Pathological Structural Remodeling Research Articles

Omega-3 Fatty Acids as Antiarrhythmic Drugs: Upstream Target Modulators Affecting Acute and Long-Term Pathological Alterations in Cardiac Structure and Function.

Postoperative atrial fibrillation (POAF) is a common complication in the acute care period following coronary artery bypass grafting (CABG) surgery that is associated with significant morbidity and mortality in both short-term and long-term settings. Recently, the Vaughn Williams Classification of antiarrhythmic agents, first proposed in 1975 and widely viewed as the authoritative description of their electrophysiologic actions, was updated and notably omega-3 fatty acids (Ω-3 fatty acids) have been included in class VII, described as "upstream target modulators," to mitigate pathological structural and electrophysiological remodeling changes in the aged and/or injured myocardium. A PubMed literature search was performed. Studies examining the significance of complications in patients undergoing isolated CABG surgery were selected for inclusion. Relevant data were qualitatively assessed and narratively summarized. POAF occurs in approximately 30% of patients, and inflammation from chronic coronary artery disease preoperatively, as well as acute atrial inflammation from surgery postoperatively are the leading causes. Inflammation underlies its pathophysiology; therefore Ω-3 fatty acids not only exhibit antiarrhythmic properties but are an effective anti-inflammatory treatment that may reduce the clinical risks of POAF. At present no effective prophylaxis is available to address POAF following CABG surgery. Clinical approaches that focus on the inflammatory response in this setting may optimize the response to treatment. The current literature supports the hypothesis that Ω-3 fatty acids may acutely reduce the inflammatory response via favorable alterations in the metabolism of prostaglandins and leukotrienes (eicosanoids) and specialized pro-resolving mediators.

Circulating metabolic signatures of heart failure in precision cardiology.

Precision cardiology aims to implement personalized health care and precise medical decisions based on the specific characteristics of individuals. Metabolic remodeling plays a causal role in the pathogenesis of heart failure (HF). Changes in metabolic pathways such as substrate preference, high-energy phosphate metabolism and amino acid metabolism, are involved in pathological structural remodeling and functional impairment. These metabolic alterations are usually not restricted in the cardiac tissue, but also manifest in circulation. In clinical practice, blood sample is routinely used for HF screening. Metabolomics is an emerging omics technology that provides an efficient way to acquire dynamic metabolic profiles in circulation. An increasing number of metabolic biomarkers have been implicated in disease progression, making it possible to fight HF in a more effective and precise way. This review summarizes the modern analytical techniques in metabolomics as well as emerging circulating metabolites during the pathogenesis of HF, aiming to provide new insights into the prevention, diagnosis and treatment of HF in the era of precision medicine.

Metrics of high cofluctuation and entropy to describe control of cardiac function in the stellate ganglion.

Stellate ganglia within the intrathoracic cardiac control system receive and integrate central, peripheral, and cardiopulmonary information to produce postganglionic cardiac sympathetic inputs. Pathological anatomical and structural remodeling occurs within the neurons of the stellate ganglion (SG) in the setting of heart failure (HF). A large proportion of SG neurons function as interneurons whose networking capabilities are largely unknown. Current therapies are limited to targeting sympathetic activity at the cardiac level or surgical interventions such as stellectomy, to treat HF. Future therapies that target the SG will require understanding of their networking capabilities to modify any pathological remodeling. We observe SG networking by examining cofluctuation and specificity of SG networked activity to cardiac cycle phases. We investigate network processing of cardiopulmonary transduction by SG neuronal populations in porcine with chronic pacing-induced HF and control subjects during extended in-vivo extracellular microelectrode recordings. We find that information processing and cardiac control in chronic HF by the SG, relative to controls, exhibits: (i) more frequent, short-lived, high magnitude cofluctuations, (ii) greater variation in neural specificity to cardiac cycles, and (iii) neural network activity and cardiac control linkage that depends on disease state and cofluctuation magnitude.

Emerging role of transient receptor potential (TRP) ion channels in cardiac fibroblast pathophysiology.

Cardiac fibroblasts make up a major proportion of non-excitable cells in the heart and contribute to the cardiac structural integrity and maintenance of the extracellular matrix. During myocardial injury, fibroblasts can be activated to trans-differentiate into myofibroblasts, which secrete extracellular matrix components as part of healing, but may also induce cardiac fibrosis and pathological cardiac structural and electrical remodeling. The mechanisms regulating such cellular processes still require clarification, but the identification of transient receptor potential (TRP) channels in cardiac fibroblasts could provide further insights into the fibroblast-related pathophysiology. TRP proteins belong to a diverse superfamily, with subgroups such as the canonical (TRPC), vanilloid (TRPV), melastatin (TRPM), ankyrin (TRPA), polycystin (TRPP), and mucolipin (TRPML). Several TRP proteins form non-selective channels that are permeable to cations like Na+ and Ca2+ and are activated by various chemical and physical stimuli. This review highlights the role of TRP channels in cardiac fibroblasts and the possible underlying signaling mechanisms. Changes in the expression or activity of TRPs such as TRPCs, TRPVs, TRPMs, and TRPA channels modulate cardiac fibroblasts and myofibroblasts, especially under pathological conditions. Such TRPs contribute to cardiac fibroblast proliferation and differentiation as well as to disease conditions such as cardiac fibrosis, atrial fibrillation, and fibroblast metal toxicity. Thus, TRP channels in fibroblasts represent potential drug targets in cardiac disease.

Atrial Fibrillation is Not A Dead Horse

Prevalence and incidence of Atrial Fibrillation (AF) is high in western countries. It is apparently lower in developing countries, because of unrecognition, undertreatment and related complications and mortality. Studies in subjects wearing cardiac implantable electronic devices showed a wide burden of AF, ranging from subclinical episodes to permanent AF. The aim of our study was to identify haematological and haemodynamic differences between Paroxysmal Atrial Tachyarrhythmias (PAT) compared to Non-Paroxysmal AF (NPAF), detected by 24 hours Holter ECG, and predictive negative factors associated with increased risk of evolution from paroxysmal to persistent or permanent AF. Our data highlight the dynamic nature of PAT and NPAF. PAT in young subjects is a red flag, requiring at least changes in lifestyle and further diagnostic examinations to avoid progression to irreversible pathological myocardial electrical and structural remodeling. Comorbidities, scarce compliance, or inappropriate treatments account for high incidence of acute cerebrovascular events with disabling outcomes in elderly patients. Further studies are needed on genetic susceptibility and vulnerability. Educational campaign is the most effective, long- term strategy. Personalized approach and therapeutical scheme are recommended based on patient compliance and actual risk. A holistic approach to patient is the pillar for any clinical decision and practice.

Transcriptomic Analysis of Polyhexamethyleneguanidine-Induced Lung Injury in Mice after a Long-Term Recovery.

Polyhexamethyleneguanidine phosphate (PHMG-P) is one of the causative agents of humidifier disinfectant-induced lung injury. Direct exposure of the lungs to PHMG-P causes interstitial pneumonia with fibrosis. Epidemiological studies showed that patients with humidifier disinfectant-associated lung injuries have suffered from restrictive lung function five years after the onset of the lung injuries. We investigated whether lung damage was sustained after repeated exposure to PHMG-P followed by a long-term recovery and evaluated the adverse effects of PHMG-P on mice lungs. Mice were intranasally instilled with 0.3 mg/kg PHMG-P six times at two weeks intervals, followed by a recovery period of 292 days. Histopathological examination of the lungs showed the infiltration of inflammatory cells, the accumulation of extracellular matrix in the lung parenchyma, proteinaceous substances in the alveoli and bronchiolar–alveolar hyperplasia. From RNA-seq, the gene expression levels associated with the inflammatory response, leukocyte chemotaxis and fibrosis were significantly upregulated, whereas genes associated with epithelial/endothelial cells development, angiogenesis and smooth muscle contraction were markedly decreased. These results imply that persistent inflammation and fibrotic changes caused by repeated exposure to PHMG-P led to the downregulation of muscle and vascular development and lung dysfunction. Most importantly, this pathological structural remodeling induced by PHMG-P was not reversed even after long-term recovery.

If not now, when? Enhancing cardiologists’ psychological well-being as a COVID-19 gain

<h3>Abstract</h3> Stellate ganglia within the intrathoracic cardiac control system receive and integrate central, peripheral, and cardiopulmonary information to produce postganglionic cardiac sympathetic inputs. Pathological anatomical and structural remodeling occurs within...

Biomarkers of myocardial fibrosis and their genetic regulation in patients with heart failure

Currently, the development of chronic heart failure (CHF) is considered from the perspective of pathological structural remodeling of myocardium and fibrosis. Despite the widespread use of molecular genetic markers in clinical practice, only a small number of them are used to evaluate remodeling processes, as well as to predict potential complications associated with heart failure (HF). In addition, the relationship between many biomarkers with instrumental and histological confirmation of myocardial fibrosis has not yet been determined. Myocardial fibrosis remains quite debatable and controversial subject, which actualizes the further study of this direction. The discovery of pathogenetic and diagnostic markers of myocardial fibrosis could contribute to the development of targeted therapy. Of particular interest is the search for possible pathogenetic markers, since this is relevant for clinical practice.

P3767Progressive left atrial remodeling associates with cholesterol efflux capacity of HDL in atrial fibrillation patients

Abstract Background The clinical significance of high-density lipoprotein (HDL) function, represented by cholesterol efflux capacity (CEC), in addition to serum HDL cholesterol (HDL-C) levels, has been recognized in the pathogenesis and prognosis in patients with atherosclerotic cardiovascular diseases. However, the roles of HDL in the development and the progression of atrial fibrillation (AF), has been rarely evaluated. In this study, we thus hypothesized that the compromised HDL function may be associated with the progression of pathological structural remodeling in left atrium (LA). Objective We explored the association between CEC of HDL and the left atrial dimension (LAD), a maker of structural remodeling in the LA, in patients with AF and control. Methods This is a single center case-control study including consecutive 260 AF patients (AF group) and 34 paroxysmal supraventricular tachycardia (PSVT) patients (PSVT group, served as a control group), who underwent catheter ablation from July 2017 to December 2018. Blood samples were collected before catheter ablation procedure. CEC of HDL was measured by using ex vivo radiotracer system that involved incubation of [3H] cholesterol-loaded J774.1 murine macrophage-like cells with apoB-depleted serum. Results Serum HDL-C level was lower in AF group compared to those of PSVT group (55.3±15.3mg/dl vs 61.7±13.3mg/dl: p=0.024). As a marker of HDL function, CEC of HDL was significantly lower in patients with AF group compared to those in PSVT patients (4.74±0.84% vs 5.20±0.99%: p=0.005, Fig 1). In all patients including both groups, CEC of HDL was inversely correlated with LAD (r=−0.25; p&lt;0.001, Fig 2), indicating the inverse association between HDL function and the progression of structural remodeling in AF. Moreover, multivariate logistic regression analysis adjusted by age, gender, body mass index, ejection fraction, and HDL-C demonstrated that increase in CEC of HDL was associated with the lower risk to be highest quartiles of LAD (&gt;42mm), even adjusted by serum HDL-C levels (odds ratio of 1-SD elevation in CEC of HDL for LAD&gt;42mm: 0.63; 95% confidence interval: 0.40–0.97, p=0.037), which implicated the link between HDL function and progression of left atrial structural remodeling. Conclusion Findings in this study may suggest that compromised HDL functionality is associated with the pathogenesis of left atrial structural remodeling in AF patients.

Reduction of Sympathetic Innervation Following Transition to Sacubitril/Valsartan in the Remodel (Reverse Remodeling Effects of Entresto) Study

Background Increased sympathetic nervous system activity is commonly observed in heart failure with reduced ejection fraction and is one cause of pathological structural remodeling of the left ventricle. Sacubitril/valsartan reduces mortality and heart failure hospitalizations, but its effect on sympathetic nervous system activity is unknown. Methods Patients enrolled in the prospective, longitudinal REMODEL study underwent 123-meta-iodobenzylguanidine scintigraphy prior to and three months following conversion from angiotensin converting enzyme inhibitor or angiotensin receptor blocker therapy to sacubitril/valsartan. The early heart-to-mediastinum (H/M) ratio, late H/M ratio and washout rate were calculated. Baseline and on-therapy values were compared using a paired t-test analysis. Results 40 patients were enrolled in this study. The mean age was 55 ± 12 years, 25 (63%) were male, and 30 (75%) had a non-ischemic heart failure etiology. Following transition to sacubitril/valsartan therapy, the late H/M ratio increased from 1.39 ± 0.19 to 1.52 ± 0.19 (p Conclusions Addition of sacubitril/valsartan to baseline heart failure therapy resulted in a decrease in cardiac sympathetic activity, as shown by a decrease in both the early and late H/M ratio and an increase in the washout rate on MIBG imaging. The decrease in sympathetic nervous system activity may underlie the improvement in survival seen with sacubitril/valsartan and can serve as a good measure of medication response.

The Development of Compartmentation of cAMP Signaling in Cardiomyocytes: The Role of T-Tubules and Caveolae Microdomains.

3′-5′-cyclic adenosine monophosphate (cAMP) is a signaling messenger produced in response to the stimulation of cellular receptors, and has a myriad of functional applications depending on the cell type. In the heart, cAMP is responsible for regulating the contraction rate and force; however, cAMP is also involved in multiple other functions. Compartmentation of cAMP production may explain the specificity of signaling following a stimulus. In particular, transverse tubules (T-tubules) and caveolae have been found to be critical structural components for the spatial confinement of cAMP in cardiomyocytes, as exemplified by beta-adrenergic receptor (β-ARs) signaling. Pathological alterations in cardiomyocyte microdomain architecture led to a disruption in compartmentation of the cAMP signal. In this review, we discuss the difference between atrial and ventricular cardiomyocytes in respect to microdomain organization, and the pathological changes of atrial and ventricular cAMP signaling in response to myocyte dedifferentiation. In addition, we review the role of localized phosphodiesterase (PDE) activity in constraining the cAMP signal. Finally, we discuss microdomain biogenesis and maturation of cAMP signaling with the help of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Understanding these mechanisms may help to overcome the detrimental effects of pathological structural remodeling.

Rad GTPase Deletion Attenuates Post-Ischemic Cardiac Dysfunction and Remodeling

The protein Rad interacts with the LTCC to modulate trigger Ca2+, hence to govern contractility. Reducing Rad levels increases cardiac output. Ablation of Rad also attenuated the inflammatory response following acute myocardial infarction (AMI). Future studies to target deletion of Rad in the heart could be conducted to establish a novel treatment paradigm whereby pathologically stressed hearts would be given a safe, stable positive inotropic support without arrhythmias and without pathological structural remodeling. Future investigations will also focus on establishing inhibitors of Rad, and testing the efficacy of Rad-deletion in cardioprotection relative to the time of onset of AMI.

Cortical Bone Stem Cell Therapy Preserves Cardiac Structure and Function After Myocardial Infarction.

Cortical bone stem cells (CBSCs) have been shown to reduce ventricular remodeling and improve cardiac function in a murine myocardial infarction (MI) model. These effects were superior to other stem cell types that have been used in recent early-stage clinical trials. However, CBSC efficacy has not been tested in a preclinical large animal model using approaches that could be applied to patients. To determine whether post-MI transendocardial injection of allogeneic CBSCs reduces pathological structural and functional remodeling and prevents the development of heart failure in a swine MI model. Female Göttingen swine underwent left anterior descending coronary artery occlusion, followed by reperfusion (ischemia-reperfusion MI). Animals received, in a randomized, blinded manner, 1:1 ratio, CBSCs (n=9; 2×107 cells total) or placebo (vehicle; n=9) through NOGA-guided transendocardial injections. 5-ethynyl-2'deoxyuridine (EdU)-a thymidine analog-containing minipumps were inserted at the time of MI induction. At 72 hours (n=8), initial injury and cell retention were assessed. At 3 months post-MI, cardiac structure and function were evaluated by serial echocardiography and terminal invasive hemodynamics. CBSCs were present in the MI border zone and proliferating at 72 hours post-MI but had no effect on initial cardiac injury or structure. At 3 months, CBSC-treated hearts had significantly reduced scar size, smaller myocytes, and increased myocyte nuclear density. Noninvasive echocardiographic measurements showed that left ventricular volumes and ejection fraction were significantly more preserved in CBSC-treated hearts, and invasive hemodynamic measurements documented improved cardiac structure and functional reserve. The number of EdU+ cardiac myocytes was increased in CBSC- versus vehicle- treated animals. CBSC administration into the MI border zone reduces pathological cardiac structural and functional remodeling and improves left ventricular functional reserve. These effects reduce those processes that can lead to heart failure with reduced ejection fraction.

Cardiac Med1 deletion promotes early lethality, cardiac remodeling, and transcriptional reprogramming

The mediator complex, a multisubunit nuclear complex, plays an integral role in regulating gene expression by acting as a bridge between transcription factors and RNA polymerase II. Genetic deletion of mediator subunit 1 (Med1) results in embryonic lethality, due in large part to impaired cardiac development. We first established that Med1 is dynamically expressed in cardiac development and disease, with marked upregulation of Med1 in both human and murine failing hearts. To determine if Med1 deficiency protects against cardiac stress, we generated two cardiac-specific Med1 knockout mouse models in which Med1 is conditionally deleted (Med1cKO mice) or inducibly deleted in adult mice (Med1cKO-MCM mice). In both models, cardiac deletion of Med1 resulted in early lethality accompanied by pronounced changes in cardiac function, including left ventricular dilation, decreased ejection fraction, and pathological structural remodeling. We next defined how Med1 deficiency alters the cardiac transcriptional profile using RNA-sequencing analysis. Med1cKO mice demonstrated significant dysregulation of genes related to cardiac metabolism, in particular genes that are coordinated by the transcription factors Pgc1α, Pparα, and Errα. Consistent with the roles of these transcription factors in regulation of mitochondrial genes, we observed significant alterations in mitochondrial size, mitochondrial gene expression, complex activity, and electron transport chain expression under Med1 deficiency. Taken together, these data identify Med1 as an important regulator of vital cardiac gene expression and maintenance of normal heart function.NEW & NOTEWORTHY Disruption of transcriptional gene expression is a hallmark of dilated cardiomyopathy; however, its etiology is not well understood. Cardiac-specific deletion of the transcriptional coactivator mediator subunit 1 (Med1) results in dilated cardiomyopathy, decreased cardiac function, and lethality. Med1 deletion disrupted cardiac mitochondrial and metabolic gene expression patterns.

Targeting the Cardiac Myofibroblast Secretome to Treat Myocardial Fibrosis in Heart Failure.

Therapeutic strategies for heart failure (HF) should increasingly consider measures directly targeting the myocardium itself rather than strictly focusing on agents that unload the heart or target systemic neurohormones. In this regard, a new view is emerging that proposes the direct intervention on the pathological structural remodeling of the myocardium as part of HF therapy. One hallmark myocardial lesion in HF is the diffuse accumulation of collagen fibers (namely, collagen type I) within the interstitium and around the microvasculature of the myocardium (ie, myocardial fibrosis [MF]). MF is the result of the predominance of collagen synthesis over its degradation as a result of the actions of a population of persistent metabolically active cells: the myofibroblasts. MF impairs cardiac function and contributes to the development and worsening of HF, in addition to facilitating arrhythmias and ischemia, and thus adversely influences the evolution and outcome of nearly all cardiac diseases.1 Therefore, MF regression is an unmet medical need, and the search for new drugs aiming its reversal is active. However, the efficacy and safety of novel antifibrotic strategies currently under investigation seem questionable.2 We thus propose a therapeutic approach based on targeting the cardiac myofibroblast secretome with already available drugs, which have proven to be both efficient in reducing MF and safe in protecting cardiac function. In addition, we will discuss how to identify those HF patients in whom these therapies can be more beneficial and thus should be personalized. Cardiac myofibroblasts are cells expressing α-smooth muscle actin microfilaments that originate from the differentiation of several cell types (including resident cardiac fibroblasts) under the influence of many local and systemic factors (Figure 1). Myofibroblasts exhibit a synthetic phenotype that includes a secretome consisting of molecules requisite to modify the quantity and quality of the myocardial collagen network and facilitate MF …

Asiatic Acid Attenuates the Progression of Left Ventricular Hypertrophy and Heart Failure Induced by Pressure Overload by Inhibiting Myocardial Remodeling in Mice.

Cardiac structural remodeling, including cardiomyocyte apoptosis, interstitial fibrosis, and inflammation, appears to be a key event associated with the progression of left ventricular hypertrophy and heart failure. Asiatic acid (AA) is a triterpenoid compound extracted from Centella asiatica that exhibits antiapoptotic, antifibrotic, and anti-inflammatory activities. In the present study, a transverse aortic constriction (TAC) model was created in mice to mimic the progression of hypertrophy (2 weeks post-TAC) and heart failure (4 weeks post-TAC) to investigate whether the potential therapeutic drug AA ameliorates hypertrophy progression and which mechanisms are involved in this amelioration. Our results demonstrated that AA markedly inhibited the process of progression induced by pressure overload. The increases cardiomyocyte apoptosis and interstitial fibrosis, and inflammatory responses were significantly suppressed by AA. Our investigation revealed that this inhibitory effect was mediated by blocking the activation of both mitochondrial and death receptor-dependent apoptotic signaling pathways. Additional experiments demonstrated that AA attenuated fibrosis by blocking both transforming growth factor-β1/Smad and interleukin-6, signaling activation. Consequently, these findings indicated that AA attenuated pathological cardiac structural remodeling and preserved cardiac function via multiple intracellular signaling pathways in response to cardiac stimuli.

Protective effect of pulmonary hypertension against right-sided tamponade in pericardial effusion.

Patients with pericardial effusion are susceptible to cardiac tamponade. A compressing circumferential pericardial effusion typically results in an equalization of intracardiac and pericardial pressure during diastole and a progressive collapse of the right atrium and ventricle. Pulmonary hypertension that increases the afterload of the right ventricle may result in elevated pressures initially in the right ventricle and subsequently in the right atrium. This may lead to right ventricular hypertrophy and a pathologic structural and functional remodeling of both right heart chambers. Conversely, elevated pressures within the right heart chambers caused by longstanding pulmonary hypertension may resist and protect against tamponade of these chambers in the setting of a coexisting pericardial effusion. In such cases, a sudden reduction in pulmonary arterial pressures may result in tamponade of the right heart chambers.

Arterial Hypertension in Patients with Heart Failure

Hypertensive heart disease (HHD) has been considered the adaptive hypertrophy of the left ventricle wall to increased blood pressure. Recent findings in hypertensive animals and patients now challenge this paradigm by showing that HHD also results from pathologic structural remodeling of the myocardium in response to hemodynamic and nonhemodynamic factors that are altered in arterial hypertension. The possibility that hypertensive patients predisposed to develop heart failure may be detected before the appearance of clinical manifestations provides a new way to prevent this major arterial complication.

Mapping cardiac surface mechanics with structured light imaging

Cardiovascular disease often manifests as a combination of pathological electrical and structural heart remodeling. The relationship between mechanics and electrophysiology is crucial to our understanding of mechanisms of cardiac arrhythmias and the treatment of cardiac disease. While several technologies exist for describing whole heart electrophysiology, studies of cardiac mechanics are often limited to rhythmic patterns or small sections of tissue. Here, we present a comprehensive system based on ultrafast three-dimensional (3-D) structured light imaging to map surface dynamics of whole heart cardiac motion. Additionally, we introduce a novel nonrigid motion-tracking algorithm based on an isometry-maximizing optimization framework that forms correspondences between consecutive 3-D frames without the use of any fiducial markers. By combining our 3-D imaging system with nonrigid surface registration, we are able to measure cardiac surface mechanics at unprecedented spatial and temporal resolution. In conclusion, we demonstrate accurate cardiac deformation at over 200,000 surface points of a rabbit heart recorded at 200 frames/s and validate our results on highly contrasting heart motions during normal sinus rhythm, ventricular pacing, and ventricular fibrillation.

Is Smad3 the Key to Inflammation and Fibrosis in Hypertensive Heart Disease?

Hypertensive heart disease (HHD) is characterized by myocardial remodeling not only in the left ventricle but also the left atrium and right ventricle. Clinically it is characterized by intact systolic function and diastolic dysfunction, which make up the major cause of congestive heart failure in the elderly, also termed “heart failure with preserved ejection fraction.” Hypertension is the major determinant for developing heart failure with preserved ejection fraction.1 As reviewed recently by Diez and Frohlich,2 most findings in hypertensive animals and patients demonstrate that HHD also results from pathological structural remodeling of the myocardium in response to a number of hemodynamic and nonhemodynamic factors altered in hypertension. HHD is histologically characterized by left ventricular hypertrophy, cardiac inflammation, and fibrosis. The histological characteristics of inflammation and fibrosis extend from the perivascular space into the intermuscular interstitium. The mismatch of excessive myocyte hypertrophy and disproportionate myocardial fibrosis leads to increased myocardial stiffness and impaired diastolic function in patients with chronic hypertension and heart failure with preserved ejection fraction. The activation of the renin-angiotensin (Ang) system (RAS) plays an important pathophysiological role in HHD and the development of myocardial inflammation and fibrosis. This is supported by the findings that blockade of the RAS, either with Ang-converting enzyme inhibitors or its type 1 receptor blockers, significantly improves cardiac function and regresses cardiac remodeling in patients with hypertension. …