Ryanodine receptor dysfunction causes senescence and fibrosis in Duchenne dilated cardiomyopathy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked disorder characterized by progressive muscle weakness due to the absence of functional dystrophin. DMD patients also develop dilated cardiomyopathy (DCM). We have previously shown that DMD (mdx) mice and a canine DMD model (GRMD) exhibit abnormal intracellular calcium (Ca2+) cycling related to early-stage pathological remodelling of the ryanodine receptor intracellular calcium release channel (RyR2) on the sarcoplasmic reticulum (SR) contributing to age-dependent DCM. METHODS: Here, we used hiPSC-CMs from DMD patients selected by Speckle-tracking echocardiography and canine DMD cardiac biopsies to assess key early-stage Duchenne DCM features. RESULTS: Dystrophin deficiency was associated with RyR2 remodelling and SR Ca2+ leak (RyR2 Po of 0.03 ± 0.01 for HC vs. 0.16 ± 0.01 for DMD, P < 0.01), which led to early-stage defects including senescence. We observed higher levels of senescence markers including p15 (2.03 ± 0.75 for HC vs. 13.67 ± 5.49 for DMD, P < 0.05) and p16 (1.86 ± 0.83 for HC vs. 10.71 ± 3.00 for DMD, P < 0.01) in DMD hiPSC-CMs and in the canine DMD model. The fibrosis was increased in DMD hiPSC-CMs. We observed cardiac hypocontractility in DMD hiPSC-CMs. Stabilizing RyR2 pharmacologically by S107 prevented most of these pathological features, including the rescue of the contraction amplitude (1.65 ± 0.06 µm for DMD vs. 2.26 ± 0.08 µm for DMD + S107, P < 0.01). These data were confirmed by proteomic analyses, in particular ECM remodelling and fibrosis. CONCLUSIONS: We identified key cellular damages that are established earlier than cardiac clinical pathology in DMD patients, with major perturbation of the cardiac ECC. Our results demonstrated that cardiac fibrosis and premature senescence are induced by RyR2 mediated SR Ca2+ leak in DMD cardiomyocytes. We revealed that RyR2 is an early biomarker of DMD-associated cardiac damages in DMD patients. The progressive and later DCM onset could be linked with the RyR2-mediated increased fibrosis and premature senescence, eventually causing cell death and further cardiac fibrosis in a vicious cycle leading to further hypocontractility as a major feature of DCM. The present study provides a novel understanding of the pathophysiological mechanisms of the DMD-induced DCM. By targeting RyR2 channels, it provides a potential pharmacological treatment.

Dilated cardiomyopathy: causes, mechanisms, and current and future treatment approaches.

Dilated cardiomyopathy is conventionally defined as the presence of left ventricular or biventricular dilatation or systolic dysfunction in the absence of abnormal loading conditions (eg, primary valve disease) or significant coronary artery disease sufficient to cause ventricular remodelling. This definition has been recognised as overly restrictive, as left ventricular hypokinesis without dilation could be the initial presentation of dilated cardiomyopathy. The causes of dilated cardiomyopathy comprise genetic (primary dilated cardiomyopathy) or acquired factors (secondary dilated cardiomyopathy). Acquired factors include infections, toxins, cancer treatment, endocrinopathies, pregnancy, tachyarrhythmias, and immune-mediated diseases. 5-15% of patients with acquired dilated cardiomyopathy harbour a likely pathogenic or pathogenic gene variant (ie, gene mutation). Therefore, the diagnostic tests and therapeutic approach should always consider both genetic and acquired factors. This Seminar will focus on the current multidimensional diagnostic and therapeutic approach and discuss the underlying pathophysiology that could drive future treatments aiming to repair or replace the existing gene mutation, or target the specific inflammatory, metabolic, or pro-fibrotic drivers of genetic or acquired dilated cardiomyopathy.

A Comprehensive Review of Dilated Cardiomyopathy in Pre-clinical Animal Models in Addition to Herbal Treatment Options and Multi-modality Imaging Strategies.

Dilated cardiomyopathy (DCM) is distinguished by ventricular chamber expansion, systolic dysfunction, and normal left ventricular (LV) wall thickness, and is mainly caused due to genetic or environmental factors; however, its aetiology is undetermined in the majority of patients. The focus of this work is on pathogenesis, small animal models, as well as the herbal medicinal approach, and the most recent advances in imaging modalities for patients with dilated cardiomyopathy. Several small animal models have been proposed over the last few years to mimic various pathomechanisms that contribute to dilated cardiomyopathy. Surgical procedures, gene mutations, and drug therapies are all characteristic features of these models. The pros and cons, including heart failure stimulation of extensively established small animal models for dilated cardiomyopathy, are illustrated, as these models tend to procure key insights and contribute to the development of innovative treatment techniques for patients. Traditional medicinal plants used as treatment in these models are also discussed, along with contemporary developments in herbal therapies. In the last few decades, accurate diagnosis, proper recognition of the underlying disease, specific risk stratification, and forecasting of clinical outcome, have indeed improved the health of DCM patients. Cardiac magnetic resonance (CMR) is the bullion criterion for assessing ventricular volume and ejection fraction in a reliable and consistent direction. Other technologies, like strain analysis and 3D echocardiography, have enhanced this technique's predictive and therapeutic potential. Nuclear imaging potentially helps doctors pinpoint the causative factors of left ventricular dysfunction, as with cardiac sarcoidosis and amyloidosis.

Dilated cardiomyopathy and chronic cardiac inflammation: Pathogenesis, diagnosis and therapy.

Dilated cardiomyopathy (DCM) is typically defined by left ventricular dilation and systolic dysfunction in the absence of a clear precipitant. Idiopathic disease is common; up to 50% of patients with DCM have no cause found despite imaging, genetic and biopsy assessments. Treatment remains focused on managing symptoms, reducing the risk of sudden cardiac death and ameliorating the structural and electrical complications of disease progression. In the absence of aetiology-specific treatments, the condition remains associated with a poor prognosis; mortality is approximately 40% at 10 years. The role of immune-mediated inflammatory injury in the development and progression of DCM was first proposed over 30 years ago. Despite the subsequent failures of three large clinical trials of immunosuppressive treatment (ATTACH, RENEWAL and the Myocarditis Treatment Trial), evidence for an abnormal adaptive immune response in DCM remains significant. In this review, we summarise and discuss available evidence supporting immune dysfunction in DCM, with a specific focus on cellular immunity. We also highlight current clinical and experimental treatments. We propose that the success of future immunosuppressive treatment trials in DCM will be dependent on the deep immunophenotyping of patients, to identify those with active inflammation and/or an abnormal immune response who are most likely to respond to therapy.

Von Hippel-Lindau syndrome with a rare complication of dilated cardiomyopathy: a case report.

BACKGROUND: Von Hippel-Lindau (VHL) syndrome is an autosomal dominant hereditary disease affecting multiple organs, with pheochromocytoma in 26% of cases. However, VHL syndrome with congestive heart failure and dilated cardiomyopathy as the primary clinical manifestations has been rarely reported. CASE PRESENTATION: A 35-year-old male patient was admitted to the hospital with dyspnea. The patient had a history of cerebellar hemangioblastoma that had been resected, and a one-year history of hypertension. Echocardiography and cardiac magnetic resonance imaging demonstrated a dilated left ventricle, decreased systolic function, and nonischemic myocardial changes. Contrast-enhanced abdominal computed tomography showed pheochromocytoma, neoplastic lesions, and multiple cysts in the kidneys and pancreas. Genetic analysis revealed a missense mutation of the VHL gene, c.269 A > T (p.Asn90Ile), which was identified as the cause of the disease. Dilated cardiomyopathy and VHL syndrome type 2 were diagnosed. The patient was administered a diuretic, α-blocker, ß-blocker, and an angiotensin receptor neprilysin inhibitor (ARNI), but refused pheochromocytoma resection. At the six-month follow-up, the patient was asymptomatic with improved cardiac function. CONCLUSION: Cardiac involvement is an atypical manifestation in VHL syndrome. Early diagnosis with genetic screening is essential for avoiding life-threatening complications associated with VHL. The management of this rare manifestation of VHL syndrome requires further investigation.

Biomarkers for Myocarditis and Inflammatory Cardiomyopathy.

PURPOSE OF REVIEW: Myocarditis is a disease caused by inflammation of the heart that can progress to dilated cardiomyopathy, heart failure, and eventually death in many patients. Several etiologies are implicated in the development of myocarditis including autoimmune, drug-induced, infectious, and others. All causes lead to inflammation which causes damage to the myocardium followed by remodeling and fibrosis. This review aims to summarize recent findings in biomarkers for myocarditis and highlight the most promising candidates. RECENT FINDINGS: Current methods of diagnosing myocarditis, including imaging and endomyocardial biopsy, are invasive, expensive, and often not done early enough to affect progression. Research is being done to find biomarkers of myocarditis that are cost-effective, accurate, and prognostically informative. These biomarkers would allow for earlier screening for myocarditis, as well as earlier treatment, and a better understanding of the disease course for specific patients. Early diagnosis of myocarditis with biomarkers may allow for prompt treatment to improve outcomes in patients.

[Myocarditis and development of dilated cardiomyopathy].

Inflammation is increasingly recognised as a causal factor in the development and progression of cardiovascular disease. With the introduction of immune checkpoint inhibitors in oncology and the ongoing COVID-19 pandemic the role of the immune system in myocardial inflammation (myocarditis) and subsequent inflammatory cardiomyopathy has once again regained attention. In this review, we want to bring myocardial inflammation to the clinician's attention and provide up-to-date knowledge on its diagnostic workup, prognostication, and current management recommendations.

Trends and Outcomes of Patients With Amyloid Cardiomyopathy Listed for Heart Transplantation.

BACKGROUND: Heart transplantation in patients with amyloid cardiomyopathy (ACM) has been historically underused owing to the risk of amyloid recurrence. METHODS: Using data from the United Network for Organ Sharing database on patients listed for single-organ heart transplant between 2010 and 2019, we evaluated trend in heart transplant and compared waitlist mortality and graft survival between patients with ACM and dilated cardiomyopathy (DCM). Also, we evaluated for independent predictors of outcomes. RESULTS: Over the study period, 411 adult patients with ACM were added to the heart transplant waitlist. In the propensity-matched cohorts, the rates of waitlist mortality were significantly higher for ACM compared with DCM (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.16-2.65). Over the study period, 330 patients with ACM underwent heart transplant. The number of transplants increased from 22 in 2010 to 59 in 2019 (168% increase). The 5-year graft survival rate was, however, significantly worse for ACM (78%) compared with DCM (82%) (HR,1.46, 1.03-2.08). We identified 2 predictors of graft failure among patients with ACM: namely, renal failure requiring dialysis (HR, 5.4, 1.6-17) and previous history of malignancy (HR, 1.6, 1.0-28). Patients with ACM with neither risk factor had 5-year graft survivals of 82%, which is comparable with DCM (HR, 1.28, 0.90-1.91). On the other hand, patients with ACM and either risk factor had worse 5-year graft survivals of 62% (HR, 2.44, 1.39-4.28). CONCLUSIONS: Increasing numbers of patients with ACM are undergoing heart transplants. Although patients with ACM experience higher waitlist mortality and worse graft survival compared with DCM, selecting carefully screened ACM patients may result in improved outcomes following heart transplant.

Coronary fibromuscular dysplasia with three-vessel involvement: a rare cause of ischaemic dilated cardiomyopathy in a very young male.

Coronary artery disease of non-atherosclerotic aetiology, while rare in incidence, can have a wide aetiology, such as fibromuscular dysplasia, which is a non-inflammatory arteriopathy of numerous histopathological types of fibromuscular tissue accumulation. This brief report describes the case of a 22-year-old male with a recently developed dilated cardiomyopathy and a history of aborted cardiac arrest at the age of 14 years. Coronary angiogram revealed severe three vessels disease, while optical coherence tomography established fibromuscular dysplasia as aetiology. Balloon and stent angioplasty was performed guided by fractional flow reserve with acceptable angiographic result.

Short-term outcomes of EXCOR Paediatric implantation.

OBJECTIVES: The aim of this study was to review a single institution's experience with EXCOR Paediatric implantation. METHODS: Patients <15 years old who underwent EXCOR implantation as a bridge to transplantation between 2015 and 2021 were enrolled. Major adverse events included death, cerebrovascular event resulting in sequelae, major infection (sepsis or surgical site infection requiring open sternal irrigation or device removal) and device malfunction requiring surgical treatment. RESULTS: Overall median age and weight for all 20 children at implantation were 10.8 (interquartile range, 7.9-33.2) months and 6.3 (4.6-10.2) kg. Ten patients (50%) weighed <5 kg. Primary diagnoses were dilated cardiomyopathy in 13 patients, fulminant myocarditis in 3, restrictive cardiomyopathy in 2 and congenital heart disease in 2. Two patients required biventricular assist support. The median support time was 365 (241-636) days. Six patients (30%) were supported for >20 months. One patient died. Seven patients underwent heart transplant. Heart transplant has not been performed in the last 1.5 years. Five patients were weaned from EXCOR support after native myocardial recovery, including a patient with dilated cardiomyopathy who recovered after 24 months of EXCOR support. Major complication-free survival at 6, 12 and 18 months were 79.3%, 49.6% and 38.6%, respectively. Body weight <5 kg at implantation was a risk factor for decreased major complication-free survival. CONCLUSIONS: Survival during EXCOR Paediatric support was good, but it prolonged the wait time for a heart transplant. The number of major complications increased over time and was not negligible, especially in small children.

Autophagy during left ventricular redilation after ventriculoplasty: Insights from a rat model of ischemic cardiomyopathy.

OBJECTIVES: Myocardial autophagy has been recognized as an important factor in heart failure. It is not known whether changes in ventricular geometry by left ventriculoplasty influence autophagy in ischemic cardiomyopathy. We hypothesized that myocardial autophagy plays an important role in left ventricular (LV) redilation after ventriculoplasty. METHODS: Four weeks after ligation of the left anterior descending artery, ventriculoplasty or sham operation was performed. The animals were euthanized at 2 days (early) or 28 days (late) after the second operation. Ventricular autophagy was evaluated by protein expression of microtubule-associated protein light chain 3 II, an autophagosome marker. Cardiomyocyte area was assessed by histologic examination. LV function was evaluated by echocardiography. To examine the implications of autophagy, an autophagy inhibitor (3-methyladenine) was injected intraperitoneally for 3 weeks before sacrifice. RESULTS: The LV was reduced in size early and redilated late after ventriculoplasty. LV systolic function was improved early and later worsened after ventriculoplasty. Light chain 3 II expression decreased early after ventriculoplasty and increased in the late period. Myocyte area increased from the early to late stage after ventriculoplasty. Autophagic inhibition exaggerated the increased myocyte hypertrophy and LV redilation. CONCLUSIONS: In a rat model of myocardial infarction, autophagy decreased early after ventriculoplasty and increased again during LV redilation. These results provide new insights into the mechanism underlying the late failure of ventriculoplasty.

Outcomes after surgical ventricular restoration for ischemic cardiomyopathy.

OBJECTIVE: The study objective was to evaluate the short- and long-term outcomes of patients with ischemic cardiomyopathy after surgical ventricular restoration and to identify risk factors related to poor results. METHODS: Between August 2002 and April 2016, 62 patients affected by ischemic cardiomyopathy underwent surgical left ventricular restoration at our unit. Patients' mean age at operation was 63 years (39-79 years). Mean ejection fraction was 29.6%. The Surgical Treatment for Ischemic Heart Failure trial criteria have been used as indications for surgery. Fifty-seven patients (91%) received surgical myocardial revascularization. Mitral valve repair was performed in 39 patients (63%). The surgical technique consisted of the classic Dor operation or a different approach reducing the equatorial diameter of the left ventricle and avoiding the use of a patch. The data were analyzed retrospectively for perioperative results and short- and long-term clinical outcomes. RESULTS: One patient died of noncardiac causes within 30 days (1.6%). All-cause death occurred in 36 patients (58%) during follow-up (0.6-14.7 years; median follow-up time, 7.02 years), of whom 15 died of cardiac causes. Age, need for preoperative intra-aortic balloon pump, reduction less than 35% of postoperative left ventricular end-diastolic and end-systolic volumes, type of surgical technique, and ejection fraction less than 25% were identified as risk factors for late cardiac mortality. Perioperative levosimendan administration and presence of preoperative moderate to severe mitral regurgitation influenced early and intermediate-term outcomes, but no statistical relevance on long-term results was demonstrated. CONCLUSIONS: Patients with ischemic dilative cardiomyopathy have favorable short- and long-term outcomes after ventricular restoration. Age, preoperative ejection fraction less than 25%, inadequate left ventricular surgical reverse remodeling, and type of surgical technique negatively affect long-term survival.

Recurrent hypoglycaemia and dilated cardiomyopathy: delayed presentation of Sheehan's syndrome.

Sheehan's syndrome (SS) is ischaemic necrosis of the pituitary gland due to massive postpartum haemorrhage. The clinical manifestations may vary from subtle to life-threatening and may present immediately after delivery or many years later. We present a case history of a 58-year-old non-diabetic woman who had undetected SS and presented with two unusual manifestations, including recurrent hypoglycaemia and dilated cardiomyopathy 34 years after delivery. The dilated cardiomyopathy reversed partially after treatment.

Neutrophil degranulation biomarkers characterize restrictive echocardiographic pattern with diastolic dysfunction in patients with diabetes.

OBJECTIVE: To investigate the potential association between neutrophil degranulation and patterns of myocardial dysfunction in a cohort of patients with type 2 diabetes mellitus (T2DM). BACKGROUND: Two distinct phenotypes of diabetic cardiomyopathy have been described: a restrictive phenotype with diastolic dysfunction (restrictive/DD) and a dilative phenotype with systolic dysfunction (dilative/SD). However, the underlying determinants of these two patterns are not yet recognized. METHODS: In this single-centre, observational, cross-sectional study, 492 patients were recruited. Ultrasonographic measurements were performed by two experienced sonographers, blinded to the clinical data of the participants. Serum biomarkers of neutrophil degranulation were measured by enzyme-linked immunosorbent sandwich assay (ELISA). RESULTS: After adjustment for confounders, resistin, myeloperoxidase, matrix metalloproteinase 8 and matrix metalloproteinase 9/tissue inhibitor of metalloproteinases 1 complex were positively associated with the restrictive/DD pattern compared with the normal pattern. Similarly, MPO was positively associated with the dilative/SD pattern compared with the normal pattern, and resistin was negatively associated with the dilative/SD pattern compared with the restrictive/DD pattern. CONCLUSIONS: Neutrophil degranulation is associated with the restrictive/DD echocardiographic pattern in patients with T2DM, but not with the normal pattern and dilative/SD patterns. Neutrophils could have a pivotal role in the pathogenesis of myocardial dysfunction, and particularly diastolic dysfunction, in patients with T2DM.

Heavy alcohol drinking and subclinical echocardiographic abnormalities of structure and function.

OBJECTIVE: The aim of the study is to assess changes in heart structure and function associated with heavy alcohol use by comparing echocardiographic indices in a population-based sample to those in patients admitted to an inpatient facility with severe alcohol problems. METHODS AND RESULTS: We used data from the Know Your Heart study (2015-2017) which is a cross-sectional study that recruited 2479 participants aged 35-69 years from the general population of the city of Arkhangelsk in Northwest Russia and 278 patients from the Arkhangelsk Regional Psychiatric Hospital with a primary diagnosis related to chronic alcohol use (narcology clinic subsample). The drinking patterns of the population-based sample were characterised in detail. We used regression models controlling for age, sex, smoking, education and waist to hip ratio to evaluate the differences in echocardiographic indices in participants with different drinking patterns. The means of left ventricular end-diastolic diameter and indexed left atrial systolic diameter were increased among heavy drinkers (narcology clinic subsample), while mean left ventricular ejection fraction was decreased in this group compared with the population-based sample. In contrast, the harmful and hazardous drinkers in the population-based sample did not differ from non-problem drinkers with respect to echocardiographic indices of systolic and diastolic function. CONCLUSIONS: Extremely heavy drinking is associated with a specific set of structural and functional abnormalities of the heart that may be regarded as precursors of alcohol-related dilated cardiomyopathy.

Cardiac mitofusin-1 is reduced in non-responding patients with idiopathic dilated cardiomyopathy.

Prognosis of severe heart failure remains poor. Urgent new therapies are required. Some heart failure patients do not respond to established multidisciplinary treatment and are classified as "non-responders". The outcome is especially poor for non-responders, and underlying mechanisms are largely unknown. Mitofusin-1 (Mfn1), a mitochondrial fusion protein, is significantly reduced in non-responding patients. This study aimed to elucidate the role of Mfn1 in the failing heart. Twenty-two idiopathic dilated cardiomyopathy (IDCM) patients who underwent endomyocardial biopsy of intraventricular septum were included. Of the 22 patients, 8 were non-responders (left ventricular (LV) ejection fraction (LVEF) of < 10% improvement at late phase follow-up). Electron microscopy (EM), quantitative PCR, and immunofluorescence studies were performed to explore the biological processes and molecules involved in failure to respond. Studies in cardiac specific Mfn1 knockout mice (c-Mfn1 KO), and in vitro studies with neonatal rat ventricular myocytes (NRVMs) were also conducted. A significant reduction in mitochondrial size in cardiomyocytes, and Mfn1, was observed in non-responders. A LV pressure overload with thoracic aortic constriction (TAC) c-Mfn1 KO mouse model was generated. Systolic function was reduced in c-Mfn1 KO mice, while mitochondria alteration in TAC c-Mfn1 KO mice increased. In vitro studies in NRVMs indicated negative regulation of Mfn1 by the ß-AR/cAMP/PKA/miR-140-5p pathway resulting in significant reduction in mitochondrial respiration of NRVMs. The level of miR140-5p was increased in cardiac tissues of non-responders. Mfn1 is a biomarker of heart failure in non-responders. Therapies targeting mitochondrial dynamics and homeostasis are next generation therapy for non-responding heart failure patients.

LncRNA AC061961.2 overexpression inhibited endoplasmic reticulum stress induced apoptosis in dilated cardiomyopathy rats and cardiomyocytes via activating wnt/ß-catenin pathway.

Down-regulated lncRNA AC061961.2 in dilated cardiomyopathy (DCM) patients was previous reported. Whether AC061961.2 has regulatory effect on DCM still need exploration. Here, we tried to investigate the effect of AC061961.2 on DCM. After DCM model rat was established through injecting Adriamycin, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS) were measured by echocardiography. Histopathological changes and apoptosis were detected by hematoxylin-eosin, Masson staining, and TUNEL. After cardiomyocytes were isolated and identified by immunofluorescence, DCM cell model was established by injecting adriamycin. After transfected with overexpressed-AC061961.2 plasmids, cell apoptosis was detected by flow cytometry. The expressions of AC061961.2, ß-catenin, Axin2, c-Myc, CRP78, CHOP, Caspase-3, Bcl-2, and Bax in cardiomyocytes and heart tissues were detected by RT-qPCR or western blot. LVEDD and LVESD were increased while LVEF and LVFS were decreased in DCM rats. The histopathological of heart tissues showed a typical sign of DCM. Apoptosis were increased in heart tissues of DCM rats. In DCM rats, the expressions of AC061961.2, ß-catenin, Axin2, c-Myc, and Bcl-2 were decreased, the expressions of CRP78, CHOP, Caspase-3, and Bax were increased. After the overexpression of AC061961.2, levels of ß-catenin, Axin2, c-Myc, and Bcl-2 were increased, while levels of CRP78, CHOP, Caspase-3, and Bax were decreased, compared with that in DCM cardiomyocytes. LncRNA AC061961.2 overexpression inhibited endoplasmic reticulum stress induced apoptosis in DCM rats and cardiomyocytes via activating Wnt/ß-catenin pathway.