Fibrosis In Hypertensive Heart Disease Research Articles

Possible Role of Gut Microbiota Alterations in Myocardial Fibrosis and Burden of Heart Failure in Hypertensive Heart Disease.

Epidemiological studies have revealed that hypertensive heart disease is a major risk factor for heart failure, and its heart failure burden is growing rapidly. The need to act in the face of this threat requires first an understanding of the multifactorial origin of hypertensive heart disease and second an exploration of new mechanistic pathways involved in myocardial alterations critically involved in cardiac dysfunction and failure (eg, myocardial interstitial fibrosis). Increasing evidence shows that alterations of gut microbiota composition and function (ie, dysbiosis) leading to changes in microbiota-derived metabolites and impairment of the gut barrier and immune functions may be involved in blood pressure elevation and hypertensive organ damage. In this review, we highlight recent advances in the potential contribution of gut microbiota alterations to myocardial interstitial fibrosis in hypertensive heart disease through blood pressure-dependent and blood pressure-independent mechanisms. Achievements in this field should open a new path for more comprehensive treatment of myocardial interstitial fibrosis in hypertensive heart disease and, thus, for the prevention of heart failure.

Myocardial Interstitial Fibrosis in Hypertensive Heart Disease: From Mechanisms to Clinical Management.

Hypertensive heart disease (HHD) can no longer be considered as the beneficial adaptive result of the hypertrophy of cardiomyocytes in response to pressure overload leading to the development of left ventricular hypertrophy. The current evidence indicates that in patients with HHD, pathological lesions in the myocardium lead to maladaptive structural remodeling and subsequent alterations in cardiac function, electrical activity, and perfusion, all contributing to poor outcomes. Diffuse myocardial interstitial fibrosis is probably the most critically involved lesion in these disorders. Therefore, in this review, we will focus on the histological characteristics, the mechanisms, and the clinical consequences of myocardial interstitial fibrosis in patients with HHD. In addition, we will consider the most useful tools for the noninvasive diagnosis of myocardial interstitial fibrosis in patients with HHD, as well as the most effective available therapeutic strategies to prevent its development or facilitate its regression in this patient population. Finally, we will issue a call to action for the need for more fundamental and clinical research on myocardial interstitial fibrosis in HHD.

Sacubitril/valsartan versus valsartan in regressing myocardial fibrosis in hypertension: a prospective, randomized, open-label, blinded endpoint clinical trial protocol.

Diffuse interstitial myocardial fibrosis is a key common pathological manifestation in hypertensive heart disease (HHD) progressing to heart failure (HF). Angiotensin receptor-neprilysin inhibitors (ARNi), now a front-line treatment for HF, confer benefits independent of blood pressure, signifying a multifactorial mode of action beyond hemodynamic regulation. We aim to test the hypothesis that compared with angiotensin II receptor blockade (ARB) alone, ARNi is more effective in regressing diffuse interstitial myocardial fibrosis in HHD. Role of ARNi in Ventricular Remodeling in Hypertensive LVH (REVERSE-LVH) is a prospective, randomized, open-label, blinded endpoint (PROBE) clinical trial. Adults with hypertension and left ventricular hypertrophy (LVH) according to Asian sex- and age-specific thresholds on cardiovascular magnetic resonance (CMR) imaging are randomized to treatment with either sacubitril/valsartan (an ARNi) or valsartan (an ARB) in 1:1 ratio for a duration of 52 weeks, at the end of which a repeat CMR is performed to assess differential changes from baseline between the two groups. The primary endpoint is the change in CMR-derived diffuse interstitial fibrosis volume. Secondary endpoints include changes in CMR-derived left ventricular mass, volumes, and functional parameters. Serum samples are collected and stored to assess the effects of ARNi, compared with ARB, on circulating biomarkers of cardiac remodeling. The endpoints will be analyzed with reference to the corresponding baseline parameters to evaluate the therapeutic effect of sacubitril/valsartan vs. valsartan. REVERSE-LVH will examine the anti-fibrotic potential of sacubitril/valsartan and will offer mechanistic insights into the clinical benefits of sacubitril/valsartan in hypertension in relation to cardiac remodeling. Advancing the knowledge of the pathophysiology of HHD will consolidate effective risk stratification and personalized treatment through a multimodal manner integrating complementary CMR and biomarkers into the conventional care approach.Clinical Trial Registration: ClinicalTrials.gov, identifier, NCT03553810.

Hypertensive Heart Disease: A Narrative Review Series—Part 1: Pathophysiology and Microstructural Changes

Sustained hypertension causes structural, functional, and neurohumoral abnormalities in the heart, a disease commonly termed hypertensive heart disease (HHD). Modern concepts of HHD, including processes of remodeling leading to the development of various LVH patterns, HF patterns accompanied by micro- and macrovasculopathies, and heart rhythm and conduction disturbances, are missing in the available definitions, despite copious studies being devoted to the roles of myocardial and vascular fibrosis, and neurohumoral and sympathetic regulation, in HHD development and progression. No comprehensive and generally accepted universal definition and classification of HHD is available to date, implementing diagnostic criteria that incorporate all the possible changes and adaptions to the heart. The aim of this review series is to summarize the relevant literature and data, leading to a proposal of a definition and classification of HHD. This first article reviews the processes of initial myocardial remodeling, and myocardial and vascular fibrosis, occurring in HHD. We discuss important pathophysiological and microstructural changes, the different patterns of fibrosis, and the biomarkers and imaging used to detect fibrosis in HHD. Furthermore, we review the possible methods of targeting myocardial fibrosis in HHD, and highlight areas for further research.

Redox Regulation of Cardiac ASK1 (Apoptosis Signal-Regulating Kinase 1) Controls p38-MAPK (Mitogen-Activated Protein Kinase) and Orchestrates Cardiac Remodeling to Hypertension.

Systemic hypertension increases cardiac workload causing cardiomyocyte hypertrophy and increased cardiac fibrosis. An underlying feature is increased production of reactive oxygen species. Redox-sensitive ASK1 (apoptosis signal-regulating kinase 1) activates stress-regulated protein kinases (p38-MAPK [mitogen-activated protein kinases] and JNKs [c-Jun N-terminal kinases]) and promotes fibrosis in various tissues. Here, we determined the specificity of ASK1 signaling in the heart, with the hypothesis that ASK1 inhibitors may be used to manage fibrosis in hypertensive heart disease. Using immunoblotting, we established that moderate levels of H2O2 activate ASK1 in neonatal rat cardiomyocytes and perfused rat hearts. ASK1 was activated during ischemia in adult rat hearts, but not on reperfusion, consistent with activation by moderate (not high) reactive oxygen species levels. In contrast, IL (interleukin)-1β activated an alternative kinase, TAK1 (transforming growth factor-activated kinase 1). ASK1 was not activated by IL1β in cardiomyocytes and activation in perfused hearts was due to increased reactive oxygen species. Selonsertib (ASK1 inhibitor) prevented activation of p38-MAPKs (but not JNKs) by oxidative stresses in cultured cardiomyocytes and perfused hearts. In vivo (C57Bl/6J mice with osmotic minipumps for drug delivery), selonsertib (4 mg/[kg·d]) alone did not affect cardiac function/dimensions (assessed by echocardiography). However, it suppressed hypertension-induced cardiac hypertrophy resulting from angiotensin II (0.8 mg/[kg·d], 7d), with inhibition of Nppa/Nppb mRNA upregulation, reduced cardiomyocyte hypertrophy and, notably, significant reductions in interstitial and perivascular fibrosis. Our data identify a specific reactive oxygen species→ASK1→p38-MAPK pathway in the heart and establish that ASK1 inhibitors protect the heart from hypertension-induced cardiac remodeling. Thus, targeting the ASK1→p38-MAPK nexus has potential therapeutic viability as a treatment for hypertensive heart disease.

Cardiac magnetic resonance-derived fibrosis, strain and molecular biomarkers of fibrosis in hypertensive heart disease.

Myocardial fibrosis is a relevant component of hypertensive heart disease (HHD). Novel cardiovascular magnetic resonance (CMR) imaging techniques have shown potential in quantification of diffuse cardiac fibrosis, with T1 mapping, and estimating preclinical cardiac dysfunction, with strain analysis. Molecular biomarkers of fibrosis have been related with clinical outcomes and histologically proven myocardial fibrosis. The relationship between these CMR-imaging techniques and circulating biomarkers is not fully understood. CMR was performed on a 3T scanner in 36 individuals with HHD. Extracellular volume fraction (ECV) and the partition coefficient were assessed using the T1 mapping technique shMOLLI. Longitudinal, circumferential and radial strain was assessed using CMR-Feature Tracking. Molecular biomarkers of collagen synthesis (PICP and PIIINP) and collagen degradation (CITP and MMP-1) were measured in blood using commercial kits. Correlation models showed a significant relationship of T1 mapping measures with left atrial diameter, LV mass, LV posterior wall thickness, LV end-diastolic volume and longitudinal strain. In fully adjusted regression models, ECV was associated with left atrial diameter (β=0.75, P = 0.005) and longitudinal strain (β = 0.43, P = 0.030); the partition coefficient was associated with LV posterior wall thickness (β = 0.53, P = 0.046). Strain measures were associated with cardiac geometry, and longitudinal strain was marginally associated with CITP. In individuals with HHD, CMR-derived measures of myocardial fibrosis and function are related and might be useful tools for the identification and characterization of preclinical cardiac dysfunction and diffuse myocardial fibrosis. Molecular biomarkers of fibrosis were marginally associated with myocardial strain, but not with the extension of CMR-measured cardiac fibrosis.

Mast cells: Promoters of myocardial fibrosis in hypertensive heart disease?

Mast cells: Promoters of myocardial fibrosis in hypertensive heart disease?

Mast cells: Promoters of myocardial fibrosis in hypertensive heart disease?

Mast cells: Promoters of myocardial fibrosis in hypertensive heart disease?

Fibroblast growth factor-21 protects against fibrosis in hypertensive heart disease.

FGF21 is an endocrine factor that contributes to multiple pathophysiological processes, mainly via its action as a metabolic regulator and cardioprotective agent. Recent studies have shown increased circulating FGF21 levels in hypertensive patients and in mouse models of hypertension. However, the relevance of FGF21 in hypertensive heart disease has not been addressed. Hypertension was induced by treating 4-month old WT and Fgf21-/- mice with angiotensin II (AngII) for 1week, resulting in a similar increase in blood pressure in both genotypes. Plasma FGF21 levels and expression in heart and liver were significantly increased in hypertensive WT mice relative to controls, an effect that was associated with increased expression levels of β-klotho specifically in the heart. Fgf21-/- mice developed a greater degree of hypertensive heart disease than WT mice, notably characterized by extensive cardiac dysfunction and fibrosis. In vitro and in vivo studies further showed that FGF21 exerted a marked protective effect against cardiac fibrosis. Finally, left ventricle biopsies from human hypertensive heart donors, especially those developing cardiomyopathy, showed a significant increase in FGF21expression compared with normotensive controls, a finding that was associated with significantly enhanced cardiac hypertrophy and fibrosis. We conclude that during hypertension, both systemic and cardiac-produced FGF21 are induced and act on the heart, protecting it from hypertensive heart disease. Thus, FGF21 acts as key factor in the fibrogenesis associated with hypertensive heart disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Radiomic Analysis of Myocardial Native T1 Imaging Discriminates Between Hypertensive Heart Disease and Hypertrophic Cardiomyopathy

ObjectivesThis study sought to examine the diagnostic ability of radiomic texture analysis (TA) on quantitative cardiovascular magnetic resonance images to differentiate between hypertensive heart disease (HHD) and hypertrophic cardiomyopathy (HCM). BackgroundHHD and HCM are associated with increased left ventricular wall thickness (LVWT). Contemporary guidelines define HCM as LVWT ≥15 mm that is unexplained by other disease, which complicates diagnosis in cases of co-occurrences. Conventional global native T1 mapping involves calculation of mean T1 values as a surrogate for fibrosis. However, there may be differences in its spatial localization, such as diffuse and more focal fibrosis in HHD and HCM, respectively. MethodsThis study identified 232 subjects (53 with HHD, 108 with HCM, and 71 control subjects) for TA who consecutively underwent free-breathing multislice native T1 mapping. Four sets of texture descriptors were applied to capture spatially dependent and independent pixel statistics. Six texture features were sequentially selected with the best discriminatory capacity between HHD and HCM and were tested using a support vector machine (SVM) classifier. Each disease group was randomly split 4:1 (feature selection/test validation), in which the reproducibility of the pattern was analyzed in the test validation dataset. ResultsThe selected texture features provided the maximum diagnostic accuracy of 86.2% (c-statistic: 0.820; 95% confidence interval [CI]: 0.769 to 0.903) using the SVM. For the test validation dataset, the accuracy of the pattern remained high at 80.0% (c-statistic: 0.89; 95% CI: 0.77 to 1.00). Global native T1, with an accuracy of 64%, separated HHD and HCM patients modestly (c-statistic: 0.549; 95% CI: 0.452 to 0.640). ConclusionsRadiomics analysis of native T1 images discriminates between HHD and HCM patients and provides incremental value over global native T1 mapping.

Recent Advances in Imaging of Hypertensive Heart Disease.

To review recent advances in the imaging of hypertensive heart disease (HHD) with an emphasis on developments in the imaging of diffuse myocardial fibrosis using cardiac magnetic resonance (CMR). HHD results from long-standing hypertension and is characterized by the development of left ventricular hypertrophy and diffuse interstitial fibrosis. Diffuse fibrosis traditionally required endomyocardial biopsy to diagnose, but recent developments using T1 mapping in CMR allow for noninvasive assessment. Studies using T1 mapping have shown an increase in extracellular volume fraction (ECV) in patients with HHD compared to normal controls, suggesting ECV can be used as a noninvasive marker for fibrosis in HHD. In addition to T1 mapping, other recent advances in HHD imaging include improvements in three-dimensional echocardiography, allowing for accurate real-time volumetric measurements, and the use of speckle tracking echocardiography to detect subclinical systolic dysfunction. Measurement of ECV using T1 mapping in CMR can be used as a noninvasive marker of diffuse myocardial fibrosis in HHD. While further studies are needed to validate this approach with larger patient cohorts, ECV can potentially be used to both monitor disease progression and assess therapeutic interventions in HHD.

Regression of Established Cardiac Fibrosis in Hypertensive Heart Disease.

Established cardiac fibrosis (ECF) with symptomatic heart failure preserved ejection fraction represents an ever-increasing segment of the hypertensive population. The regression of ECF with attendant improvement in myocardial stiffness and symptomatic failure represents an unmet health care need. Is the regression of ECF in hypertensive heart disease feasible and will stiffness and symptomatic failure be improved? What is the cellular/molecular signaling involved in its regression? What incremental knowledge is needed to proceed effectively? These issues are addressed in this Review.

Differential Regulatory Role of Soluble Klothos on Cardiac Fibrogenesis in Hypertension.

Soluble Klotho functions as an endocrine factor that plays important roles in a variety of pathophysiological processes. Soluble Klotho contains 130 KDa and 65 KDa isoforms. However, their distinct individual functional heterogeneity remains uncertain. Herein, we investigated the regulatory role of two soluble Klothos on cardiac fibrogenic responses. The effect of soluble Klothos on myofibroblast differentiation, proliferation, and collagen synthesis/degradation were examined in cultured mouse cardiac myofibroblasts. The role of 130 KDa Klotho on fibrosis in hypertensive heart disease were examined in wild type (WT) and Klotho transgenic (Tg/+) mice receiving chronic angiotensin (Ang)II infusion. Our in vitro studies revealed that addition of 130 KDa soluble Klotho isoform increased collagen synthesis in a dose dependent manner. Furthermore, 130 KDa Klotho significantly stimulated myofibroblast differentiation, proliferation, and ERK phosphorylation, which were abolished by fibroblast growth factor (FGF) receptor antagonist (SU5402). In contrast, 65 KDa soluble Klotho treatment significantly suppressed myofibroblast proliferation and collagen synthesis. In vivo study further demonstrated that chronic AngII infusion lead to cardiac fibrosis in both WT and Tg/+ mice. However, cardiac collagen, TGF-β1, TIMP-2, and α-smooth muscle actin (SMA) levels were markedly upregulated in Tg/+ mice compared to WT cohort. Taken together, these findings implicate that 130 KDa soluble Klotho plays a stimulatory role in cardiac myofibroblast growth and activity through FGF pathway, whereas 65 KDa soluble Klotho exerts an anti-fibrotic effect in cardiac myofibroblasts. Thus, two distinct isoforms of soluble Klotho appear to play the counter-regulatory roles in cardiac fibrogenic responses.

Fragmented QRS complexes are a marker of myocardial fibrosis in hypertensive heart disease.

Carboxy-terminal propeptide of type 1 procollagen (PICP) is a marker of extracellular collagen synthesis. Fragmented QRS (fQRS) on a 12-lead electrocardiogram (ECG) has been demonstrated as a marker of myocardial fibrosis. The present objective was to investigate the association between serum PICP concentration and presence of fQRS on ECG in hypertensive patients. Consecutive patients with previously or newly diagnosed hypertension were included. fQRS was defined as the presence of additional R-wave (R'), or notching of R- or S-waves, or the presence of fragmentation in 2 contiguous ECG leads. Serum PICP levels were measured by ELISA method. The study group consisted of 90 hypertensive patients (74% females, with a mean age of 54.7±8.5 years). Of these patients, 47 (52.2%) had fQRS on ECG. Age (p=0.121) and gender distribution (p=0.625) were similar in patients with or without fQRS. Receiver operating characteristic curve analysis yielded a strong predictive ability of PICP levels for the presence of fQRS (area under the curve: 0.850; 95% CI: 0.772-0.929; p<0.0001). In multivariate logistic regression analysis, PICP levels were strongly and independently associated with the presence of fQRS (OR: 1.938; 95% CI: 1.398-2.688). Serum PICP level is a strong and independent predictor of fQRS. Discriminative performance of serum PICP levels for the presence of fQRS is high. The present results are the first to demonstrate that fQRS may indicate myocardial fibrosis in patients with hypertension.

Increased Extracellular Volume and Altered Mechanics Are Associated With LVH in Hypertensive Heart Disease, Not Hypertension Alone

ObjectivesThe goal of this study was to assess the relationship among extracellular volume (ECV), native T1, and systolic strain in hypertensive patients with left ventricular hypertrophy (HTN LVH), hypertensive patients without LVH (HTN non-LVH), and normotensive controls. BackgroundDiffuse myocardial fibrosis in HTN LVH patients, as reflected by increased ECV and native T1, may be an underlying mechanism contributing to increased cardiovascular risk compared with HTN non-LVH subjects and controls. Furthermore, increased diffuse fibrosis in HTN LVH subjects may be associated with reduced peak systolic and early diastolic strain rate compared with the other 2 groups. MethodsT1 mapping was performed in 20 HTN LVH (mean age, 55 ± 11 years), 23 HTN non-LVH (mean age, 61 ± 12 years), and 22 control subjects (mean age, 54 ± 7 years) on a Siemens 1.5-T Avanto (Siemens Healthcare, Erlangen, Germany) using a previously validated modified look-locker inversion-recovery pulse sequence. T1 was measured pre-contrast and 10, 15, and 20 min after injection of 0.15 mmol/kg gadopentetate dimeglumine, and the mean ECV and native T1 were determined for each subject. Measurement of circumferential strain parameters were performed using cine displacement encoding with stimulated echoes. ResultsHTN LVH subjects had higher native T1 compared with controls (p < 0.05). HTN LVH subjects had higher ECV compared with HTN non-LVH subjects and controls (p < 0.05). Peak systolic circumferential strain and early diastolic strain rates were reduced in HTN LVH subjects compared with HTN non-LVH subjects and controls (p < 0.05). Increased levels of ECV and native T1 were associated with reduced peak systolic and early diastolic circumferential strain rate across all subjects. ConclusionsHTN LVH patients had higher ECV, longer native T1 and associated reduction in peak systolic circumferential strain, and early diastolic strain rate compared with HTN non-LVH and control subjects. Measurement of ECV and native T1 provide a noninvasive assessment of diffuse fibrosis in hypertensive heart disease.

The importance of myocardial fibrosis in hypertensive heart disease

The importance of myocardial fibrosis in hypertensive heart disease

Novel magnetic resonance imaging marker of diffuse myocardial fibrosis in hypertensive heart disease: the role of transcytolemmal water-exchange

Summary Transcytolemal water exchange and its effect on myocardial T1 relaxation can, if neglected, lead to a significant underestimate of the myocardial extracellular volume fraction, a novel marker of diffuse fibrosis. Background LGE may fail to detect diffuse fibrosis in several cardiac conditions. A novel approach uses the myocardial extracellular volume-fraction (MECVF), measured as distribution volume of a gadolinium constrast, as a marker of extracellular expansion. Previous studies have assumed the fast-exchange (FX) limit for the transcytolemal waterexchange, yet the administration of an extracellular-agent can create significant transcytolemal T1-differences, and cause an underestimation of extracellular volume fraction under the FX assumption. We hypothesized that the quantitative measure of MECVF with using a 2-site H-exchange model (2SX-model) correlates positively with the extracellular volume fraction, while the FX approach underestimates extra-cellular matrix expansion in a rodent model of hypertensive heart disease and diffuse myocardial fibrosis created by administration of L-NAME. Methods L-NAME(3mg/ml) or placebo was administered respectively to 22(bw=36.9±2.3g) and 15(bw=37.6±2.5g) wildtype mice. Animals were imaged at baseline and 7weeks after treatment on a 4.7T small-animal MRI-system. T1(#of T1’s>5/mouse) was quantified with a modified Look-Locker gradient-echo-cine technique, before and after fractionated Gd-DPTA administration (mean max. R1 in blood post-contrast=5.0±2.26 1/s). MECVF obtained from the T1 measurements with the 2SX and FX-models, and by using blood hematocrit to adjust the partition coefficient. Connective tissue volume fraction (CTVF) was measured using Masson’s trichrome.

Fibrosis in hypertensive heart disease: molecular pathways and cardioprotective strategies

Fibrosis is a fundamental component of the adverse structural remodelling of myocardium found in hypertensive heart disease (HHD). A replacement fibrosis appears at sites of previous cardiomyocyte necrosis to preserve the structural integrity of the myocardium. Such scarring has adverse functional consequences. The extensive distribution of fibrosis involving the right and left heart suggests cardiomyocyte necrosis is widespread. Together, the loss of these contractile elements and fibrous tissue deposition in the form of stiff in-series and in-parallel elastic elements contribute to the progressive failure of this normally efficient muscular pump. Pathogenic mechanisms modulating fibrous tissue formation at sites of repair include auto/paracrine properties of locally generated angiotensin II and endothelin-1. This study focuses on the signal-transducer-effector pathway involved in cardiomyocyte necrosis and the crucial pathogenic role of intracellular calcium overloading, and the subsequent induction of oxidative stress originating within its mitochondria that dictates the opening of the mitochondrial permeability transition pore. The ensuing osmotic destruction of these organelles is followed by necrotic cell death. It is now further recognized that calcium overloading of cardiac myocytes and mitochondria functioning as pro-oxidant is pathophysiologically counterbalanced by an intrinsically coupled zinc entry, which serves as an antioxidant. The prospect of raising intracellular zinc by adjuvant nutriceutical supplementation can, therefore, be preferentially exploited to uncouple this intrinsically coupled calcium-zinc dyshomeostasis in favour of endogenous antioxidant defences. Novel cardioprotective strategies may thus be at hand and deserve to be explored further in the overall management of patients with HHD.

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

HomeHypertensionVol. 55, No. 5Is Smad3 the Key to Inflammation and Fibrosis in Hypertensive Heart Disease? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBIs Smad3 the Key to Inflammation and Fibrosis in Hypertensive Heart Disease? Kristof Graf and Ute M. Schaefer-Graf Kristof GrafKristof Graf From the Department of Medicine I, Cardiology, Angiology, and Intensive Care Medicine (K.G.), Jüdisches Krankenhaus Berlin, Berlin, Germany; Berlin Center for Diabetes and Pregnancy (U.M.S.-G.), St Joseph Hospital, Berlin, Germany. Search for more papers by this author and Ute M. Schaefer-GrafUte M. Schaefer-Graf From the Department of Medicine I, Cardiology, Angiology, and Intensive Care Medicine (K.G.), Jüdisches Krankenhaus Berlin, Berlin, Germany; Berlin Center for Diabetes and Pregnancy (U.M.S.-G.), St Joseph Hospital, Berlin, Germany. Search for more papers by this author Originally published15 Mar 2010https://doi.org/10.1161/HYPERTENSIONAHA.110.150466Hypertension. 2010;55:1088–1089Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 15, 2010: Previous Version 1 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.3 These protective effects were already observed less than low-dose RAS inhibition without a significant reduction of elevated blood pressures.4Understanding the components of remodeling has led to advances in therapeutic strategies. Currently available medications have been used to counteract the compensatory mechanism of postinfarction ventricular remodeling and, consequently, to reduce morbidity and mortality. In some instances, these strategies have improved left ventricular morphology and function in HHD. However, in clinical settings, a convincing or powerful antifibrotic strategy is lacking.Inflammation as an Early Event in Hypertensive DiseaseVarious authors have demonstrated that local inflammation and macrophage infiltration are early key events for reactive myocardial fibrosis, especially perivascular fibrosis, in experimental models of Ang II-mediated HHD.4Also, it has been shown that Ang II supports leukocyte transmigration via Ang II type 1 receptor-dependent, but arterial pressure-independent, mechanisms. Infiltrated macrophages are known to produce a variety of cytokines and growth factors, which, in turn, amplify the inflammatory process and activate tissue fibrosis.5 Monocyte chemoattractant protein 1 plays a central role by mediating macrophage accumulation, inducing myocardial fibrosis in pressure-overloaded hearts through a transforming growth factor (TGF)-β–mediated process.5In particular, the TGF-β/Smad3 pathway is of interest because of its regulatory effects on the inflammatory response. This pathway suppresses cytokine and chemokine expression in immune and endothelial cells and reduces neutrophil and macrophage chemotaxis. In the context of ventricular remodeling, another interesting aspect of the TGF-β/Smad3 pathway is the regulation of fibroblast activity.6 In general, TGF-β inhibits fibroblast proliferation. However, it induces phenotypic changes in fibroblasts to increase production of extracellular matrix proteins. A growing body of evidence suggests involvement of the TGF-β/Smad3 pathway in both induction and resolution of the inflammatory response. Smad3-null animals showed decreased local infiltration of monocytes7 in skin excisional wounds and had reduced cutaneous inflammation after exposure to ionizing radiation6 Furthermore, Smad3−/− monocytes exhibited a blunted chemotactic response to TGF-β.Bujak et al8 investigated the effects of Smad3 gene disruption on myocardial infarct healing and the pathogenesis of cardiac remodeling. Interstitial fibrosis was markedly reduced. Compared with wild-type animals, Smad3−/− mice exhibited decreased dilative remodeling and attenuated diastolic dysfunction, whereas infarct size was comparable between both groups. They suggested that decreased fibrotic remodeling in infarcted Smad3-null hearts may be attributable to abrogation of the profibrotic TGF-β responses.Divakaran et al9 investigated the role of Smad3 deletion in a model of pressure-induced hypertrophy induced by aortic constriction. Loss of Smad3 signaling resulted in a significant 60% decrease in myocardial fibrosis. Using microRNA microarray, they showed that microRNAs were differentially expressed in Smad3−/− mice, and, of 10 candidate microRNAs, 2 were sufficient to decrease collagen gene expression in isolated cardiac fibroblasts.9 Surprisingly, the mortality of Smad3−/− mice and the cardiac hypertrophy (primarily the size of the myocytes) after pressure overload were significantly increased, also indicating deleterious effects after Smad3 deletion in this specific model and supporting the hypothesis that the TGF-β/Smad3 pathway mediates profibrotic and antihypertrophic signals in the heart.In the present issue of Hypertension, Huang et al10 identified Smad3 as a critical mediator of Ang II-mediated cardiac inflammation and fibrosis. They demonstrated that Ang II-induced cardiac inflammation, particularly perivascular inflammation, increase in LV mass, and the development of cardiac fibrosis was inhibited in Smad3−/− mice infused with Ang II. The authors present findings that Smad3−/− mice were protected against Ang II-mediated cardiac fibrosis and inflammation.These findings suggest that targeting Smad3 may be a novel therapeutic strategy for prevention of inflammation and fibrosis in HHD (Figure). This is in accordance with the studies in myocardial infarction presented by Bujak et al8 recently, where Smad3−/− mice demonstrated less interstitial fibrosis in the noninfarcted myocardium and improved cardiac function. However, the recent observation by Divakaran et al9 indicate that inhibition/deletion of Smad3 might not only be beneficial. Whether this is a specific problem of the studied model (aortic constriction in Smad3−/− mice) is not clear. Additional studies investigating these negative effects of Smad3 deletion are needed. Download figureDownload PowerPointFigure. Mechanism(s) of Smad3-mediated effects on hypertensive remodeling leading to HHD. Elevated blood pressure leads to activation of the RAAS (renin-angiotensin-aldosterone system). This leads to activation of TGF-β/Smad3 signaling, which stimulates inflammatory events, such as monocyte chemoattractant protein (MCP) 1 and intercellular adhesion molecule (ICAM) 1 in the vasculature and the myocardium. Smad3 signaling is essential for an increase in interstitial macrophages and local inflammation, which is subsequently followed by an increase in extracellular matrix production and enhanced fibrosis. Recent studies indicate an involvement of microRNAs into the enhanced fibrotic process mediated by Smad3.9 Elevated blood pressure and activation of the RAAS continuously stimulate inflammatory signaling and coactivate growth factor pathways leading to inflammation, fibrosis, myocyte hypertrophy, and fibroblast proliferation. Inhibition of Smad3 signaling prevents hypertensive remodeling by inhibiting important early events of this process, including interstitial inflammation and fibrosis.Nevertheless, the present findings further strengthen the central role of the TGF-β/Smad3 pathway in the regulation of cardiac fibrosis and inflammation leading to HHD and cardiac remodeling. Smad3 is clearly an interesting target for novel therapeutic strategies, especially preventing the deleterious effects of progressing fibrosis in the myocardium.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Sources of FundingThe work of K.G. is supported by the Zukunftsfond Berlin/Investionsbank Berlin Brandenburg, project number 10142873.DisclosuresNone.FootnotesCorrespondence to Kristof Graf, Department of Medicine I, Jüdisches Krankenhaus Berlin, Heinz-Galinski-Str 1, 13347 Berlin, Germany. 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Bladder Stromal Loss of Transforming Growth Factor Receptor II Decreases Fibrosis After Bladder Obstruction

Transforming growth factor-beta is a potent stimulator of extracellular matrix production. Several studies show that loss of transforming growth factor-beta signaling decreases kidney, liver and lung fibrosis. However, the role of transforming growth factor-beta signaling in bladder fibrosis is not entirely understood. We investigated the effect of stromal loss of such signaling in mice after partial bladder outlet obstruction. We performed partial bladder outlet obstruction by urethral ligation in 5-week-old female Tgfbr2(colTKO) mice. These mice were compared to WT mice with partial bladder outlet obstruction and to WT nonobstructed controls. After 4 weeks and before sacrifice urodynamics were performed. Bladder tissue was harvested, and p-Smad2 and collagen (Masson's trichrome) staining were performed. Bladder compliance was increased in partially obstructed Tgfbr2(colTKO) mice and decreased in partially obstructed WT mice. The latter had increased smooth muscle hypertrophy and increased collagen deposition between smooth muscle bundles compared to those in Tgfbr2(colTKO) mice and nonobstructed controls. Transforming growth factor-beta responsive collagen promoter activity was significantly decreased in Tgfbr2 knockout bladder stromal cells vs WT stromal cells. Stromal loss of transforming growth factor-beta signaling decreased collagen deposition after partial bladder outlet obstruction. In contrast to collagen production by recruited macrophages, stromal transforming growth factor-beta signaling appears to be the primary source of fibrosis after partial bladder outlet obstruction. These findings further support the hypothesis that manipulating transforming growth factor-beta signaling in bladder stromal cells would provide a future avenue for neuropathic bladder and bladder fibrosis treatment.