both ECV and late gadolinium enhancement were more extensive in sarcomeric HCM than sarcomere-negative HCM. Conclusions—Myocardial ECV is increased in HCM sarcomere mutation carriers even in the absence of LVH. These data provide additional support that fibrotic remodeling is triggered early in disease pathogenesis. Quantifying ECV may help characterize the development of myocardial fibrosis in HCM and ultimately assist in developing novel disease-modifying therapy, targeting interstitial fibrosis.

BACKGROUND.: The assessment of carotid intima-media thickness (CIMT) may improve cardiovascular risk prediction. The optimal protocol for CIMT measurement is unclear. CIMT may be measured in the common carotid artery (CCA), carotid bifurcation (CB), and internal carotid artery (ICA), but measurements from CB and ICA are more difficult to obtain. We studied the influence of body mass index (BMI) and atheroma plaques on the capacity to obtain CIMT measurements at different carotid sites. METHODS.: Using an automatic system, CIMT was measured in 700 subjects aged 45-75, in the near and far walls of CCA, CB, and ICA bilaterally. The presence of atheroma plaques, BMI and vascular risk factors were recorded. RESULTS.: CIMT measurements in CCA were possible in all except one subject. It was not possible to obtain CIMT measurements at CB or ICA in 24.1% of normal weight and 58.8% of obese subjects. The likelihood of obtaining CIMT measurement at all carotid sites decreased as the BMI increased. Atheroma plaques in a carotid segment did not preclude CIMT measurement at this site. CONCLUSIONS.: CIMT measurements in distal carotid segments are more challenging in obese subjects. Measuring CIMT at CCA remains feasible in obese subjects and should be the primary endpoint in these subjects. Nevertheless, CB and ICA measurements, when feasible, would improve risk classification.

Activation of apoptosis contributes to cardiomyocyte dysfunction and death in diabetic cardiomyopathy. The peptide glucagon-like peptide-1 (GLP-1), a hormone that is the basis of emerging therapy for type 2 diabetic patients, has cytoprotective actions in different cellular models. We investigated whether GLP-1 inhibits apoptosis in HL-1 cardiomyocytes stimulated with staurosporine, palmitate, and ceramide. Studies were performed in HL-1 cardiomyocytes. Apoptosis was induced by incubating HL-1 cells with staurosporine (175 nM), palmitate (135 μM), or ceramide (15 μM) for 24 h. In staurosporine-stimulated HL-1 cardiomyocytes, phosphatidylserine exposure, Bax-to-Bcl-2 ratio, Bad phosphorylation (Ser(136)), BNIP3 expression, mitochondrial membrane depolarization, cytochrome c release, caspase-3 activation, DNA fragmentation, and mammalian target of rapamycin (mTOR)/p70S6K phosphorylation (Ser(2448) and Thr(389), respectively) were assessed. Apoptotic hallmarks were also measured in the absence or presence of low (5 mM) and high (10 mM) concentrations of glucose. In addition, phosphatidylserine exposure and DNA fragmentation were analyzed in palmitate- and ceramide-stimulated cells. Staurosporine increased apoptosis in HL-1 cardiomyocytes. GLP-1 (100 nM) partially inhibited staurosporine-induced mitochondrial membrane depolarization and completely blocked the rest of the staurosporine-induced apoptotic changes. This cytoprotective effect was mainly mediated by phosphatidylinositol 3-kinase (PI3K) and partially dependent on ERK1/2. Increasing concentrations of glucose did not influence GLP-1-induced protection against staurosporine. Furthermore, GLP-1 inhibited palmitate- and ceramide-induced phosphatidylserine exposure and DNA fragmentation. Incretin GLP-1 protects HL-1 cardiomyocytes against activation of apoptosis. This cytoprotective ability is mediated mainly by the PI3K pathway and partially by the ERK1/2 pathway and seems to be glucose independent. It is proposed that therapies based on GLP-1 may contribute to prevent cardiomyocyte apoptosis

The heart is a remarkably adaptive organ, capable of increasing its minute output and overcoming short-term or prolonged pressure overload. The structural response, in addition to the foregoing functional demands, is that of myocardial hypertrophy. Then, why should an adaptive response increase cardiovascular risk in hypertensive patients with left ventricular hypertrophy (LVH)? Evidence shows that the functional performance of hypertrophied cardiomyocytes is impaired, and that additional alterations develop in cardiomyocytes themselves, the extracellular matrix and the intramyocardial vasculature, leading to myocardial remodelling and providing the basis for the adverse prognosis associated with pathological LVH in hypertensive patients (i.e., hypertensive heart disease, HHD). As molecular information accumulates, the pathophysiological understanding and the clinical approach to HHD are changing. The time has come to develop novel diagnostic and therapeutic strategies aimed at improving the prognosis of HHD on the basis of reversing or even preventing the aforementioned changes in the ventricular myocardium.

The European Society of Hypertension Task Force on the management of hypertension has recently reappraised the 2007 European guidelines. This reevaluation was based on a number of studies published in the previous 2 years. From a renal point of view, several conclusions of the reevaluation merit consideration. Firstly, the importance of including subclinical renal organ damage when evaluating total cardiovascular risk is reemphasized. Secondly, recommendations for reducing blood pressure to below 130/80 mmHg in diabetic and high-risk hypertensive patients (i.e., patients with renal damage) are critically reappraised, since the expected benefits are not consistently supported by trial evidence. Moreover, in these patients, the J-curve phenomenon may occur, thus compromising renal function. Thirdly, some of the drug combinations recommended in 2007 should be used with extreme precaution in hypertensive patients with renal involvement, especially those interfering with the renin-angiotensin system at different levels.

OBJECTIVE: Experimental and clinical evidence supports a role of cardiotrophin-1 (CT-1) in the development of hypertensive left ventricular hypertrophy (LVH). The goal of this study was to investigate the relationship between human CT-1 genetic background and LVH in essential hypertension. METHODS: A total of 900 individuals were genotyped for the 1742(C/G) polymorphism of the human CT-1 gene. Serum CT-1 levels were assessed by ELISA in 681 individuals. Left ventricular parameters were determined by two-dimensional echocardiography in 297 individuals. RESULTS: The prevalence of the GG genotype of the 1742(C/G) polymorphism was reduced in essential hypertension (8.4% in normotensive individuals, 4.9% in hypertensive patients, P = 0.046 versus CC/CG individuals) and in LVH (11.5% in nonhypertrophic normotensive individuals, 12.2% in nonhypertrophic hypertensive patients, 2.6% in hypertensive patients with LVH, P = 0.008 versus CC/CG individuals). Apart from this, GG individuals presented lower serum concentration of CT-1 (GG, 147.1 ± 10.5 fmol/ml; CC/CG, 187.1 ± 4.8 fmol/ml; P = 0.036) and left ventricular mass index (GG, 91 ± 6 g/m; CC/CG, 119 ± 3 g/m; P = 0.002). Multivariate analyses showed that the 1742(C/G) polymorphism was a significant determinant of both left ventricular mass index and serum CT-1, after adjusting for confounding factors. Finally, in-vitro studies supported the functionality of the 1742(C/G) polymorphism. CONCLUSION: Our results indicate that the 1742(C/G) polymorphism of the human CT-1 gene is associated with LVH in hypertension and that the GG genotype may have a protective role. It is suggested that CT-1 is one of the mediators of this association.

OBJECTIVE: Insulin resistance is associated with the pathogenesis of metabolic disorders as type 2 diabetes and obesity. Given the emerging role of signal transduction in these syndromes, we set out to explore the possible role that G protein-coupled receptor kinase 2 (GRK2), first identified as a G protein-coupled receptor regulator, could have as a modulator of insulin responses. RESEARCH DESIGN AND METHODS: We analyzed the influence of GRK2 levels in insulin signaling in myoblasts and adipocytes with experimentally increased or silenced levels of GRK2, as well as in GRK2 hemizygous animals expressing 50% lower levels of this kinase in three different models of insulin resistance: tumor necrosis factor-α (TNF-α) infusion, aging, and high-fat diet (HFD). Glucose transport, whole-body glucose and insulin tolerance, the activation status of insulin pathway components, and the circulating levels of important mediators were measured. The development of obesity and adipocyte size with age and HFD was analyzed. RESULTS: Altering GRK2 levels markedly modifies insulin-mediated signaling in cultured adipocytes and myocytes. GRK2 levels are increased by ∼2-fold in muscle and adipose tissue in the animal models tested, as well as in lymphocytes from metabolic syndrome patients. In contrast, hemizygous GRK2 mice show enhanced insulin sensitivity and do not develop insulin resistance by TNF-α, aging, or HFD. Furthermore, reduced GRK2 levels induce a lean phenotype and decrease age-related adiposity. CONCLUSIONS: Overall, our data identify GRK2 as an important negative regulator of insulin effects, key to the etiopathogenesis of insulin resistance and obesity, which uncovers this protein as a potential therapeutic target in the treatment of these disorders.

Because of its dynamic nature, the composition and structure of the myocardial collagen network can be reversibly modified to adapt to transient cardiac injuries. In response to persistent injury, however, irreversible, maladaptive changes of the network occur leading to fibrosis, mostly characterized by the excessive interstitial and perivascular deposition of collagen types I and III fibers. It is now becoming apparent that myocardial fibrosis directly contributes to adverse myocardial remodeling and the resulting alterations of left ventricular (LV) anatomy and function present in the major types of cardiac diseases. The enzyme lysyl oxidase (LOX) is a copper-dependent extracellular enzyme that catalyzes lysine-derived cross-links in collagen and elastin. LOX-mediated cross-linking of collagen types I and III fibrils leads to the formation of stiff collagen types I and III fibers and their subsequent tissue deposition. Evidence from experimental and clinical studies shows that the excess of LOX is associated with an increased collagen cross-linking and stiffness. It is thus conceivable that LOX upregulation and/or overactivity could underlie myocardial fibrosis and altered LV mechanics and contribute to the compromise of LV function in cardiac diseases. This review will consider the molecular aspects related to the regulation and actions of LOX, namely, in the context of collagen synthesis. In addition, it will address the information related to the role of myocardial LOX in heart failure and the potential benefits of controlling its expression and function.

Fibrosis is an established morphological feature of the structural myocardial remodeling that occurs in several cardiac diseases. This feature confers an increased risk for adverse cardiovascular events such as ventricular dysfunction and arrhythmias. The molecular mechanisms that lead to a fibrogenic cardiac phenotype are still being elucidated. A small number of studies have demonstrated that altered expression of several microRNAs (miRNAs) in myocardial fibrosis is associated with ischemia or mechanical overload; however, much work is still required to identify which miRNAs have a direct role in the development of fibrosis, and which develop alterations in expression that are secondary to the cardiac insult. Characterization of individual miRNAs or miRNA expression profiles that are specifically associated with myocardial fibrosis might allow us to develop diagnostic tools and innovative therapies for fibrogenic cardiac diseases.

AIM: We investigated whether P144, a synthetic peptide from transforming growth factor-beta(1) (TGF-beta(1)) type III receptor betaglycan, exhibits cardiac antifibrotic properties. METHODS AND RESULTS: The study was carried out in one group of 10-week-old normotensive Wistar-Kyoto rats treated with vehicle (V-WKY), one group of 10-week-old spontaneously hypertensive rats treated with vehicle (V-SHR), and one group of 10-week-old SHR treated with P144 (P144-SHR) for 12 weeks. Two more groups of 10-week-old untreated WKY and SHR were used to assess baseline values of the parameters tested. In addition, the effects of P144 on rat cardiac fibroblasts stimulated with TGF-beta(1) were also studied. Compared with V-WKY, V-SHR exhibited significant increases in the myocardial expression of phosphorylated Smad2, 38 and 42 kDa connective tissue growth factor (CTGF) isoforms, procollagen alpha1 (I) mRNA, and collagen type I protein, as well as in the expression of lysyl oxidase (LOX) mRNA and protein, collagen cross-linking and deposition. P144 administration was associated with significant reduction in all these parameters in P144-SHR. TGF-beta(1)-stimulated fibroblasts exhibited significant increases in phosphorylated Smad2, 38 and 42 kDa CTGF proteins, and procollagen alpha(1) (I) mRNA compared with control fibroblasts. No significant differences were found in these parameters between fibroblasts incubated with TGF-beta(1) and P144 and control fibroblasts. CONCLUSION: These results show that P144 inhibits TGF-beta(1)-dependent signalling pathway and collagen type I synthesis in cardiac fibroblasts. These effects may be involved in the ability of this peptide to prevent myocardial fibrosis in SHR.

Oxidative stress plays a critical role in the pathogenesis of hypertension. The NADPH oxidase constitutes a major source of superoxide anion in phagocytic cells, and its activation is associated with matrix metalloproteinase (MMP)-9 secretion by these cells. We investigated the effects of the angiotensin II type 1 receptor antagonist losartan and its metabolites (EXP3174 and EXP3179) on NADPH oxidase activity and MMP-9 secretion in human phagocytic cells. EXP3179, but not losartan and EXP3174, dose-dependently inhibited (P

The renin-angiotensin system plays a key role in the regulation of blood pressure, and blockade of this system now forms a central part of strategies to reduce the risk for cardiovascular events in hypertensive patients, namely in those with renal disease and high risk. Blockade of the renin-angiotensin system with angiotensin converting enzyme inhibitors or angiotensin II type 1 receptor antagonists has proved effective in the treatment of hypertensive patients with or without renal disease, thus providing first-line therapy in the nephrological setting. Studies comparing the two classes of have shown that they appear to have similar efficacy though angiotensin II type 1 receptor antagonists are better tolerated. Although previous studies found that combinations of these two classes of drugs have greater antihypertensive and renoprotective effects than monotherapy, data from recent large trials suggest that combination therapy may be detrimental, namely in terms of renal complications.

A new pathophysiologic paradigm on HHD is emerging. This entity is the result of the pathologic structural remodeling of the myocardium in response to a mosaic of hemodynamic and nonhemodynamic factors altered in hypertension more than just the adaptive hypertrophy of the left ventricular wall to increased pressure. The potential clinical relevance of this paradigm is given by the fact that it entails a new approach to HHD in terms of more detailed diagnosis and more demanding treatment. But this novel view of HHD may also have epidemiologic importance. In fact, the possibility that myocardial individuals prone to develop HHD may be detected before the appearance of clinical detectable LVH opens a new way to the prevention of cardiac complications associated with hypertension and its impact on the heart, namely heart failure.

Although hypertensive heart disease (HHD) is clinically characterized by development of left ventricular hypertrophy in the absence of a cause other than arterial hypertension, changes in the composition of myocardial tissue also develop in arterial hypertension, leading to structural remodeling of the myocardium (eg, fibrosis). Myocardial fibrosis is the major determinant of diastolic dysfunction/failure in patients with HHD. Recent available data on the determination of serum concentrations of collagen-derived serum peptides, as well as quantitative analysis of echoreflectivity to address the presence of fibrosis in the myocardium of hypertensive patients, are promising. In addition, preliminary data suggest that the goal of reducing myocardial fibrosis is achievable using specific pharmacological agents in patients with HHD.

Oxidative stress plays a key role in the pathophysiology of several major cardiovascular diseases, including atherosclerosis, hypertension, heart failure, stroke and diabetes. ROS (reactive oxygen species) affect multiple tissues either directly or through NO depletion. ROS induce cardiovascular dysfunction by modulating cell contraction/dilation, migration, growth/apoptosis and extracellular matrix protein turnover, which contribute to vascular and cardiac remodelling. Of the several sources of ROS within the cardiovascular system, a family of multisubunit NADPH oxidases appears to be a predominant contributor of superoxide anion. Recent findings suggest a significant role of the genetic background in NADPH oxidase regulation. Common genetic polymorphisms within the promoter and exonic sequences of CYBA, the gene that encodes the p22(phox) subunit of NADPH oxidase, have been characterized in the context of cardiovascular diseases. This review aims to present the current state of research into these polymorphisms in their relationship to cardiovascular diseases.

Changes in the composition of cardiac tissue develop in arterial hypertension and lead to structural remodelling of the myocardium. Cardiomyocyte hypertrophy and apoptosis, fibrous tissue accumulation within the myocardial interstitium and wall hypertrophy of the microvasculature are alterations of the adverse structural remodeling of cardiac tissue seen with hypertensive heart disease. Its clinical relevance is that it might contribute to the myocardial dysfunction and failure, therefore noninvasive monitoring of myocardial remodeling by using circulating markers could prove a clinically useful tool. Emerging evidences hold promise for the use of various markers of cellular response to biomechanical stress (i.e, cardiotrophin-1 and natriuretic peptides), cardiac apoptosis (i.e, annexin V) and fibrillar collagen synthesis and degradation (i.e., carboxy-terminal propeptide of procollagen type I and matrix metalloproteinase and its inhibitory system) in arterial hypertension. Available data set the stage for larger trials, where noninvasive measures of myocardial remodeling could prove useful for handling of patients with hypertensive heart disease.

AIMS: Our goal was to analyse whether truncated peroxisome proliferator-activated receptor alpha (PPARalpha) overexpression induces apoptosis of cardiomyocytes. METHODS AND RESULTS: We constructed a recombinant vector of human truncated PPARalpha and a mammalian expression vector to transfect PPARalpha into a line of murine cardiomyocytes designated HL-1. Four hallmarks of apoptosis were measured in these transfected cells: depolarization of mitochondrial membrane, activation of caspase-3, phosphatidylserine (PS) externalization, and DNA fragmentation. Co-transfection with human cyclic adenosine monophosphate response element-binding protein (CREB) and human CREB binding protein (CBP) and analysis of apoptosis regulatory proteins, Bcl-2 and Bax, were also performed in truncated PPARalpha-transfected cells to determine the potential mechanisms by which truncated PPARalpha may influence apoptosis. Progressive depolarization of mitochondrial membrane, activation of caspase-3, PS externalization, DNA fragmentation, and cell death were observed in HL-1 cells upon increasing levels of transfected truncated PPARalpha. The expression of the antiapoptotic protein Bcl-2 decreased in transfected HL-1 cardiomyocytes, whereas no changes in the proapoptotic protein Bax were observed in these cells. Overexpression of CREB plus CBP abolished the inhibitory effect of truncated PPARalpha on Bcl-2 protein. CONCLUSION: These results demonstrate that human truncated PPARalpha overexpression induces apoptosis in HL-1 cardiomyocytes. In addition, our findings suggest that truncated PPARalpha may induce cardiomyocyte apoptosis through the inhibition of the antiapoptotic protein, Bcl-2. It is proposed that competition with CREB for coactivators like CBP could be involved in this inhibitory effect.

BACKGROUND AND OBJECTIVE: We assessed whether an independent association between inflammatory markers and age-related subclinical atherosclerosis could be found in subjects free from cardiovascular disease. PATIENTS AND METHOD: Metabolic parameters, inflammatory and endothelial markers, such as high-sensitivity C-reactive protein, interleukin-6, fibrinogen and von Willebrand factor, as well as the carotid intima-media thickness were assessed in 890 asymptomatic subjects (mean age: 55 years; range: 20-80 years; 80% men) with cardiovascular risk factors. RESULTS: Subjects in the upper quartile (age 61-80 years) showed a significant increase of traditional risk factors, particularly arterial pressure and glucose levels (p < 0.01) as compared with lower quartiles. We also found a significant increase in the levels on inflammatory and endothelial markers (p < 0.001) and intima-media thickness (p < 0.001) in older adults. In the multivarate analysis, after adjustment for cardiovascular risk factors, intima-media thickness was independently associated with inflammation and endothelial dysfunction in older adults (p < 0.01). CONCLUSIONS: Besides age, systemic inflammation and vascular damage are associated with subclinical atherosclerosis in asymptomatic subjects. The age-related inflammatory profile may predispose to cardiovascular complications.

AIMS: We investigated whether collagen type I turnover influences the long-term response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Serum carboxy-terminal propeptide of procollagen type I or PICP (a marker of collagen type I synthesis) and carboxy-terminal telopeptide of collagen type I or CITP (a marker of collagen type I degradation) were measured in heart failure patients at baseline and after 1 year of CRT. Patients were categorized as responders or non-responders if they increased the distance walked in 6 min by > or

OBJECTIVES: Cardiomyocyte loss is involved in the transition from compensatory left ventricular hypertrophy (LVH) to heart failure (HF). Our aim was to investigate the status of the leukaemia inhibitory factor receptor (LIFR)/gp130 survival pathway and its cytoprotective activity in intact cardiac tissue and in cardiomyocytes obtained from adult spontaneously hypertensive rats (SHR) with LVH (non-failing SHR) and from aged SHR with overt HF (failing SHR). METHODS: Cardiac morphometry was assayed by planimetry in an image analysis system. mRNA and protein expression were quantified by real time RT-PCR and Western blotting. Receptors were localized by immunocytochemistry. Trypan blue staining, TUNEL, and MTT cell viability assays were employed to study the cytoprotective activity of cardiotrophin-1 (CT-1) in isolated caridomyocytes. RESULTS: Compared to non-failing SHR, failing SHR exhibited enhanced myocardial cell death (p

Inappropriate left ventricular mass is present when the value of left ventricular mass exceeds individual needs to compensate hemodynamic load imposed by increased blood pressure. The goal of this study was to investigate whether plasma concentration of cardiotrophin-1, a cytokine that induces exaggerated hypertrophy in cardiomyocytes with hypertensive phenotype, is related to inappropriate left ventricular mass in patients with essential hypertension. The study was performed in 118 patients with never-treated hypertension and without prevalent cardiac disease. The left ventricular mass prediction from stroke work (systolic blood pressurexDoppler stroke volume), sex, and height (in meters(2.7)) was derived. An observed left ventricular mass/predicted left ventricular mass value >128% defined inappropriate left ventricular mass. Plasma cardiotrophin-1 was measured by an enzyme-linked immunosorbent assay. The studies were repeated in a group of 45 patients after 1 year of antihypertensive treatment. At baseline 67 and 51 patients presented with appropriate and inappropriate left ventricular mass, respectively. Plasma cardiotrophin-1 was higher (P

Arterial pressure in most experimental and clinical hypertensions is exacerbated by salt. The effects of salt excess on right and left ventricular (RV and LV, respectively) functions and their respective coronary vasodilatory responses have been less explored. We therefore examined the effects of 8 wk of NaCl excess (8% in food) on arterial pressure, RV and LV functions (maximal rate of increase and decrease of ventricular pressure; dP/dt(max) and dP/dt(min)), coronary hemodynamics (microspheres), and collagen content (hydroxyproline assay and collagen volume fraction) in young adult normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR), aged 16 wk by the end of the study. Prolonged salt excess in WKY and SHR elevated pressure only modestly, but it markedly increased LV mass, especially in SHR. Moreover, salt excess significantly impaired RV and LV diastolic function in SHR but only LV diastolic function in WKY rats. However, salt loading affected neither RV nor LV contractile function in both strains. Interstitial and perivascular collagen deposition was increased, whereas coronary vasodilatory responses to dipyridamole diminished in both ventricles in the salt-loaded SHR but not in WKY rats. Therefore, accumulation of ventricular collagen as well as altered myocardial perfusion importantly contributed to the development of salt-related RV and LV dysfunctions in this model of naturally occurring hypertension. The unique effects of salt loading on both ventricles in SHR, but not WKY rats, strongly suggest that nonhemodynamic mechanisms in hypertensive disease participate pathophysiologically with salt-loading hypertension. These findings point to the conclusion that the concept of "salt sensitivity" in hypertension is far more complex than simply its effects on arterial pressure or the LV.

OBJECTIVE: To investigate whether cardiac expression of the nuclear peroxisome proliferator-activated receptor alpha (PPARalpha) is altered in patients with hypertensive heart disease (HHD). METHODS: We studied endomyocardial septal biopsies from 24 patients with essential hypertension divided into three groups: 6 without left ventricular hypertrophy (LVH) (HT group), 10 with LVH (LVH group), and 8 with LVH and heart failure (HF) (HF group). The expression of two PPARalpha isoforms (the native active and the truncated inhibitory) was analyzed by Western blot and reverse transcription polymerase chain reaction (RT-PCR), and two PPARalpha target genes were evaluated by RT-PCR. Histomorphological features were evaluated in a second myocardial sample from LVH and HF groups. RESULTS: Whereas the expression of native PPARalpha protein was lower (p

BACKGROUND: The Losartan Intervention For End-point reduction in hypertension (LIFE) study found that a losartan-based regimen, compared with an atenolol-based regimen, resulted in a significantly lower risk of stroke in hypertensive patients with left ventricular hypertrophy, despite similar reductions in blood pressure. OBJECTIVE: The purpose of this review was to examine the molecular and pharmacologic mechanisms that may be associated with the different outcomes observed in the LIFE study. METHODS: A PubMed/MEDLINE search of English-language articles (1990 to February 2006) with the terms angiotensin II antagonists or AIIAs or angiotensin receptor blockers or losartan or atenolol or beta blocker and terms including, but not limited to, atherosclerosis, left ventricular hypertrophy, carotid artery hypertrophy, fatty streaks, atrial fibrillation, arrhythmias, endothelial function, myocyte hypertrophy, myocardial fibrosis, platelet aggregation, tissue factor, plasminogen activator inhibitor-1, PAI-1, anti-inflammatory, uric acid, or oxidative stress. RESULTS: Losartan's significant effect on stroke may be related to several possible mechanisms that are independent of blood-pressure reductions. These include improvements in endothelial function and vascular structure; decreases in vascular oxidative stress; reductions in left ventricular hypertrophy, reductions in myocardial fibrosis, or both; and modulation of atherosclerotic disease progression. Although some of these effects may be shared by other angiotensin II receptor antagonists (AIIAs), and perhaps other anti-hypertensive classes (eg, angiotensin-converting enzyme inhibitors), the ability of losartan to lower serum uric acid levels-a proposed independent risk factor for cardiovascular disease-appears to be a molecule-specific effect. Alternative explanations of the results of the LIFE study have also been hypothesized, including inappropriate choice of atenolol as an active comparator and differences in central pulse pressures between study groups. CONCLUSIONS: This review of the literature suggests that losartan (and perhaps other AIIAs) may possess a number of properties, independent of its antihypertensive effects, that may be associated with decreased vulnerability of the plaque, myocardium, and blood.

OBJECTIVES: We examined the effect of C-reactive protein (CRP) on matrix metalloproteinase (MMP) and inhibitor expression in endothelial cells and in patients with clinical and subclinical atherosclerosis. BACKGROUND: In addition to predicting atherosclerotic vascular disease, CRP may directly promote a proinflammatory/proatherosclerotic phenotype. METHODS: Human umbilical vein endothelial cells (HUVECs) and aortic endothelial cells (HAECs) were incubated in the presence or absence of CRP (50 mug/ml). Microarray analysis, real-time polymerase chain reaction, immunological and activity assays for MMPs were performed. Specific inhibitors of mitogen-activated protein kinase pathway were used. The MMP-1 and -10 plasma levels were measured in apparently healthy subjects (n = 70). Immunolocalization of CRP, MMP-1, and MMP-10 was performed in human mammary arteries and carotid endarterectomy specimens. RESULTS: C-reactive protein augmented MMP-1 and -10 messenger ribonucleic acid expression in HUVEC (p < 0.05) and HAEC (p < 0.01). C-reactive protein stimulation also increased MMP-1 and -10 protein in conditioned culture medium (p < 0.001), as well as MMP activity (p = 0.001). Specific inhibition of p38 or MEK abolished the CRP induction of the MMP-1, whereas MMP-10 induction blockade required the simultaneous inhibition of p38 and Jun N-terminal kinase pathways. Subjects with CRP values >3 mg/l (n = 37) had increased plasma MMP-1 and -10 (p < 0.05), the association being significant after adjustment for confounding variables (p = 0.04 and p = 0.008, respectively). The MMP-10 levels were elevated in subjects with higher carotid intima-media thickness (p = 0.009). Increased CRP and MMP-10 colocalized in endothelial layer and macrophage-rich areas in advanced atherosclerotic plaques. CONCLUSIONS: Increased local and systemic CRP-related MMP activation might provide a link between inflammation and plaque vulnerability.

PURPOSE OF REVIEW: This article will review briefly the emerging new concepts in the diagnosis and treatment of myocardial fibrosis in patients with hypertensive heart disease. RECENT FINDINGS: Although hypertensive heart disease is characterized clinically by development of left-ventricular hypertrophy in the absence of a cause other than arterial hypertension, changes in the composition of myocardial tissue also develop in arterial hypertension leading to structural remodeling of the myocardium (e.g. fibrosis). Recent available data on the determination of serum concentrations of collagen-derived serum peptides and quantitative analysis of echoreflectivity to address the presence of fibrosis in the myocardium of hypertensive patients are promising. In addition, preliminary data suggest that the goal of reducing myocardial fibrosis is achievable in patients with hypertensive heart disease using specific antihypertensive agents (e.g. those interfering with angiotensin II). SUMMARY: The time has come to revisit the current management of hypertensive heart disease simply focused on detecting left-ventricular hypertrophy and controlling blood pressure to reduce left-ventricular mass. It is necessary to develop new approaches aimed at assessing and repairing alterations of myocardial structure and protect myocardial function and, in so doing, to reduce in a more-effective manner adverse risk associated with hypertensive heart disease.

Given the importance of fibrous tissue in leading to myocardial dysfunction and failure in hypertensive heart disease, non-invasive assessment of fibrosis could prove a clinically useful tool in hypertensive patients, particularly given the potential for cardioprotective and cardioreparative pharmacological strategies. In this regard, an emerging experimental and clinical experience holds promise for the assessment of various serum peptides arising from the metabolism of collagen types I and III in arterial hypertension. More specifically, the measurement of serum concentrations of procollagen type I carboxy-terminal propeptide (a peptide that is cleaved from procollagen type I during the synthesis of fibril-forming collagen type I) may provide indirect diagnostic information on both the extent of myocardial fibrosis and the ability of antihypertensive treatment to diminish collagen type I synthesis and reduce myocardial fibrosis in hypertensive patients. The available data set the stage for large and long-term trials to definitively validate this approach.

BACKGROUND AND OBJECTIVE: Although impaired diastolic function is frequently found in systemic hypertension, the diagnosis of hypertensive heart disease (HHD) is based on the demonstration of left ventricular (LV) growth. The aim of the current work was to investigate the potential interactions between diastolic function and LV growth in patients with arterial hypertension. PATIENTS AND METHOD: One hundred and sixteen never-treated asymptomatic hypertensives underwent an echocardiographic evaluation. Classification of diastolic dysfunction (DD) was based on alterations in parameters assessing transmitral inflow, Doppler tissue imaging of mitral annular motion, and color M-mode propagation velocity. Classification of LV growth was based on alterations in left ventricular mass index and/or relative will thickness. RESULTS: Ninety-four patients (81%) exhibited DD and 22 (19%) exhibited normal diastolic function. Amongst patients with DD, 79 (84%) exhibited a pattern of impaired relaxation and 15 (16%) a pseudonormal pattern. The presence of LV growth was documented in 41% of patients without DD and 75% of patients with DD (p < 0.05). None of the studied patients exhibited echocardiographic signs of systolic dysfunction. CONCLUSIONS: These findings indicate that DD is an early and highly frequent cardiac alteration in arterial hypertension. In addition, our data show that one fifth of hypertensive patients have DD in the absence of LV growth. It is thus suggested that the diagnosis of HHD can not be further based exclusively on morphologic criteria and should include also the evaluation of alterations in LV filling.

Changes in the composition of cardiac tissue develop in arterial hypertension and lead to structural remodeling of the myocardium. Structural remodeling is the consequence of a number of pathologic processes, mediated by mechanical, neurohormonal and cytokine routes, occurring in the cardiomyocyte and the noncardiomyocyte compartments of the heart. One of these processes is related to the disruption of the equilibrium between the synthesis and degradation of collagen type I and III molecules, which results in an excessive accumulation of collagen type I and III fibers in the interstitium and the perivascular regions of the myocardium. The clinical relevance of ventricular fibrosis is that it might contribute to the increased cardiac risk of patients with hypertensive heart disease. This review focuses on the mechanisms of hypertensive ventricular fibrosis and its clinical consequences. In addition, we discuss the noninvasive methods for the diagnosis of cardiac fibrosis and the therapeutic strategies aimed to promote its reduction.

Fibrous tissue accumulation is an integral feature of the adverse structural remodeling of myocardial tissue following a cardiac insult. Given the importance of fibrous tissue in leading to myocardial dysfunction and failure, noninvasive assessment of fibrosis could prove a clinically useful tool, particularly given the potential for cardioprotective and cardioreparative pharmacological strategies. This approach represents an exciting and innovative strategy, and available data set the stage for large-scale and long-term trials, where this noninvasive assessment of myocardial fibrosis in patients with hypertensive heart disease and other cardiac diseases could prove useful.

Oxidative stress plays an important role in the pathophysiology of vascular diseases. Reactive oxygen species, especially superoxide anion and hydrogen peroxide, are important signalling molecules in cardiovascular cells. Enhanced superoxide production increases nitric oxide inactivation and leads to an accumulation of peroxynitrites and hydrogen peroxide. Reactive oxygen species participate in growth, apoptosis and migration of vascular smooth muscle cells, in the modulation of endothelial function, including endothelium-dependent relaxation and expression of proinflammatory phenotype, and in the modification of the extracellular matrix. All these events play important roles in vascular diseases such as hypertension, suggesting that the sources of reactive oxygen species and the signalling pathways that theymodifymay represent important therapeutic targets. Potential sources of vascular superoxide production include NADPH-dependent oxidases, xanthine oxidases, lipoxygenases, mitochondrial oxidases and nitricoxide synthases. Studies performedduring the last decadehave shownthatNADPHoxidase is the most important source of superoxide anion in phagocytic and vascular cells. Evidence from experimental animal and human studies suggests a significant role ofNADPHoxidase activation in the vascular remodelling and endothelial dysfunction found in cardiovascular diseases.

Increased vascular production of reactive oxygen species, especially superoxide anion, significantly contributes to the oxidative stress associated with hypertension. An enhanced superoxide production causes an increased inactivation of nitric oxide that diminishes nitric oxide bioavailability, thus contributing to endothelial dysfunction and hypertrophy of vascular cells. It has been shown that NADPH oxidases play a major role as the most important sources of superoxide anion in phagocytic and vascular cells. Several experimental observations have described an enhanced superoxide generation as a result of NADPH oxidase activation in hypertension. Although these enzymes respond to stimuli such as vasoactive factors, growth factors, and cytokines, recent data suggest a significant role of the genetic background in the modulation of the expression of its different components. Several polymorphisms have been identified in the promoter and in the coding region of CYBA, the gene that encodes the essential subunit of the NADPH oxidase p22phox, some of which seem to influence significantly the activity of these enzymes in the context of cardiovascular diseases. Among CYBA polymorphisms, genetic investigations have provided a novel marker, the -930(A/G) polymorphism, which determines the genetic susceptibility of hypertensive patients to oxidative stress.

BACKGROUND: We examined the influence of the 4G/5G PAI-1 (plasminogen activator inhibitor) genotype on Angiotensin II (Ang II)-induced PAI-1 expression by human endothelial cells (HUVEC) in the presence and absence of AT1-receptor blocker losartan, and screened for this polymorphism in relation to plasma PAI-1 and arterial pressure in apparently healthy subjects. METHODS AND RESULTS: Genotyped cultured HUVEC were incubated with Ang II (10(-8) M) with or without losartan up to 24 h. PAI-1 mRNA was determined in cell extracts and protein and activity assessed in supernatants and extracellular matrix (ECM). Ang II increased PAI-1 mRNA and activity in a genotype-dependent manner, higher values observed for 4G/4G HUVEC compared with 4G/5G and 5G/5G genotypes (p

Structural homogeneity of cardiac tissue is governed by mechanical and humoral factors that regulate cell growth, apoptosis, phenotype, and extracellular matrix turnover. ANGII has endocrine, autocrine, and paracrine properties that influence the behavior of cardiac cells and matrix by AT1 receptor binding. Various paradigms have been suggested, including ANGII-mediated up-regulation of collagen types I and III formation and deposition in cardiac conditions, such as HHD. A growing body of evidence, however, deals with the potential role of aldosterone, either local or systemic, in inducing cardiac fibrosis. Aldosterone might also mediate the profibrotic actions of ANGII. To reduce the risk of heart failure that accompanies HHD, its adverse structural remodeling (eg, myocardial hypertrophy and fibrosis) must be targeted for pharmacologic intervention. Cardioprotective agents must reverse not only the exaggerated growth of cardiac cells, but also regress existing abnormalities in fibrillar collagen. Available experimental and clinical data suggest that agents interfering with ACE, the AT1 receptor, or the mineralocorticoid receptor may provide such a cardioprotective effect.

BACKGROUND: We investigated whether increased collagen type I synthesis and deposition contribute to enhancement of myocardial fibrosis and deterioration of cardiac function in patients with hypertensive heart disease (HHD). METHODS AND RESULTS: We studied 65 hypertensives with left ventricular hypertrophy subdivided into 2 groups: 34 patients without heart failure (HF) and 31 patients with HF. Transvenous endomyocardial biopsies of the interventricular septum were performed to quantify the amount of fibrotic tissue and the extent of collagen type I deposition. The carboxy-terminal propeptide of procollagen type I (PIP), an index of collagen type I synthesis, was measured by radioimmunoassay in serum samples from the coronary sinus and the antecubital vein. Compared with normotensives, the amount of collagen tissue, the extent of collagen type I deposition, and coronary and peripheral PIP were increased (P

PURPOSE OF REVIEW: The potential contribution of alterations in matrix metalloproteinase activity to the development of myocardial fibrosis in hypertensive heart disease is reviewed. RECENT FINDINGS: A number of experimental and clinical studies provide information on alterations in the balance between matrix metalloproteinase-1 or collagenase and tissue inhibitor of matrix metalloproteinases-1, which result in depressed proteolytic activity of the enzyme in animals and humans with hypertensive heart disease. While some recent data point to a genetic origin of such an imbalance, other findings suggest that depressed collagenase activity may contribute to disturbances of cardiac function via facilitation of myocardial fibrosis. On the other hand, emerging information is providing the basis for the notion that other matrix metalloproteinases, namely gelatinases, may participate in the process of myocardial fibrosis through stimulation of fibrillar collagen synthesis. Some fragmented matrix peptides or matrikines may be the mediators of the profibrotic action of these matrix metalloproteinases. SUMMARY: The matrix metalloproteinases represent an important biological system within the myocardium designed to maintain the complex and dynamic microenvironment of the extracellular matrix. Improved understanding of how this system is dysregulated in hypertensive heart disease will probably provide new insights into, and strategies for, heart failure.