Dilated Cardiomyopathy Phenotype Research Articles

Embarazo en mujeres portadoras de variantes genéticas de miocardiopatía dilatada

Introduction and objectives: Limited information is available on the safety of pregnancy in patients with genetic dilated cardiomyopathy (DCM) and in carriers of DCM-causing genetic variants without the DCM phenotype. We assessed cardiac, obstetric, and fetal or neonatal outcomes in this group of patients.Methods: We studied 48 women carrying pathogenic or likely pathogenic DCM-associated variants (30 with DCM and 18 without DCM) who had 83 pregnancies. Adverse cardiac events were defined as heart failure (HF), sustained ventricular tachycardia, ventricular assist device implantation, heart transplant, and/or maternal cardiac death during pregnancy, or labor and delivery, and up to the sixth postpartum month.Results: A total of 15 patients, all with DCM (31% of the total cohort and 50% of women with DCM) experienced adverse cardiac events. Obstetric and fetal or neonatal complications were observed in 14% of pregnancies (10 in DCM patients and 2 in genetic carriers). We analyzed the 30 women who had been evaluated before their first pregnancy (12 with overt DCM and 18 without the phenotype). Five of the 12 (42%) women with DCM had adverse cardiac events despite showing NYHA class I or II before pregnancy. Most of these women had a history of cardiac events before pregnancy (80%). Among the 18 women without phenotype, 3 (17%) developed DCM toward the end of pregnancy.Conclusions: Cardiac complications during pregnancy and postpartum were common in patients with genetic DCM and were primarily related to HF. Despite apparently good tolerance of pregnancy in unaffected genetic carriers, pregnancy may act as a trigger for DCM onset in a subset of these women.

Pregnancy in women with dilated cardiomyopathy genetic variants

Introduction and objectives: Limited information is available on the safety of pregnancy in patients with genetic dilated cardiomyopathy (DCM) and in carriers of DCM-causing genetic variants without the DCM phenotype. We assessed cardiac, obstetric, and fetal or neonatal outcomes in this group of patients.Methods: We studied 48 women carrying pathogenic or likely pathogenic DCM-associated variants (30 with DCM and 18 without DCM) who had 83 pregnancies. Adverse cardiac events were defined as heart failure (HF), sustained ventricular tachycardia, ventricular assist device implantation, heart transplant, and/or maternal cardiac death during pregnancy, or labor and delivery, and up to the sixth postpartum month.Results: A total of 15 patients, all with DCM (31% of the total cohort and 50% of women with DCM) experienced adverse cardiac events. Obstetric and fetal or neonatal complications were observed in 14% of pregnancies (10 in DCM patients and 2 in genetic carriers). We analyzed the 30 women who had been evaluated before their first pregnancy (12 with overt DCM and 18 without the phenotype). Five of the 12 (42%) women with DCM had adverse cardiac events despite showing NYHA class I or II before pregnancy. Most of these women had a history of cardiac events before pregnancy (80%). Among the 18 women without phenotype, 3 (17%) developed DCM toward the end of pregnancy.Conclusions: Cardiac complications during pregnancy and postpartum were common in patients with genetic DCM and were primarily related to HF. Despite apparently good tolerance of pregnancy in unaffected genetic carriers, pregnancy may act as a trigger for DCM onset in a subset of these women.

Myocardial injury in dogs: a retrospective analysis on etiological, echocardiographic, electrocardiographic, therapeutic, and outcome findings in 102 cases

IntroductionIn dogs, myocardial injury (MI) is a poorly characterized clinical entity; therefore, this study aimed to provide a detailed description of dogs affected by this condition. Animals, materials, and methodsDogs diagnosed with MI according to the concentration of cardiac troponin I (cTnI) were retrospectively searched. Signalment, diagnostic, therapeutic, and outcome data were retrieved. Dogs were divided into six echocardiographic (dilated cardiomyopathy phenotype; hypertrophic cardiomyopathy phenotype; hypertrophic cardiomyopathy phenotype with systolic dysfunction; abnormal echogenicity only; endocarditis; and no echocardiographic abnormalities suggestive of MI), four electrocardiographic (abnormalities of impulse formation; abnormalities of impulse conduction; abnormalities of ventricular repolarization; and no electrocardiographic abnormalities suggestive of MI), and nine etiological (infective; inflammatory; neoplastic; metabolic; toxic; nutritional; immune-mediated; traumatic/mechanical; and unknown) categories. Statistical analysis was performed to compare cTnI values among different categories and analyze survival. ResultsOne hundred two dogs were included. The median cTnI value was 3.71 ng/mL (0.2–180 ng/mL). Echocardiographic and electrocardiographic abnormalities were documented in 86 of 102 and 89 of 102 dogs, respectively. Among echocardiographic and electrocardiographic categories, the dilated cardiomyopathy phenotype (n = 52) and abnormalities of impulse formation (n = 67) were overrepresented, respectively. Among dogs in which a suspected etiological trigger was identified (68/102), the infective category was overrepresented (n = 20). Among dogs belonging to different echocardiographic, electrocardiographic, and etiological categories, cTnI did not differ significantly. The median survival time was 603 days; only eight of 102 dogs died due to MI. ConclusionsDogs with MI often have an identifiable suspected trigger, show various echocardiographic and electrocardiographic abnormalities, and frequently survive to MI-related complications.

Gene-expression profiling of endomyocardial biopsies from dogs with dilated cardiomyopathy phenotype

IntroductionThe employment of advanced molecular biology technologies has expanded the diagnostic investigation of cardiomyopathies in dogs; these technologies have predominantly been performed on postmortem samples, although the recent use of endomyocardial biopsy in living dogs has enabled a better premortem diagnostic approach to study the myocardial injury. Animals, materials, and methodsEndomyocardial biopsies were collected in nine dogs with a dilated cardiomyopathy phenotype (DCM-p) and congestive heart failure and submitted to histologic examination, next-generation sequencing (NGS), and polymerase chain reaction analysis. Data from three healthy dogs (Fastq files) were retrieved from a previously approved study and used as a control group for ribonucleic acid sequencing. ResultsHistologic examination revealed endocardial fibrosis in 6 of 9 dogs, whereas lymphocytic interstitial infiltrates were detected in two of nine dogs, and lymphoplasmacytic and macrophage infiltrates were detected in one of nine dogs. On polymerase chain reaction analysis, two dogs tested positive for canine parvovirus two and one dog for canine distemper virus. Gene-expression pathways involved in cellular energy metabolism (especially carbohydrates-insulin) and cardiac structural proteins were different in all DCM-p dogs compared to those in the control group. When dogs with lymphocytic interstitial infiltrates were compared to those in the control group, NGS analysis revealed the predominant role of genes related to inflammation and pathogen infection. ConclusionsNext-generation sequencing technology performed on in vivo endomyocardial biopsies has identified different molecular and genetic factors that could play a role in the development and/or progression of DCM-p in dogs.

Kiosk 8R-FC-01 - Clinical Implication of Dilated Cardiomyopathy Phenotypes Identified by Cluster Analysis

Kiosk 8R-FC-01 - Clinical Implication of Dilated Cardiomyopathy Phenotypes Identified by Cluster Analysis

Myocarditis and Chronic Inflammatory Cardiomyopathy, from Acute Inflammation to Chronic Inflammatory Damage: An Update on Pathophysiology and Diagnosis.

Acute myocarditis covers a wide spectrum of clinical presentations, from uncomplicated myocarditis to severe forms complicated by hemodynamic instability and ventricular arrhythmias; however, all these forms are characterized by acute myocardial inflammation. The term "chronic inflammatory cardiomyopathy" describes a persistent/chronic inflammatory condition with a clinical phenotype of dilated and/or hypokinetic cardiomyopathy associated with symptoms of heart failure and increased risk for arrhythmias. A continuum can be identified between these two conditions. The importance of early diagnosis has grown markedly in the contemporary era with various diagnostic tools available. While cardiac magnetic resonance (CMR) is valid for diagnosis and follow-up, endomyocardial biopsy (EMB) should be considered as a first-line diagnostic modality in all unexplained acute cardiomyopathies complicated by hemodynamic instability and ventricular arrhythmias, considering the local expertise. Genetic counseling should be recommended in those cases where a genotype-phenotype association is suspected, as this has significant implications for patients' and their family members' prognoses. Recognition of the pathophysiological pathway and clinical "red flags" and an early diagnosis may help us understand mechanisms of progression, tailor long-term preventive and therapeutic strategies for this complex disease, and ultimately improve clinical outcomes.

Phenotype and genotype characteristics of children with cardiomyopathy associated with MYH7 gene mutation: a retrospective analysis

To investigate the clinical phenotype and genotype characteristics of children withcardiomyopathy (CM) associated with MYH7 gene mutation. A retrospective analysis was conducted on the medical data of five children with CM caused by MYH7 gene mutation who were diagnosed and treated in the Department of Cardiology, Hebei Children's Hospital. Among the five children with CM, there were three girls and two boys, all of whom carried MYH7 gene mutation. Seven mutation sites were identified, among which five were not reported before. Among the five children, there were three children with hypertrophic cardiomyopathy, one child with dilated cardiomyopathy, and one child with noncompaction cardiomyopathy. The age ranged from 6 to 156 months at the initial diagnosis. At the initial diagnosis, two children had the manifestations of heart failure such as cough, shortness of breath, poor feeding, and cyanosis of lips, as well as delayed development; one child had palpitation, blackness, and syncope; one child had fever, runny nose, and abnormal liver function; all five children had a reduction in activity endurance. All five children received pharmacotherapy for improving cardiac function and survived after follow-up for 7-24 months. The age of onset varies in children with CM caused by MYH7 gene mutation, and most children lack specific clinical manifestations at the initial diagnosis and may have the phenotype of hypertrophic cardiomyopathy, dilated cardiomyopathy or noncompaction cardiomyopathy. The children receiving early genetic diagnosis and pharmacological intervention result in a favorable short-term prognosis.

Immunomodulation to target biopsy-proven myocardial inflammation in genetic cardiomyopathies: a pilot report

Abstract Background Preclinical data support the rationale for targeting myocardial inflammation (M-Infl) in genetic nonischemic cardiomyopathies. However, no consistent clinical reports have been provided so far. Purpose To provide a pilot report on multimodal detection and targeting of biopsy-proven M-Infl in genetic cardiomyopathies. Methods We describe a series of patients (n=25) with genetic cardiomyopathy and M-Infl proven by endomyocardial biopsy (EMB). Multimodal diagnostic workup was extensively applied. Patient-tailored immunomodulatory therapy (IMT) was empirically started to target M-Infl whenever feasible. Multiple outcomes were retrospectively assessed by a dedicated multidisciplinary disease unit. Results Patients carrying desmosomal (DGV), cytoskeletal (CGV) and other gene variants, were 12 (48%), 10 (40%), and 3 (12%), respectively. DGV carriers uniformly presented with myocarditis-like chest pain and ventricular arrhythmias, whereas heart failure symptoms were found only in CGV carriers. Dilated cardiomyopathy phenotype and ring-like pattern on cardiac magnetic resonance allowed the best discrimination among genotypes. Noninvasive imaging was concordant with EMB in detecting M-Infl in 21 patients (83%). IMT was started in 17 patients (71%) with no safety issues. By the end of follow-up (median 69 months, range 21-182), signs of M-Infl were documented in 6/18 IMT receivers (33%) and 4/7 untreated cases (57%). For most genotypes, paucity of adverse events was noted while on IMT as compared to the off-treatment period. Conclusion Our preliminary data provide a clinical rationale for the research and targeting of M-Infl in a spectrum of genetic nonischemic cardiomyopathies.

Genotype influences end-stage heart failure occurrence in dilated cardiomyopathy

Abstract Introduction A monogenic cause of a dilated cardiomyopathy (DCM) phenotype is found in upto 37% of patients [1]. Purpose Evaluate the influence of genotype on end-stage heart failure (ESHF) outcomes in DCM. Methods Consecutive patients carrying variants from the 3 most prevalent DCM genotypes in a database from a cardiomyopathy unit (TTN, DSP and LMNA) and with features of DCM at baseline were retrospectively recruited. Consecutive DCM patients returning a negative result from a next generation DCM panel were recruited for comparison. ESHF was defined as left ventricular assist device implantation, heart transplantation or heart-failure related death. The incidence of ESHF was compared between genotypes during follow-up. Results 493 patients from 445 families (311 (63.1%) males, presenting at a median [IQR] age of 50.8 years [37.3 – 59.8]) with a median follow-up of 46.5 [28.1 – 88.2] months were recruited (Table 1). 26/493 (5.3%) of patients had ESHF by last evaluation. The highest incidence of ESHF was seen in LMNA variant-carriers and the lowest in genotype-negative patients (Figure 1). In a multivariable Cox model including age at presentation, sex and proband status, LMNA variant-carriage was associated with an increased risk of ESHF (HR 9.7 [4.6 – 20.6], p < 0.001) and genotype-negative status was associated with a reduced risk of ESHF (HR 0.08 [0.02 – 0.41], p = 0.002) Conclusions Genotype impacts the incidence of ESHF in patients with DCM. Close monitoring with early initiation of heart failure therapies is essential to mitigate this risk, particularly in LMNA variant-carriers.Table 1Figure 1

Abstract 14975: SIRT1 Ameliorates Cardiac Dysfunction Caused by Lamin A/C Deficiency via Mitochondrial Bioenergetics Improvement

Background: The LMNA gene encodes lamin A/C and is the second most frequently mutated gene associated with dilated cardiomyopathy (DCM) but lacks effective therapeutic options. Recent transcriptomic studies have shown that mutation of LMNA leads to abnormal expression of genes related to mitochondrial function, however, the mechanisms have not been investigated further. Hypothesis: LMNA protects against cardiac dysfunction via mitochondrial bioenergetics maintenance. Aims To decipher the mechanism by which LMNA mediates mitochondrial bioenergetics and DCM phenotype. Methods: Proteomics was performed to decipher the pathogenesis of DCM in Lmna -/- mice. Neonatal rat ventricular myocytes (NRVMs) were used to dissect molecular mechanisms. Adenovirus and adeno-associated virus (AAV) were constructed to overexpress SIRT1 in vitro and in vivo , respectively. Results: Lmna -/- mice at 1 month of age showed obvious cardiac dysfunction, while 2-week-old Lmna -/- mice showed no obvious cardiac phenotype. Proteomics revealed downregulated mitochondrial function-related pathways in Lmna -/- hearts. Early injured mitochondria with decreased cristae density were detected and the only reduced mitochondrial biogenesis regulator SIRT1 was found in 2 week-old Lmna -/- hearts. Overexpression of SIRT1 in lamin A/C knockdown NRVMs effectively improved mitochondrial oxidative respiration capacity. AAV-SIRT1 injection significantly alleviated mitochondrial injury, DCM phenotype of Lmna -/- mice, and prolonged lifespan (Figure 1). Mechanistically, LMNA maintains mitochondrial bioenergetics through SIRT1-PARKIN axis. Conclusions: Lamin A/C deficiency leads to mitochondrial damage in cardiomyocytes and promotes the development of DCM through SIRT1 downregulation. Targeting SIRT1 ameliorates mitochondrial injury and DCM phenotype in Lmna -/- mice, which may provide a novel therapeutic strategy for LMNA mutation-associated DCM.

Abstract 11661: Genotypic and Phenotypic Guided Antiarrhythmic Drug Management of Multifocal Premature Ventricular Contractions

Introduction: Antiarrhythmic selection for progressive and intractable PVCs unresponsive to first and second line regimens can prove challenging. Genetic analysis assists by targeting specific genes, such as the SCN5a gene, which encodes for the alpha subunit of cardiac sodium channel NaV1.5. Mutations are associated with autosomal dominant phenotypes of multifocal ectopic Purkinje-related premature Contractions (MEPPCs). Case: A 38 year old female with a history of syncope and moderate left ventricular systolic dysfunction status post AICD and a family history of SCD presented for follow-up with complaints of frequent palpitations. ECG and a 72 hour Holter monitor had multifocal PVCs of purkinje origin with a burden of 31%. Despite a therapeutic trial with sotalol and amiodarone in various doses, she remained unresponsive with multifocal purkinje-related PVCs. TTE revealed global LV hypokinesia with worsening LVEF, and a cardiac MRI revealed features suggestive of a dilated cardiomyopathy (DCM) phenotype. Whole exome DNA analysis showed a heterozygous missense mutation pArg814Tryp on exon 16 of the SCN5A gene. Her specific variant, R814W, is a gain-of-function variant responsible for the hyperexcitability of the Purkinje fibers, making it amenable to sodium channel blockade with flecainide. After starting gene-directed flecainide, her PVC burden drastically reduced from 31% to 3% on repeat Holter monitor after 2 months. She has remained asymptomatic with an improved LVEF. Discussion: This is a unique case of SCN5A channelopathy with a MEPPC phenotype demonstrating a dramatic response to genotype guided management of multifocal PVCs. Clinicians should include such phenotypes in their differentials for patients that fail first and second line treatment regimens and have significant family history. It is essential to offer genetic testing to patients with a MEPPC phenotype in a DCM setting to choose the appropriate therapy and prevent SCD.

Prospective evaluation of echocardiographic parameters and cardiac biomarkers in healthy dogs eating four custom-formulated diets

IntroductionDiet-associated dilated cardiomyopathy (DCM) has been suspected in breeds that have not been previously noted to have a predisposition to the DCM phenotype. This study hypothesized that over 210 days, dogs fed diets with varying amounts of animal-sourced protein and carbohydrate sources would not be negatively impacted in terms of their cardiac parameters and function.MethodsThirty-two purebred beagles and 33 mixed-breed hounds were randomized into four diet groups and studied for 210 days. The diet groups were as follows: the high-animal-protein grain-free (HAGF) group, the low-animal-protein grain-free (LAGF) group, the high-animal-protein grain-inclusive (HAGI), and the low-animal-protein grain-inclusive (LAGI) group. Cardiac-specific biomarkers, endomyocardial biopsies, and linear and volumetric echocardiographic parameters were evaluated.ResultsThere was a treatment-by-day-by-breed effect observed for the normalized left ventricular internal diameter at end-diastole (p = 0.0387) and for the normalized left ventricular internal diameter at end-systole (p = 0.0178). On day 210, mixed-breed hounds fed the LAGI diet had a smaller normalized left ventricular internal diameter at end-diastole than on day 90. On day 210, beagles fed the LAGF diet had a larger normalized left ventricular internal diameter at end-systole than those fed the LAGI diet. Fractional shortening for beagles in the LAGF group was significantly lower (p = 0.007) than for those in the HAGI and LAGI groups. Cardiac-specific biomarkers and endomyocardial biopsies were not significantly different between breeds, diets, and various time points.DiscussionThis study did not detect the development of cardiac dysfunction throughout the study period through the echocardiographic parameters measured, select cardiac biomarkers, or endomyocardial biopsies. There were noted interactions of treatment, breed, and time; therefore, isolating a diet association was not possible. Future research should further investigate the other factors that may help to identify the variable(s) and possible mechanisms underlying suspected diet-associated DCM in dogs.

Danicamtiv Increases Myosin Recruitment and Alters Cross-Bridge Cycling in Cardiac Muscle.

Modulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Danicamtiv is a novel myosin activator with promising preclinical data that is currently in clinical trials. While it is known that danicamtiv increases force and cardiomyocyte contractility without affecting calcium levels, detailed mechanistic studies regarding its mode of action are lacking. Permeabilized porcine cardiac tissue and myofibrils were used for X-ray diffraction and mechanical measurements. A mouse model of genetic dilated cardiomyopathy was used to evaluate the ability of danicamtiv to correct the contractile deficient. Danicamtiv increased force and calcium sensitivity via increasing the number of myosins in the on state and slowing cross-bridge turnover. Our detailed analysis showed that inhibition of ADP release results in decreased cross-bridge turnover with cross bridges staying attached longer and prolonging myofibril relaxation. Danicamtiv corrected decreased calcium sensitivity in demembranated tissue, abnormal twitch magnitude and kinetics in intact cardiac tissue, and reduced ejection fraction in the whole organ. As demonstrated by the detailed studies of Danicamtiv, increasing myosin recruitment and altering cross-bridge cycling are 2 mechanisms to increase force and calcium sensitivity in cardiac muscle. Myosin activators such as Danicamtiv can treat the causative hypocontractile phenotype in genetic dilated cardiomyopathy.

Abstract P3195: Mitochondrial CaMKII Drives Cardiometabolic Dysfunction In Heart Failure

Background: Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is an established negative regulator of cardiac injury. Both the expression and activity levels of CaMKII delta, the primary cardiac isoform of this kinase, are elevated in models of heart failure (HF) such as ischemia-reperfusion (I/R) injury and following myocardial infarction (MI). This upregulation is due in part to CaMKII’s role in the regulation of excitation-contraction coupling, apoptosis, activation of hypertrophic programming, arrhythmias and pro-inflammatory signaling. Recently, a pool of mitochondrial CaMKII (mtCaMKII) has been identified; we have demonstrated that there is an observed increase in mitochondrial CaMKII activation with left ventricular dilation acutely following injury in a mouse model of MI. This deleterious post-MI phenotype is rescued with genetic mitochondrial CaMKII inhibition; conversely, mice with myocardial mitochondrial CaMKII overexpression present with a severe dilated cardiomyopathy phenotype, alterations in electron transport chain (ETC) activity, and decreased ATP production. Objective: To date, the molecular mechanisms by which CaMKII regulates mitochondrial energetics are unknown and present a novel therapeutic target for HF which we are currently studying. Methods: As we have identified changes in the activity of enzymes, particularly complexes I and II, in the mitochondrial ETC as well as TCA cycle in response to increased CaMKII levels or activity, we are in the process of assessing changes in the mitochondrial CaMKII interactome between uninjured and failing hearts. Utilizing liquid chromatography-mass spectrometry (LCMS) and proteomics analysis of both scaffolding interactions alongside a novel ATP analogue labeling technique, we have mapped novel mitochondrial proteins which interact with mtCaMKII. Significance: The identification of previously unknown mitochondrial pathways involving CaMKII may uncover promising pharmacological targets for cardiovascular therapeutics, as this kinase is a critical player in the progression of HF.

Mitral annulus excursion depression as the expression of left ventricle strain parameters damage in patients with dilated cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: None. Background 4D echocardiography is a useful tool to identify both decreasing of mitral annular excursion (MAE) and left ventricle (LV) strain damage in patients with dilated cardiomyopathy (DCM). Our study aimed to identify a correlation between MAE decreasing and LV strain parameters in patients with DCM. Methods We enrolled 75 patients with DCM and 30 healthy volunteers. The evaluation consisted of clinical examination, laboratory tests, 12 leads electrocardiography. All participants underwent a complete transthoracic echocardiogram to determine cardiac structure and function according to the current guidelines. The study evaluated MAE by 4D Auto Mitral Valve Quantification (4D - MVQ). 4D LV Quantification (4D-LVQ) measured global longitudinal strain (GLS), global circumferential strain (GCS), global area strain (GAS), and global radial strain (GRS). Results 1. We divided the patients into two groups: 27 with DCM and atrial fibrillation (AF) and 48 with DCM and sinus rhythm (SR). 2. Mean values of MAE were 3.89 (SD=2.2, CV=0.56) in patients with DCM and 11.1 (SD 1.08, CV 0.09) in the healthy volunteers’ group. (P<0.0001). In patients with DCM and RS MAE mean value was 4.24 (SD=2.34, CV=0.54), and in the AF group was 2.98 (SD=1.38, CV=0.45) (p = 0.0125). 3. Mean values of strain in patients with DCM and RS compared with those in AF were: GLS −6,63 vs. −4,1 (P = 0.0005), GCS −6.08 vs. −5,2 (P = 0.1931), GAS −11.22 vs. −8.47 (P = 0.0181), GRS = 14.5 vs. 10.89 (P = 0.0493). 4. The correlations obtained between MAE and LV strain in patients with DCM were: GLS (r=-0.67), GAS (r=-0.61), GRS (r=0.5), and GCS (r=-0.39). Conclusions 1. MAE was significantly reduced in patients with DCM compared with healthy volunteers. 2. The patients with DCM and AF presented the lowest values of MAE and LV global strain parameters. 3. MAE correlated better with GLS and GAS, moderate with GRS, and weak with GAS in patients with dilated cardiomyopathy phenotype.

Left atrium function depression and left ventricle rotational parameters in patients with dilated cardiomyopathy and narrow QRS

Abstract Funding Acknowledgements Type of funding sources: None. Background In advanced stages of dilated cardiomyopathy (DCM), both atrial function and left ventricle (LV) myocardial mechanics are blunted. Left atrial reservoir strain (LASr) is a sensitive parameter for left atrial (LA) function evaluation. Our study aimed to find a correlation between LASr depression and rotational parameters damage in patients with DCM, using 4-Dimensional automated LA and LV quantification. Methods We enrolled 75 patients with DCM and narrow QRS and 30 healthy volunteers. The evaluation consisted of clinical examination, laboratory tests, 12 leads electrocardiography. All participants underwent a complete transthoracic echocardiogram to determine cardiac structure and function according to the current guidelines. Measurement of LA and LV strain was performed using 4D Auto-quantification software. The study evaluated LASr by 4D Auto Atrial Quantification. 4D LV Quantification measured twist and torsion. Results 1. We divided the patients into two groups: 27 with DCM and atrial fibrillation (AF) and 48 with DCM and sinus rhythm (SR). 2. Mean values of LASr were 10.20 in patients with DCM and 30.36 in the healthy volunteers’ group. (P<0.0001). Rotational parameters were LV twist=1.66, LV torsion=0.44 in DCM patients, LV twist=10.1, and LV torsion=1,73 in the healthy group. (P<0.0001). In DCM patients with AF, mean values were lower ( LASr =9.52, LV twist=0.97, LV torsion=0.28, LV torsion=0.4) than in patients with SR (LASr=10.59, LVtwist=1.93, LV torsion=0.5) 3. A correlation was found between LASr and LV twist (r=-0.8), between LASr and torsion (r=-0.78), in patients with AF, and also in those with DCM and SR ( r=-0.74 for the twist, r=-0.73 for torsion). Conclusions 1. LASr reduction was related to rotational damage of the left ventricle in DCM patients. 2. LASr, LV twist, and LV torsion were lower in cases with AF. 3. LA function is a parameter of chronic increased LV filling pressure. The correlation between LASr decrease and anomalies of twist and torsion may suggest a link between increased LV filling pressure and rotational dysfunction in patients with dilated cardiomyopathy phenotype.

Association of rs505080 Single Nucleotide Polymorphism in Lamin-A Gene with Familial Dilated Cardiomyopathy in Iranian Population; A Case-Control Study

Background: Dilated cardiomyopathy (DCM) is among the most prevalent causes of heart failure and sudden cardiac death worldwide. Nuclear lamin protein coding genes are believed to have a definitive role in the DCM phenotype. The rs505058 thymine (T) to cytosine (C) polymorphism in the lamin-A gene is one of the most common mutations reported in familial DCM in previous studies. Objectives: We aimed to demonstrate the possible role of this SNP in the lamin A and C (LMNA) gene in the incidence of DCM among the south of Iran population. Methods: This case-control study included 65 patients with familial DCM and 70 healthy participants in south Iran. DNA was extracted from nucleated blood cells, and polymerase chain reaction (PCR) was performed. First, the sequence of the LMNA gene was investigated. Then the frequency of alleles C (mutated allele) and T (normal) of the LMNA gene (rs505058) was compared between the case and controls. Results: No notable differences were seen in gender and age between the case and controls. The genotype frequencies of the LMNA rs505058 T/C polymorphism were 6% (CC), 31% (CT), and 63% (TT) amongst cases, and 1% (CC), 13% (CT) and 86% (TT) in controls. For allele level comparison, the LMNA rs505058 C allele has been shown to have a statistically significant association with an enhancement in the risk of dilated cardiomyopathy (OR = 2.92; 95% CI = 1.05 to 8.15, P-value = 0.034) Conclusions: The results indicated that the rs505058 T/C SNP of the LMNA gene is associated with familial DCM patients in the Iranian population.

Echocardiographic reference intervals and cut-off values to diagnose dilated cardiomyopathy in guinea pigs (Cavia porcellus)

The objective of this study was to establish reference intervals in healthy guinea pigs and to calculate optimal cut-off values for several M-Mode parameters to diagnose dilated cardiomyopathy (DCM) phenotype. This prospective study included 146 guinea pigs. The apparently healthy group included 92 animals and was used to create reference intervals for left ventricular internal diameter in diastole (LVIDd), left ventricular internal diameter in systole (LVIDS), E-point-to-septal separation (EPSS), diastolic wall thickness and left atrium and aorta. Allometric scaling was used to normalize LVIDd(-n) and LVIDs(-n) to body weight with a scaling exponent (BWexp). The DCM phenotype group included 54 subjects and was used to calculate optimal cut-off values of several M-mode parameters. Guinea pigs with DCM phenotype had significantly larger measurements of LVIDd, LVIDs and EPSS, as well as lower FS and wall thicknesses compared to apparently healthy guinea pigs. Allometric scaling exponents to normalize LVIDd and LVIDs to BW (g) were 0.336 and 0.346, respectively. The highest area under the curve (AUC) to diagnose DCM were found for LVIDs-n (cut-off value >0.74 mm, AUC 0.996), FS (cut-off value <29%, AUC 0.995), LVIDd-n (cut-off value >1.07 mm, AUC 0.980) and EPSS (cut-off value >1.4 mm, AUC 0.944). M-mode and 2D reference intervals for guinea pigs are presented, including lower and upper limits. Diagnosis of DCM phenotype in guinea pigs can be established using parameters known to be useful in other species, namely LVIDs, LVIDs-n, FS, LVIDd, LVIDd-n and EPSS.

Tools to differentiate between Filamin C and Titin truncating variant carriers: value of MRI.

Whereas truncating variants of the giant protein Titin (TTNtv) are the main cause of familial dilated cardiomyopathy (DCM), recently Filamin C truncating variants (FLNCtv) were identified as a cause of arrhythmogenic cardiomyopathy (ACM). Our aim was to characterize and compare clinical and MRI features of TTNtv and FLNCtv in the Belgian population. In index patients referred for genetic testing of ACM/DCM, FLNCtv and TTNtv were found in 17 (3.6%) and 33 (12.3%) subjects, respectively. Further family cascade screening yielded 24 and 19 additional truncating variant carriers in FLNC and TTN, respectively. The main phenotype was ACM in FLNCtv carriers whereas TTNtv carriers showed either an ACM or DCM phenotype. Non-sustained Ventricular Tachycardia was frequent in both populations. MRI data, available in 28/40 FLNCtv and 32/52 TTNtv patients, showed lower Left Ventricular (LV) ejection fraction and lower LV strain in TTNtv patients (p < 0.01). Conversely, both the frequency (68% vs 22%) and extent of non-ischemic myocardial late gadolinium enhancement (LGE) was significantly higher in FLNCtv patients (p < 0.01). Hereby, ring-like LGE was found in 16/19 (84%) FLNCtv versus 1/7 (14%) of TTNtv patients (p < 0.01).In conclusion, a large number of FLNCtv and TTNtv patients present with an ACM phenotype but can be separated by cardiac MRI. Whereas FLNCtv patients often have extensive myocardial fibrosis, typically following a ring-like pattern, LV dysfunction without or limited replacement fibrosis is the common TTNtv phenotype.

Dilated cardiomyopathy phenotype in a female patient with Danon disease

Dilated cardiomyopathy phenotype in a female patient with Danon disease