Cases Of Dilated Cardiomyopathy Research Articles

Evaluation of Cardiac Biomarkers for Early Diagnosis of Dilated Cardiomyopathy in Dogs

Cardiac biomarkers play a crucial role in diagnosing heart disease in veterinary medicine. This collaborative study, involving 2497 dogs of various breeds, ages, and genders, was conducted collaboratively at the Department of Veterinary Clinical Medicine, College of Veterinary and Animal Science, RAJUVAS, Bikaner, and the Chandrika Chimanlal Doshi Cardiovascular Unit for Animals, Department of Veterinary Clinical Medicine, Ethics, and Jurisprudence, Bombay Veterinary College, Parel, Mumbai-12.Through meticulous examination, including historical analysis, clinical evaluation, and advanced diagnostic techniques like echocardiography, researchers conclusively diagnosed 29 cases of Dilated Cardiomyopathy (DCM). Canine-specific cardiac Troponin I (cTnI) levels were measured, showing significant differences between healthy and DCM-affected dogs. Among DCM cases, bilaterally affected dogs exhibited the highest cTnI levels. Similarly, B-type natriuretic peptide (BNP) analysis revealed significant differences between healthy and DCM-affected dogs, with notably elevated levels in bilaterally affected dogs. N-Terminal-pro-BNP analysis also indicated significant differences between healthy and DCM-affected dogs. However, atrial natriuretic peptide (ANP) analysis showed no significant differences between healthy and DCM-affected dogs, except for lower levels observed in right DCM cases. Endothelin 1 analysis showed non-significant differences between healthy and DCM-affected dogs, except for higher levels in bilateral DCM cases. While these biomarkers offer promising diagnostic insights, they have limitations. Proper sample handling, longer turnaround times, and the necessity for concurrent analysis of renal and hepatic function are crucial considerations. Additionally, these biomarkers complement but do not replace other diagnostic methods such as radiography and echocardiography. Further research in larger dog populations is warranted to validate and refine these findings.

Abstract P160: Prevalence of Genetic Dilated Cardiomyopathy: A Systematic Literature Review

Background: Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation worldwide. Many cases of DCM are due to genetic or idiopathic etiology. Two prominent contributors to genetic DCM (gDCM) are the TTN and MYH7 genes, which encode proteins associated with DCM etiology. Purpose: This study aimed to synthesize the published literature on the global prevalence of adult and pediatric gDCM within the clinical DCM population and the general population. Methods: A systematic review was conducted by searching MEDLINE® and Embase from database inception to 09/19/2022. We included observational studies reporting the prevalence of gDCM within any population; prevalence of TTN and MYH7 mutations were also extracted. Excluded were studies using family history as a proxy for gDCM. Median with interquartile range (IQR) or mean with standard deviation (SD) weighted by sample size (in cases of calculations with <10 studies) were used to summarize the data. Results: Of 2,720 identified abstracts, 57 studies were included in the review. Among the adult or mixed (adults and children) DCM population in any country, median prevalence was 21.0% for overall DCM-related genetic mutations, 11.4% for TTN mutations, and 3.2% for MYH7 mutations ( Table ). The prevalence of pediatric gDCM within the DCM population was similar (weighted mean: 21.3%). Data on prevalence of gDCM within the general population were scarce. Conclusion: This study highlights the variable prevalence of gDCM reported across different populations and settings. The current evidence may underestimate the genetic causes due to technical limitations in genetic testing and limited screening. Accurately determining the prevalence of gDCM is critical for identifying high-risk populations, developing targeted prevention strategies for disease complications, and improving outcomes; epidemiological studies using long-read sequencing techniques and large cohort datasets with genotype-phenotype correlation analyses are needed.

Pregnancy and cardiac maternal outcomes in women with inherited cardiomyopathy: interest of the CARPREG II risk score.

Inherited cardiomyopathies are relatively rare but carry a high risk of cardiac maternal morbidity and mortality during pregnancy and postpartum. However, data for risk stratification are scarce. The new CARPREG II score improves prediction of prognosis in pregnancies associated with heart disease, though its role in inherited cardiomyopathies is unclear. We aim to describe characteristics and cardiac maternal outcomes in patients with inherited cardiomyopathy during pregnancy, and to evaluate the interest of the CARPREG II risk score in this population. In this retrospective single-centre study, 90 consecutive pregnancies in 74 patients were included (mean age 32±5years), including 28 cases of dilated cardiomyopathy (DCM), 46 of hypertrophic cardiomyopathy, 11 of arrhythmogenic right ventricular cardiomyopathy and 5 of left ventricular noncompaction, excluding peripartum cardiomyopathy. The discriminatory power of several risk scores was assessed by the area under the receiver-operating characteristic curve (AUC). Median CARPREG II score was 2 [0;3] and was higher in the DCM subgroup. A severe cardiac maternal complication was observed in 18 (20%) pregnancies, mainly driven by arrhythmia and heart failure (each event in 10 pregnancies), with 3 cardiovascular deaths. Forty-three pregnancies (48%) presented foetal/neonatal complications (18 premature delivery, 3 foetal/neonatal death). CARPREG II was significantly associated with cardiac maternal complications (P<0.05 for all) and showed a higher AUC (0.782) than CARPREG (0.755), mWHO (0.697) and ZAHARA (0.604). Pregnancy in women with inherited cardiomyopathy carries a high risk of maternal cardiovascular complications. CARPREG II is the most efficient predictor of cardiovascular complications in this population.

Titin domains with reduced core hydrophobicity cause dilated cardiomyopathy

The underlying genetic defect in most cases of dilated cardiomyopathy (DCM), a common inherited heart disease, remains unknown. Intriguingly, many patients carry single missense variants of uncertain pathogenicity targeting the giant protein titin, a fundamental sarcomere component. To explore the deleterious potential of these variants, we first solved the wild-type and mutant crystal structures of I21, the titin domain targeted by pathogenic variant p.C3575S. Although both structures are remarkably similar, the reduced hydrophobicity of deeply buried position 3575 strongly destabilizes the mutant domain, a scenario supported by molecular dynamics simulations and by biochemical assays that show no disulfide involving C3575. Prompted by these observations, we have found that thousands of similar hydrophobicity-reducing variants associate specifically with DCM. Hence, our results imply that titin domain destabilization causes DCM, a conceptual framework that not only informs pathogenicity assessment of gene variants but also points to therapeutic strategies counterbalancing protein destabilization.

Case Report: Mutation in TNNI3(c. 544G&gt;A): a novel likely pathogenic mechanism of neonatal dilated cardiomyopathy

BackgroundDilated cardiomyopathy (DCM) is a rare disease that causes heart failure due to malfunction of the heart muscle characterized by left ventricular dilation and poor systolic function. Genetic screening leads to advantages in early diagnosis and prognostic assessment of patients with suspected inherited cardiomyopathies. Here, we report a case of neonatal dilated cardiomyopathy due to a mutation of the TNNI3 gene, which has not been published in neonatal dilated cardiomyopathy before.Case presentationThe patient was a 22-day-old newborn boy with poor ability to respond to stimuli, presenting with shortness of breath over 11 days. He presented with irregular fever, tachypnea, difficulty in ventilator withdrawal, and mild edema of both lower limbs, and III/6SM could be heard in the precardiac area. He presented repeated weaning difficulties during hospitalization with intractable low EF heart insufficiency. Doppler echocardiography showed refractory low ejection fraction, cardiac enlargement, cardiac insufficiency, mild pulmonary hypertension, and mitral and tricuspid insufficiency with mild valve regurgitation. Whole-exome sequencing showed a mutation in the TNNI3 gene, c. 544G&amp;gt;A (p.Glu182Lys). Thus, he was diagnosed with neonatal DCM. There was no mutation in the parents, the child died 2 weeks after discharge.ConclusionsTNNI3 mutation is a novel likely pathogenic mechanism of neonatal dilated cardiomyopathy. Therefore, systematic use of diagnostic tools, advanced risk models, and a deeper understanding of the mechanism are required to reduce morbidity and mortality in this disease.

Challenges and Applications of Genetic Testing in Dilated Cardiomyopathy: Genotype, Phenotype and Clinical Implications.

Genetic tests for dilated cardiomyopathy (DCM) have a diagnostic yield of up to 40%, but there is significant genetic heterogeneity and other challenges, such as variable expressivity and incomplete penetrance. Pedigree analysis is essential for distinguishing between sporadic and familial DCM cases by assessing family history. Familial DCM yields higher results in genetic testing, but sporadic DCM does not rule out the possibility of a genetic cause. Some genes have specific phenotypes, with the Lamin gene ( LMNA ) being associated with a phenotype of malignant arrhythmias and advanced heart failure (HF). The presence of a causal genetic variant can also aid in prognostic evaluation, identifying more severe cases with lower rates of reverse remodeling (RR) compared to individuals with a negative genotype. Current guidelines recommend genetic evaluation and counseling for individuals with DCM, along with cascade screening in first-degree relatives in cases where one or more variants are identified, offering an opportunity for early diagnosis and treatment. Relatives with a positive genotype and negative phenotype are candidates for serial evaluation, with frequency varying by age. Genotype also assists in individualized recommendations for implantable cardioverter-defibrillator (ICD) placement and advice regarding physical activity and family planning. Ongoing studies are progressively elucidating the details of genotype/phenotype relationships for a large number of variants, making molecular genetics increasingly integrated into clinical practice.

Abstract 18805: Large-Scale Genome-Wide Association Study of Dilated Cardiomyopathy Identifies Genes and Pathways Contributing to Pathology

Introduction: Dilated cardiomyopathy (DCM) is a primary heart muscle disease that has long been considered a Mendelian disorder, but recent evidence highlights the important role of common genetic variation. Better characterization of the genetic architecture will provide opportunities for improved diagnosis and risk stratification. Methods: We performed a GWAS meta-analysis of 14,256 DCM cases and 1,185,671 controls of European ancestry from 16 studies. To improve discovery power, we performed multi-trait analysis of GWAS (MTAG) with three genetically correlated cardiac imaging traits in 36,203 individuals. We performed gene-level burden analysis &lt;0.1% for rare predicted truncating variants (PTV) with minor allele frequency &lt;0.1% in prioritized genes against DCM and quantitative CMR traits in UK Biobank (UKB) and 100,000 Genomes Project (GeL). A polygenic score (PGS) generated using a Bayesian framework was assessed for association with the same outcomes in UKB participants. Results: We identified 80 independent genomic loci associated with DCM at a false discovery rate &lt;1% in GWAS or at P &lt; 5 x 10 -8 in MTAG, of which 65 were novel ( Figure ). We prioritized a single high-confidence gene at 61 loci, including established genes for Mendelian cardiomyopathies ( TTN , BAG3 , FLNC , MYBPC3 , FHOD3 , ALPK3 ). Rare variant analysis highlighted novel associations with DCM and quantitative traits for PTVs in NEDD4L and MAP3K7 in UKB that were replicated in GeL. PGS was associated with DCM, with a 4-fold increased risk for those at the top centile compared to the median distribution. Penetrance of rare variants were higher for those in the top quintile of PGS compared to bottom quintile (7.3% vs. 1.7%, P &lt;0.005). Conclusion: We have performed the largest DCM GWAS, resulting in 80 significant loci (65 novel). We identify novel DCM-causing genes and generate a PGS that associates with DCM and modulates penetrance in carriers of Mendelian disease-causing rare variants.

Abstract 19052: Interferon B1A-Induced Dilated Cardiomyopathy

Introduction: Congestive heart failure is a leading causes of morbidity and mortality. Interferon therapy is a rare cause of dilated cardiomyopathy (DCM) and Heart Failure with Reduced Ejection Fraction (HFrEF). Specifically, interferon Alpha has been associated with cardiotoxicity. Here we describe a case of interferon B1A - induced HFrEF and DCM in a patient who took subcutaneous Interferon B1A for 11 years before developing clinical signs of heart failure. To our knowledge, only four other cases have been reported. Case Description: A 70-year-old man with a history of multiple sclerosis managed with Interferon B1A presented with shortness of breath, orthopnea, and lower extremity edema for 10 days. Physical examination revealed jugular venous distension and pitting edema. Brain natriuretic peptide (BNP) was 1580 pg/mL, troponin was 49 ng/L. Lipid panel, complete blood count, complete metabolic panel, Hemoglobin A1c, and thyroid stimulating hormone were within normal limits. Urine drug screen was negative. Chest X-ray revealed pulmonary vascular congestion and small pleural effusions bilaterally. A Transthoracic echocardiogram revealed mild aortic root dilatation (4.1cm), significant four-chamber dilatation, severely reduced left ventricular (LV) systolic function with an estimated ejection fraction of 20%, diastolic LV dysfunction, and moderately reduced systolic RV function, consistent with HFrEF and DCM (LVIDD 6.1cm). Coronary angiography showed normal coronary anatomy. The patient was started on guideline-directed medical therapy for HFrEF. Close follow-up was arranged to track improvement in systolic function after cessation of interferon b1a and consideration for Cardiac MRI and possible RV biopsy to evaluate for other causes of cardiomyopathy. Discussion/Conclusions: Due to the patient’s negative ischemic workup and absence of risk factors for cardiovascular disease, we strongly suspect that the patient’s cardiomyopathy was due to interferon B1A. With only 4 other cases of interferon B1A-induced DCM reported, it is a rare cause of medication-induced DCM. Interferon B1A should be considered a potential risk factor for developing heart failure, especially in high-risk patients.

Abstract 14249: Sex and Gene Based Differences in Age Related Penetrance of Dilated and Arrhythmogenic Cardiomyopathy

Background: Approximately 40% of cases of dilated (DCM) and arrhythmogenic cardiomyopathy (AC) are caused by rare genetic variants of large-effect. Sex-based differences in the penetrance of genetic DCM and AC have been described, however, findings have been inconsistent. Age at the time of diagnosis can be used as an indicator of age-related penetrance. In this study we aimed to describe differences in age at diagnosis in subgroups of patients with DCM and AC; the latter defined as ventricular arrhythmias preceding or superseding systolic LV dysfunction. Methods: Patients with DCM and AC were identified using data from 3 centers participating in the international SHaRe registry. Age at diagnosis and other baseline characteristics were compared across genetic subtypes; including patients with pathogenic and likely pathogenic (LP/P) variants (G+), variants of unknown significance (VUS), without identifiable genetic cause (G-) and subgroups with LP/P variants in 3 genes most frequent in this cohort ( TTN , LMNA , and DSP ). Results: Of 3662 patients with DCM and AC, 1341 were females (37%) and 3551 probands (97%). There were no significant differences in LVEF (38±14 vs. 41±14, p=0.07) or NYHA III-IV symptoms (14% vs. 11%, p=0.2). Genetic testing was performed more frequently in females (27% vs. 22%; p&lt;0.01) but the frequency of LP/P variants did not differ significantly by sex (female 49% vs. male 38%, p=0.07). In the entire cohort, the age of diagnosis did not vary between females and males; however, females with LP/P variants in TTN were 9 years older (p&lt;0.01) whereas females with LP/P variants in DSP were 10 years younger (p=0.037) at diagnosis than males (figure). Conclusion: Sex-based differences in age related penetrance of DCM and AC may differ across disease genes. Increased vigilance is warranted for early presentation of AC. Future research should examine the factors that underlie this heterogeneity and determine associated differences in clinical outcomes.

Abstract 16649: Clonal Hematopoiesis as a Predictor of Left Ventricular Reverse Remodeling in Non-Ischemic Dilated Cardiomyopathy

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is an independent risk factor of major adverse cardiovascular events, including heart failure (HF) with reduced left ventricular ejection fraction (LVEF). Although genetic mutations are known to affect clinical prognosis and left ventricular reverse remodeling (LVRR) in non-ischemic dilated cardiomyopathy (DCM), the prevalence and clinical significance of CHIP in DCM remain elusive. Objectives: The principal aim of this study is to delineate the distribution and prognostic impact of CHIP in non-ischemic DCM. Methods: We included 198 cases of DCM with LVEF ≤ 40% and no identifiable cause for left ventricular systolic dysfunction from the Japanese multi-center cohort. Whole exome sequencing was performed for germline analysis, and deep target sequencing focusing on CHIP driver genes for somatic analysis was conducted. We detected cardiomyopathy-related pathogenic mutations and CHIP driver mutations using GATK best practices and Mutect2, respectively. The primary endpoint was LVRR, defined as an absolute increase in LVEF by ≥ 10% at a one-year follow-up echocardiogram. Results: Twenty-seven CHIP driver mutations were detected in 24 (12%) of the DCM patients. The mean read coverage for CHIP driver mutation was 2156. DNMT3A was the most frequent mutated gene in CHIP, followed by TET2 . Ninety-two (46%) patients have cardiomyopathy-related pathogenic mutations. TTN was the most frequent mutated gene, followed by LMNA . Although the CHIP-positive group showed similar LVEF and prevalence of cardiomyopathy-related pathogenic mutations compared with the CHIP-negative group, the occurrence of LVRR was significantly lower in the CHIP-positive group (47.0% vs. 20.8%, P=0.018). Multivariate logistic regression analysis revealed that CHIP (odds ratio (OR): 0.23, P=0.022) and cardiomyopathy-related pathogenic mutations (OR: 0.28, P&lt;0.001) were independent negative predictors of LVRR. Conclusions: Determining germline and somatic mutations in DCM significantly predict clinical prognosis.

Genetics of Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is defined as dilation and/or reduced function of one or both ventricles and remains a common disease worldwide. An estimated 40% of cases of familial DCM have an identifiable genetic cause. Accordingly, there is a fast-growing interest in the field of molecular genetics as it pertains to DCM. Many gene mutations have been identified that contribute to phenotypically significant cardiomyopathy. DCM genes can affect a variety of cardiomyocyte functions, and particular genes whose function affects the cell-cell junction and cytoskeleton are associated with increased risk of arrhythmias and sudden cardiac death. Through advancements in next-generation sequencing and cardiac imaging, identification of genetic DCM has improved over the past couple decades, and precision medicine is now at the forefront of treatment for these patients and their families. In addition to standard treatment of heart failure and prevention of arrhythmias and sudden cardiac death, patients with genetic cardiomyopathy stand to benefit from gene mechanism-specific therapies.

Genetic Contribution to End-Stage Cardiomyopathy Requiring Heart Transplantation.

Many cardiovascular disorders propel the development of advanced heart failure that necessitates cardiac transplantation. When treatable causes are excluded, studies to define causes are often abandoned, resulting in a diagnosis of end-stage idiopathic cardiomyopathy. We studied whether DNA sequence analyses could identify unrecognized causes of end-stage nonischemic cardiomyopathy requiring heart transplantation and whether the prevalence of genetic causes differed from ambulatory cardiomyopathy cases. We performed whole exome and genome sequencing of 122 explanted hearts from 101 adult and 21 pediatric patients with idiopathic cardiomyopathy from a single center. Data were analyzed for pathogenic/likely pathogenic variants in nuclear and mitochondrial genomes and assessed for nonhuman microbial sequences. The frequency of damaging genetic variants was compared among cardiomyopathy cohorts with different clinical severity. Fifty-four samples (44.3%) had pathogenic/likely pathogenic cardiomyopathy gene variants. The frequency of pathogenic variants was similar in pediatric (42.9%) and adult (43.6%) samples, but the distribution of mutated genes differed (P=8.30×10-4). The prevalence of causal genetic variants was significantly higher in end-stage than in previously reported ambulatory adult dilated cardiomyopathy cases (P<0.001). Among remaining samples with unexplained causes, no damaging mitochondrial variants were identified, but 28 samples contained parvovirus genome sequences, including 2 samples with 6- to 9-fold higher levels than the overall mean levels in other samples. Pathogenic variants and viral myocarditis were identified in 45.9% of patients with unexplained end-stage cardiomyopathy. Damaging gene variants are significantly more frequent among transplant compared with patients with ambulatory cardiomyopathy. Genetic analyses can help define cause of end-stage cardiomyopathy to guide management and risk stratification of patients and family members.

Unveiling a Rare Complication: Gemcitabine-Induced Cardiomyopathy in Ovarian Serous Adenocarcinoma

Gemcitabine is a nucleoside analogue and pyrimidine antimetabolite authorized for the treatment of ovarian cancer. It is generally considered safe and well-tolerated, with only a few reported cases of cardiac adverse effects. However, we present a case of gemcitabine-induced dilated cardiomyopathy in a 33-year-old female receiving gemcitabine as second-line therapy for ovarian serous adenocarcinoma. The patient had no history of hypertension or significant cardiac issues. She presented with clinical symptoms, laboratory abnormalities, and imaging findings consistent with congestive cardiac failure, along with a Left Ventricular Ejection Fraction (LVEF) of 25-30%. Gemcitabine administration was immediately discontinued, and treatment with Furosemide, ACE inhibitors, and Beta-blocker agents was initiated. Subsequently, the patient’s condition improved, with the resolution of symptoms and normalization of cardiac findings upon discontinuation of gemcitabine. This is the first reported case demonstrating objective evidence of gemcitabine-induced dilated cardiomyopathy in a patient with ovarian serous adenocarcinoma without a significant cardiac history. Although rare, it is crucial to promptly diagnose gemcitabine-induced cardiomyopathy to initiate appropriate management protocols.

Risks of Ventricular Arrhythmia and Heart Failure in Carriers of RBM20 Variants.

Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P<0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF.

A Rare Presentation of Dilated Cardiomyopathy Along with Takayasu Arteritis in a Preschool Child

Dilated cardiomyopathy is the most common form of cardiomyopathy in children, is the cause of significant morbidity and mortality. Although the most common etiology of DCM remains idiopathic, it is estimated that upto 50% of cases are genetic. The pathogenesis of ventricular dilation and altered contractility seen in DCM varies depending on the underlying etiology; systolic dysfunction and myocyte injury are common. Takayasu arteritis also known as “pulseless disease”, is a chronic large vessel vasculitis of unknown etiology and predominantly involves the aorta and its major branches. This disease is most common in Asians and mostly diagnosed in adolescent age group, on average at the age of 13 years. TA is characterized by inflammation of the vessel wall starting from vasa vasorum. Persistent inflammation leads to progressive scarring and intimal proliferation and can result in stenotic or occluded vessels leading to systemic manifestations. We have reported a rare case of dilated cardiomyopathy along with Takayasu arteritis in a preschool child. The causality and association between both the conditions has not been fully understood yet. However DCM has been reported in only 5-6% cases of TA.

Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants

Predictors of myocardial recovery in heart failure (HF) are poorly understood. We explored if vinculin (VCL) variants are associated with myocardial recovery in dilated cardiomyopathy (DCM). Six infants with DCM with a VCL loss-of-function (LOF) variant were identified. Median age at diagnosis was 2 months, median LV ejection fraction was 24%, and median LV end-diastolic diameter z-score was 10.8. All patients received HF medications. Five patients (83%) showed normalization of LV function at a median age of 2.7 years. One patient progressed to end-stage HF requiring heart transplant. This case series identified a unique phenotype of HF with reduced ejection fraction at presentation that evolved to HF with recovered EF in over 80% of infant DCM cases with LOF VCL variants. These findings have prognostic implications for counseling and management of VCL-associated DCM and highlight a possible genetic basis for HF with recovered ejection fraction.Graphical abstract

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy.

A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear. We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed Jmjd4 in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy. We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of Jmjd4 led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with Jmjd4 deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by Jmjd4 deficiency, and heart failure induced by pressure overload, as well. Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well.

Whole-Exome Sequencing Identifies Homozygote Nonsense Variants in LMOD2 Gene Causing Infantile Dilated Cardiomyopathy.

As an essential component of the sarcomere, actin thin filament stems from the Z-disk extend toward the middle of the sarcomere and overlaps with myosin thick filaments. Elongation of the cardiac thin filament is essential for normal sarcomere maturation and heart function. This process is regulated by the actin-binding proteins Leiomodins (LMODs), among which LMOD2 has recently been identified as a key regulator of thin filament elongation to reach a mature length. Few reports have implicated homozygous loss of function variants of LMOD2 in neonatal dilated cardiomyopathy (DCM) associated with thin filament shortening. We present the fifth case of DCM due to biallelic variants in the LMOD2 gene and the second case with the c.1193G>A (p.W398*) nonsense variant identified by whole-exome sequencing. The proband is a 4-month male infant of Hispanic descent with advanced heart failure. Consistent with previous reports, a myocardial biopsy exhibited remarkably short thin filaments. However, compared to other cases of identical or similar biallelic variants, the patient presented here has an unusually late onset of cardiomyopathy during infancy. Herein, we present the phenotypic and histological features of this variant, confirm the pathogenic impact on protein expression and sarcomere structure, and discuss the current knowledge of LMOD2-related cardiomyopathy.

A Young Patient Presenting with Dilated Cardiomyopathy and Renal Infarction during Treatment with Isotretinoin: Mere Coincidence or Serious Side Effect of a Drug Commonly Used in Adolescence?

Isotretinoin or 13-cis-retinoic acid (RA) is one of the most effective and widely used drugs for the treatment of severe acne vulgaris. Despite being deemed safe, no definite consensus has been reached on the cardiovascular risk of RA derivatives. We report a case of heart failure due to dilated cardiomyopathy (DCM) and concomitant renal infarction occurring after 5 months of isotretinoin use in a previously healthy 18-year-old male. The patient, with a history of acne vulgaris, presented to our emergency department with left iliac fossa pain and effort dyspnea. A trans-thoracic echocardiogram showed DCM and severely reduced left ventricle ejection fraction (LVEF: 29%). During hospitalization, a total body computed tomography (CT) showed an ischemic lesion in the left kidney. Ischemic, autoimmune, infective, and heritable causes of DCM were ruled out. Cardiac magnetic resonance (CMR) evidenced LV circumferential mid-wall late gadolinium enhancement. Heart failure therapy was promptly started and up-titrated, but only poor LVEF improvement was detected overtime. Our case aims to raise awareness on rare life-threatening cardiovascular events possibly associated with isotretinoin use. To the best of our knowledge, this is the first described case of renal thromboembolism and severe DCM leading to implantable cardioverter-defibrillator (ICD) implantation occurring during isotretinoin treatment.

Long-term outcome of EVAHEART I implantable ventricular assist device for the treatment of end stage heart failure: clinical 3-year follow-up results of 15 cases

Objective: To evaluate the long-term efficacy and safety of the implantable ventricular assist system EVAHEART I in clinical use. Methods: Fifteen consecutive patients with end-stage heart failure who received left ventricular assist device therapy in Fuwai Hospital from January 2018 to December 2021 were enrolled in this study, their clinical data were retrospectively analyzed. Cardiac function, liver and kidney function, New York Heart Association (NYHA) classification, 6-minute walk distance and quality of life were evaluated before implantation and at 1, 6, 12, 24 and 36 months after device implantation. Drive cable infection, hemolysis, cerebrovascular events, mechanical failure, abnormally high-power consumption and abnormal pump flow were recorded during follow up. Results: All 15 patients were male, mean average age was (43.0±7.5) years, including 11 cases of dilated cardiomyopathy, 2 cases of ischemic cardiomyopathy, and 2 cases of valvular heart disease. All patients were hemodynamically stable on more than one intravenous vasoactive drugs, and 3 patients were supported by preoperative intra aortic balloon pump (IABP). Compared with before device implantation, left ventricular end-diastolic dimension (LVEDD) was significantly decreased ((80.93±6.69) mm vs. (63.73±6.31) mm, P<0.05), brain natriuretic peptide (BNP), total bilirubin and creatinine were also significantly decreased ((3 544.85±1 723.77) ng/L vs. (770.80±406.39) ng/L; (21.28±10.51) μmol/L vs. (17.39±7.68) μmol/L; (95.82±34.88) μmol/L vs. (77.32±43.81) μmol/L; P<0.05) at 1 week after device implantation. All patients in this group were in NYHA class Ⅳ before implantation, and 9 patients could recover to NYHA class Ⅲ, 3 to class Ⅱ, and 3 to class Ⅰ at 1 month after operation. All patients recovered to class Ⅰ-Ⅱ at 6 months after operation. The 6-minute walk distance, total quality of life and visual analogue scale were significantly increased and improved at 1 month after implantation compared with those before operation (P<0.05). All patients were implanted with EVAHEART I at speeds between 1 700-1 950 rpm, flow rates between 3.2-4.5 L/min, power consumption of 3-9 W. The 1-year, 2-year, and 3-year survival rates were 100%, 87%, and 80%, respectively. Three patients died of multiple organ failure at 412, 610, and 872 d after surgery, respectively. During long-term device carrying, 3 patients developed drive cable infection on 170, 220, and 475 d after surgery, respectively, and were cured by dressing change. One patient underwent heart transplantation at 155 d after surgery due to bacteremia. Three patients developed transient ischemic attack and 1 patient developed hemorrhagic stroke events, all cured without sequelae. Conclusion: EVAHEART I implantable left heart assist system can effectively treat critically ill patients with end-stage heart failure, can be carried for long-term life and significantly improve the survival rate, with clear clinical efficacy.