Skeletal muscle derived Musclin protects the heart during pathological overload.

Cachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood. Here, we investigate whether the dysregulation of myokine expression from wasting skeletal muscle exaggerates heart failure. RNA sequencing from wasting skeletal muscles of mice with heart failure reveals a reduced expression of Ostn, which encodes the secreted myokine Musclin, previously implicated in the enhancement of natriuretic peptide signaling. By generating skeletal muscle specific Ostn knock-out and overexpressing mice, we demonstrate that reduced skeletal muscle Musclin levels exaggerate, while its overexpression in muscle attenuates cardiac dysfunction and myocardial fibrosis during pressure overload. Mechanistically, Musclin enhances the abundance of C-type natriuretic peptide (CNP), thereby promoting cardiomyocyte contractility through protein kinase A and inhibiting fibroblast activation through protein kinase G signaling. Because we also find reduced OSTN expression in skeletal muscle of heart failure patients, augmentation of Musclin might serve as therapeutic strategy.

Rejuvenating the Aging Heart by Enhancing the Expression of the Cisd2 Prolongevity Gene.

Aging is the major risk factor for cardiovascular disease, which is the leading cause of mortality worldwide among aging populations. Cisd2 is a prolongevity gene that mediates lifespan in mammals. Previously, our investigations revealed that a persistently high level of Cisd2 expression in mice is able to prevent age-associated cardiac dysfunction. This study was designed to apply a genetic approach that induces cardiac-specific Cisd2 overexpression (Cisd2 icOE) at a late-life stage, namely a time point immediately preceding the onset of old age, and evaluate the translational potential of this approach. Several discoveries are pinpointed. Firstly, Cisd2 is downregulated in the aging heart. This decrease in Cisd2 leads to cardiac dysfunction and impairs electromechanical performance. Intriguingly, Cisd2 icOE prevents an exacerbation of age-associated electromechanical dysfunction. Secondly, Cisd2 icOE ameliorates cardiac fibrosis and improves the integrity of the intercalated discs, thereby reversing various structural abnormalities. Finally, Cisd2 icOE reverses the transcriptomic profile of the aging heart, changing it from an older-age pattern to a younger pattern. Intriguingly, Cisd2 icOE modulates a number of aging-related pathways, namely the sirtuin signaling, autophagy, and senescence pathways, to bring about rejuvenation of the heart as it enters old age. Our findings highlight Cisd2 as a novel molecular target for developing therapies targeting cardiac aging.

Analysis of the Correlation of Galectin-3 Concentration with the Measurements of Echocardiographic Parameters Assessing Left Atrial Remodeling and Function in Patients with Persistent Atrial Fibrillation.

Galectin-3 (gal-3) is a fibrosis marker and may play a role in fibrosis of the left atrium (LA). Left atrial wall fibrosis may influence the transition from paroxysmal to non-paroxysmal atrial fibrillation (AF). In this study, we assessed the correlation of gal-3 concentration with the main echocardio-graphic parameters evaluating dimensions, volume, compliance, and left atrial contractility during AF and after successful electrical cardioversion (DCCV). The study included 63 patients with left atrial enlargement who qualified for DCCV due to persistent AF. The procedure recovered sinus rhythm in 43 (68.3%) patients. The concentration of gal-3 was negatively correlated with the echocardiographic parameters of LA including dimensions (LA length pre, rho = -0.38; p = 0.003), volume (LAV pre, rho = -0.39; p = 0.003), compliance (LASr mean post, rho = -0.33) and contractility (pLASRct mean post, rho = -0.33; p = 0.038). Negative correlations of gal-3 concentration were also observed in relation to the volume and contractility of the left ventricle. The concentration of gal-3 significantly negatively correlates with the size, systolic function, and compliance of the LA wall in patients with persistent AF. Determining gal-3 concentration in patients with persistent AF may help in the assessment of remodeling of the LA wall.

Gut dysbiosis induced by cardiac pressure overload enhances adverse cardiac remodeling in a T cell-dependent manner.

Despite the existing association of gut dysbiosis and T cell inflammation in heart failure (HF), whether and how gut microbes contribute to T cell immune responses, cardiac fibrosis and dysfunction in HF remains largely unexplored. Our objective was to investigate whether gut dysbiosis is induced by cardiac pressure overload, and its effect in T cell activation, adverse cardiac remodeling, and cardiac dysfunction. We used 16S rRNA sequencing of fecal samples and discovered that cardiac pressure overload-induced by transverse aortic constriction (TAC) results in gut dysbiosis, characterized by a reduction of tryptophan and short-chain fatty acids producing bacteria in WT mice, but not in T cell-deficient mice (Tcra-/- ) mice. These changes did not result in T cell activation in the gut or gut barrier disruption. Strikingly, microbiota depletion in WT mice resulted in decreased heart T cell infiltration, decreased cardiac fibrosis, and protection from systolic dysfunction in response to TAC. Spontaneous reconstitution of the microbiota partially reversed these effects. We observed decreased cardiac expression of the Aryl hydrocarbon receptor (AhR) and enzymes associated with tryptophan metabolism in WT mice, but not in Tcra-/- mice, or in mice depleted of the microbiota. These findings demonstrate that cardiac pressure overload induced gut dysbiosis and T cell immune responses contribute to adverse cardiac remodeling, and identify the potential contribution of tryptophan metabolites and the AhR to protection from adverse cardiac remodeling and systolic dysfunction in HF.

Regenerative Potential of a Suspension and Spheroids of Multipotent Mesenchymal Stromal Cells from Human Umbilical Cord on the Model of Myocardial Infarction in Rats.

Regenerative potential of multipotent mesenchymal stromal cells from the human umbilical cord (MMSC-UC) in the suspension and spheroid form was revealed during the progression of experimental small focal myocardial infarction in rats. In isoproterenol-induced myocardial infarction, foci of necrosis and inflammatory infiltrate and at later terms fibrosis foci were found mainly in the left ventricle of rat heart. In rats receiving MMSC-UC, destructive changes in the myocardium, fibrous scars, and inflammatory process were less pronounced. MMSC-UC also contributed to normalization of the morphofunctional parameters of the heart. Spheroids exhibited higher efficiency in comparison with cell suspension.

Energy Metabolism in Cellular Regenerative Processes: Focus on PPARα.

Reduced expression of the key regulator of cardiac metabolism, transcription factor PPARα, in surgical samples of the auricles from patients with coronary heart disease and heart failure was detected by real-time quantitative PCR. These changes indicate reduced activity of this factor and a shift of energy metabolism from oxidative phosphorylation to glycolysis typical of dedifferentiated cells. Electron microscopy revealed dedifferentiated cardiomyocytes with disassembled contractile apparatus and disorganized sarcomeres. In the examined specimens from patients with heart failure, severe myocardial fibrosis was revealed.

Endomyocardial fibrosis: past, present, and future.

Endomyocardial fibrosis (EMF) is a neglected idiopathic disorder, predominant in tropical and subtropical regions of the developing world. It is characterized by fibrotic thickening of the endocardium and myocardium of one or both ventricles. EMF was an important cause of heart failure which accounted for up to 20% of the cases in endemic areas of Africa (rural community in Mozambique), but during the last few years, incidents of the disease have decreased considerably. Although its pathogenesis and etiology are not fully understood, its pathology resembles conditions such as eosinophilic cardiomyopathy and hypereosinophilic syndrome. Extensive fibrosis of the ventricular endocardium causing architectural distortion, impaired filling, and valvular insufficiency defines the disease. Confined to peculiar and limited geographical areas, the etiology remains blurred and it carries a grim prognosis. Medical care currently remains very challenging as one-third to half of patients with an advanced disease die within 2 years. Surgery in the correct setting can increase survival and especially in patients with advanced heart failure.

A case presentation of patient from northern China with endomyocardial fibrosis.

BACKGROUND: Endomyocardial fibrosis (EMF) is a rare condition and a major cause of death in tropical countries. The etiology of EMF remains elusive, and no specific treatment has been developed yet, therefore it carries poor prognosis. CASE PRESENTATION: An 81-year-old male Chinese patient with a history of long-standing exertional breathlessness, presented with worsening symptoms rapidly evolving to orthopnea. A proper specific treatment was prescribed to the patient in the following days, including diuretics, angiotensin-converting-enzyme inhibitor and beta blockers. The patient died of progressive multiple organ failure. CONCLUSION: Echocardiography is technically limited due to the acoustic shadowing as a result of the calcification. Chest computed tomography is a more accurate diagnostic tool to examine the anatomic distribution and extent of endomyocardial calcification in this rare case.

A case report of a 40-year-old woman with endomyocardial fibrosis in a non-tropical area: from initial presentation to high urgent heart transplantation.

BACKGROUND: Endomyocardial fibrosis (EMF) represents the most common cause of restrictive cardiomyopathy worldwide. Despite a high prevalence in tropical regions, it occasionally occurs in patients who have never visited these areas. While researches have proposed various possible triggers for EMF, etiology and pathogenesis remain largely unknown. Diagnosis is based on patient history, heart failure symptoms, and echocardiographic signs of restrictive ventricular filling, atrioventricular valve regurgitation and frequently apical thrombus. Following is a case report of an Austrian patient with EMF who eventually had to undergo a heart transplant. This case report strives to promote awareness for this in non-tropical areas uncommon but nevertheless detrimental disease. CASE PRESENTATION: A 40-year-old woman was presented at our emergency department with chest pain and fever up to 38.1° Celsius. Plasma troponin-T levels and inflammatory markers were slightly elevated, but the echocardiogram was without pathological findings. The patient was hospitalized on the suspicion of acute myocarditis and discharged soon after improvement. Eight months later, she was presented again with chest pain and symptoms of heart failure. The echocardiogram showed normal systolic left ventricular (LV) function with LV wall thickening and severe restrictive mitral regurgitation as well as aortic and tricuspid regurgitation. Coronary angiogram was normal but right heart catheterization showed pulmonary hypertension due to left heart disease. Further diagnostic workup with cardiac magnetic resonance imaging revealed subendocardial late enhancement and apical thrombus formation in the left ventricle compatible with the diagnosis of EMF. A comprehensive diagnostic workup showed no evidence of infection, systemic immunologic or hematological disease, in particular hypereosinophilic syndrome. After a multidisciplinary consideration of several therapeutic options, the patient was listed for heart transplantation. On the waiting list, she deteriorated rapidly due to progressive heart failure and finally underwent a heart transplantation. Histological examination confirmed the diagnosis of EMF. Six years after her heart transplantation, the patient was presented in an excellent clinical condition. CONCLUSIONS: Even in non-tropical regions, the diagnosis of EMF should always be considered in restrictive cardiomyopathy. Knowledge of the distinct phenotype of EMF facilitates diagnosis, but comprehensive workup and therapeutic management remain challenging and require a multidisciplinary approach.

Exercise Rehabilitation Improves Cardiac Volumes and Functional Capacity in Patients With Endomyocardial Fibrosis: A RANDOMIZED CONTROLLED TRIAL.

PURPOSE: Endomyocardial fibrosis (EMF) is a restrictive cardiomyopathy associated with low functional capacity and high mortality rates. Exercise training has been proved to be a nonpharmacological treatment of cardiovascular diseases. Therefore, the purpose of this study was to determine the effects of exercise rehabilitation in EMF patients. METHODS: Twenty-two EMF patients, functional classes II and III (New York Heart Association [NYHA]), were randomized to the control (C-EMF) or exercise rehabilitation (Rehab-EMF) group. Patients in the Rehab-EMF group underwent 4 mo of exercise rehabilitation, whereas patients in the C-EMF group were instructed to maintain their usual daily routine. Peak oxygen uptake ((Equation is included in full-text article.)O2), cardiac function, and quality of life were evaluated. All assessments were performed at baseline and after 4 mo. RESULTS: After 4 mo of rehabilitation, peak (Equation is included in full-text article.)O2 increased in the Rehab-EMF group (17.4 ± 3.0 to 19.7 ± 4.4 mL/kg/min, P < .001), whereas the C-EMF group showed no difference (15.3 ± 3.0 to 15.0 ± 2.0 mL/kg/min, P = .87). Also, post-intervention, peak (Equation is included in full-text article.)O2 in the Rehab-EMF group was greater than that in the C-EMF group (P < .001). Furthermore, the Rehab-EMF group, when compared to the C-EMF group, showed an increase in left ventricular end-diastolic volume (102.1 ± 64.6 to 136.2 ± 75.8 mL vs 114.4 ± 55.0 to 100.4 ± 49.9 mL, P < .001, respectively) and decrease in left atrial diastolic volume (69.0 ± 33.0 to 34.9 ± 15.0 mL vs 44.6 ± 21.0 to 45.6 ± 23.0 mL, P < .001, respectively). Quality-of-life scores also improved in the Rehab-EMF group, whereas the C-EMF group showed no change (45 ± 23 to 27 ± 15 vs 47 ± 15 to 45 ± 17, P < .001, respectively). CONCLUSION: Exercise rehabilitation is a nonpharmacological intervention that improves functional capacity, cardiac volumes, and quality of life in EMF patients after endocardial resection surgery. In addition, exercise rehabilitation should be prescribed to EMF patients to improve their clinical condition.

Myocardial global longitudinal strain: An early indicator of cardiac interstitial fibrosis modified by spironolactone, in a unique hypertensive rat model.

OBJECTIVES: Is global longitudinal strain (GLS) a more accurate non-invasive measure of histological myocardial fibrosis than left ventricular ejection fraction (LVEF) in a hypertensive rodent model. BACKGROUND: Hypertension results in left ventricular hypertrophy and cardiac dysfunction. Speckle-tracking echocardiography has emerged as a robust technique to evaluate cardiac function in humans compared with standard echocardiography. However, its use in animal studies is less clearly defined. METHODS: Cyp1a1Ren2 transgenic rats were randomly assigned to three groups; normotensive, untreated hypertensive or hypertensive with daily administration of spironolactone (human equivalent dose of 50 mg/day). Cardiac function and interstitial fibrosis development were monitored for three months. RESULTS: The lower limit of normal LVEF was calculated to be 75%. After three months hypertensive animals (196±21 mmHg systolic blood pressure (SBP)) showed increased cardiac fibrosis (8.8±3.2% compared with 2.4±0.7% % in normals), reduced LVEF (from 81±2% to 67±7%) and impaired myocardial GLS (from -17±2% to -11±2) (all p<0.001). Myocardial GLS demonstrated a stronger correlation with cardiac interstitial fibrosis (r2 = 0.58, p<0.0001) than LVEF (r2 = 0.37, p<0.006). Spironolactone significantly blunted SBP elevation (184±15, p<0.01), slowed the progression of cardiac fibrosis (4.9±1.4%, p<0.001), reduced the decline in LVEF (72±4%, p<0.05) and the degree of impaired myocardial GLS (-13±1%, p<0.01) compared to hypertensive animals. CONCLUSIONS: This study has demonstrated that, myocardial GLS is a more accurate non-invasive measure of histological myocardial fibrosis compared to standard echocardiography, in an animal model of both treated and untreated hypertension. Spironolactone blunted the progression of cardiac fibrosis and deterioration of myocardial GLS.

Early manifestation of myocardial involvement in systemic sclerosis.

INTRODUCTION: Systemic sclerosis (SSc) is a systemic autoimmune disease involving multiple organs. We present a rare case of SSc in which clinical manifestations of cardiac fibrosis occurred early in the disease course. CASE REPORT: We report the case of a 40-year-old Caucasian man, previously diagnosed with SSc, who presented with decompensated heart failure. Transthoracic echocardiography was remarkable for severe right ventricular systolic dysfunction, abnormal ventricular septal motion, severe functional tricuspid regurgitation and normal pulmonary artery systolic pressure. Left ventricular ejection fraction was 45%. Right heart catheterization revealed no signs of pulmonary hypertension. Cardiac magnetic resonance (CMR) showed diffuse myocardial infiltration, later confirmed as myocardial fibrosis by endomyocardial biopsy. CONCLUSIONS: Myocardial fibrosis is an important cause of early heart failure in SSc patients and is associated with poor prognosis. Echocardiography and CMR help establish the diagnosis and enable an appropriate therapeutic strategy to be developed in such cases.

Complex right atrial mass in endomyocardial fibrosis: a diagnostic dilemma.

Endomyocardial fibrosis, though a vanishing disease from India, remains an important cause of heart failure in children, adolescents and young adults. It may be complicated with arrhythmias and thromboembolism and is an important cause of mortality and morbidity. Moreover, usual presentation of this condition is in advanced stage with poor prognosis. Ventricular endocardial fibrosis with organised thrombus is the hall mark of this entity. Presence of associated cardiac mass poses a diagnostic challenge. We present one such case of endomyocardial fibrosis, in which a large thrombus was seen adherent to the anterolateral wall of right atrium, posing further risk of thromboembolism with complex management issues.

Endomyocardial fibrosis and myocardial infarction leading to diastolic and systolic dysfunction requiring transplantation.

Endomyocardial fibrosis (EMF) is an endemic disease in tropical areas, characterized by restrictive physiology due to endocardial fibrous thickening of the ventricular chambers. We report the case of a 25-year-old man of African origin who presented with end-stage heart failure due to both diastolic and systolic dysfunction and extensive endocavitary thrombosis as proven by echocardiography and cardiac magnetic resonance. EMF diagnosis was confirmed by endomyocardial biopsy and the patient had eventually cardiac transplantation. The explanted heart revealed, besides features consistent with EMF, transmural post- myocardial infarction scarring, in the absence of significant coronary artery disease, most probably thromboembolic in origin.

The effect of complex intramural microstructure caused by structural remodeling on the stability of atrial fibrillation: Insights from a three-dimensional multi-layer modeling study.

BACKGROUND: Recent researches have suggested that the complex three-dimensional structures caused by structural remodeling play a key role in atrial fibrillation (AF) substrates. Here we aimed to investigate this hypothesis using a multi-layer model representing intramural microstructural features. METHODS: The proposed multi-layer model was composed of the endocardium, connection wall, and epicardium. In the connection wall, intramural fibrosis was simulated using fibrotic patches randomly scattered in the myocardial tissue of fibrotic layers, while endo-epicardial dissociation was simulated using myocardial patches randomly scattered in the fibrotic tissue of isolation layers. Multiple simulation groups were generated to quantitatively analyze the effects of endo-epicardial dissociation and intramural fibrosis on AF stability, including a stochastic group, interrelated groups, fibrosis-degree-controlled groups, and dissociation-degree-controlled groups. RESULTS: 1. Stable intramural re-entries were observed to move along complete re-entrant circuits inside the transmural wall in four of 65 simulations in the stochastic group. 2. About 21 of 23 stable simulations in the stochastic group were distributed in the areas with high endo-epicardial dissociation and intramural fibrosis. 3. The difference between fibrosis-degree-controlled groups and dissociation-degree-controlled groups suggested that some distributions of connection areas may affect AF episodes despite low intramural fibrosis and endo-epicardial dissociation. 4. The overview of tracking phase singularities revealed that endo-epicardial dissociation played a visible role in AF substrates. CONCLUSION: The complex intramural microstructure is positively correlated with critical components of AF maintenance mechanisms. The occurrence of intramural re-entry further indicates the complexity of AF wave-dynamics.

Endomyocardial Fibrosis With End-Stage Heart Failure as a Consequence of a Myeloproliferative Neoplasm With Hypereosinophilia.

Hypereosinophilic syndrome is characterized by an overproduction of eosinophils that infiltrate and damage multiple organs. Cardiac dysfunction occurs frequently and is a main cause of morbidity and mortality. We describe the case of a middle-aged man diagnosed with a myeloproliferative neoplasm associated with hypereosinophilia and treated with imatinib. He was diagnosed with cardiac involvement by hypereosinophilic syndrome at a late stage, with an established restrictive cardiomyopathy. Because of end-stage heart failure, he successfully received a heart transplant. This disease might not be considered a contraindication for heart transplantation.

Is extensive atrial fibrosis in the setting of heart failure associated with a reduced atrial fibrillation burden?

Atrial fibrillation (AF) affects 10-50% of patients with chronic heart failure (HF) and is associated with poor long-term prognosis. AF is commonly associated with atrial structural remodeling (ASR), principally characterized by atrial dilatation and fibrosis. However, the occurrence of AF in the full spectrum of ASR encountered in patients with HF is poorly defined. Experimental studies have presented evidence that extensive ASR can be accompanied with a reduced burden of AF, secondary to a prominent depression of atrial excitability. This reduction in AF burden is associated with severe atrial fibrosis rather than with dilatation. Clinical studies of patients with HF point to the possibility that advanced ASR is associated with a less frequent AF occurrence than moderate ASR. Our goal in this review is to introduce the hypothesis that AF is less likely to occur in severe versus moderate atrial ASR in the setting of HF and that it is severe atrial fibrosis-associated depression of atrial excitability that reduces AF burden.

Endocardial Fibrotic Lesions Have a Greater Effect on Peak Longitudinal Strain than Epicardial Fibrotic Lesions in Hypertrophic Cardiomyopathy Patients.

Peak longitudinal strain (PLS) of the left ventricular (LV) myocardium by transthoracic echocardiogram (TTE) is useful to detect LV myocardial damage. We hypothesized that myocardial fibrosis (MF) in the LV myocardium may influence PLS. Eighteen hypertrophic cardiomyopathy (HCM) patients (14 males; 58 ± 17 years old) underwent 1.5 Tesla cardiac magnetic resonance (CMR) and TTE. Patients with previous myocardial infarction were excluded. We used TTE to assess whole-layer PLS in an American Heart Association-defined 17-segment LV model. Whole-layer PLS was calculated using Echo PAC, version 113 (GE Healthcare). MF was assessed by T1-weighted CMR of the LV endocardial layer, the LV epicardial layer, or both the LV endocardial and epicardial layers for each lesion. Of the 306 segments, MF was detected in the LV endocardial layer only (13 segments), in the LV epicardial layer only (9 segments), or in both LV endocardial and epicardial layers (59 segments). PLS values were significantly lower in segments with MF affecting only the LV endocardial layer (7% ± 4%) (P < 0.05) and where MF was observed in both the LV endocardial and epicardial layers (9% ± 5%) (P = 0.001) compared with segments without MF (13% ± 7%). No significant difference in PLS values was detected between the MF segments for the LV epicardial layer only (10% ± 6%) and those without MF (13% ± 7%) (P > 0.05). In HCM patients, fibrotic lesions in the LV endocardium have a greater adverse effect on PLS than those in the LV epicardium. Our results are significant for HCM patients with fibrotic lesions within the LV endocardium.

LncRNA PFL contributes to cardiac fibrosis by acting as a competing endogenous RNA of let-7d.

Rationale: Cardiac fibrosis is associated with various cardiovascular diseases and can eventually lead to heart failure. Dysregulation of long non-coding RNAs (lncRNAs) has recently been recognized as one of the key mechanisms involved in cardiac diseases. However, the potential roles and underlying mechanisms of lncRNAs in cardiac fibrosis have not been explicitly delineated. Methods and Results: Using a combination of in vitro and in vivo studies, we identified a lncRNA NONMMUT022555, which is designated as a pro-fibrotic lncRNA (PFL), and revealed that PFL is up-regulated in the hearts of mice in response to myocardial infarction (MI) as well as in the fibrotic cardiac fibroblasts (CFs). We found that knockdown of PFL by adenoviruses carrying shRNA attenuated cardiac interstitial fibrosis and improved ejection fraction (EF) and fractional shortening (FS) in MI mice. Further study showed that forced expression of PFL promoted proliferation, fibroblast-myofibroblast transition and fibrogenesis in mice CFs by regulating let-7d, whereas silencing PFL mitigated TGF-ß1-induced myofibroblast generation and fibrogenesis. More importantly, PFL acted as a competitive endogenous RNA (ceRNA) of let-7d, as forced expression of PFL reduced the expression and activity of let-7d. Moreover, let-7d levels were decreased in the MI mice and in fibrotic CFs. Inhibition of let-7d resulted in fibrogenesis in CFs, whereas forced expression of let-7d abated fibrogenesis through targeting platelet-activating factor receptor (Ptafr). Furthermore, overexpression of let-7d by adenoviruses carrying let-7d precursor impeded cardiac fibrosis and improved cardiac function in MI mice. Conclusion: Taken together, our study elucidated the role and mechanism of PFL in cardiac fibrosis, indicating the potential role of PFL inhibition as a novel therapy for cardiac fibrosis.