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Golden retrievers are over-represented in cases of taurine-deficient dilated cardiomyopathy and recently a surge in cases has prompted further investigation. To describe the clinical, dietary, and echocardiographic features in golden retrievers diagnosed with taurine deficiency and dilated cardiomyopathy, and to determine specific dietary associations. A second aim was to determine the whole blood taurine concentrations in a representative sample of healthy golden retrievers. Twenty-four client-owned golden retrievers with documented taurine deficiency and dilated cardiomyopathy and 52 healthy client-owned golden retrievers. In this multicenter prospective observational study, baseline and follow-up echocardiographic data, complete diet and medical histories, and whole blood, plasma, or serum taurine concentrations were obtained. Baseline and follow-up echocardiographic data were compared. Associations were evaluated between specific diets and taurine deficiency or congestive heart failure. The prevalence of low whole blood taurine concentrations in the healthy golden retrievers was calculated. Twenty-three of 24 dogs diagnosed with taurine deficiency and dilated cardiomyopathy were fed diets that were either grain-free, legume-rich, or a combination of these factors. None of these diets were feeding trial tested using Association of American Feed Control Officials (AAFCO) procedures. Twenty-three of 24 dogs had significant improvement in their echocardiographic parameters and normalization of taurine concentrations following diet change and taurine supplementation. Nine of 11 dogs diagnosed with congestive heart failure (CHF) had resolution of their congestion at follow-up with five no longer requiring diuretic therapy and four tolerating diuretic dose reduction by >50%. Certain diets and diet characteristics were associated with the development of taurine deficiency. Taurine deficiency and dilated cardiomyopathy in golden retrievers is likely multifactorial, including a combination of dietary, metabolic, and genetic factors.

Stuart Cook and colleagues study the role of TTN (titin)-truncating variants using a combination of heart physiology experiments in rats and genomic analysis in humans. Their data show that TTN variants are associated with a range of cardiac phenotypes in healthy individuals and in patients with dilated cardiomyopathy. Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ∼1% of the general population, where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn , TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism. Heart physiology in rats with TTNtv was unremarkable at baseline but became impaired during cardiac stress. In healthy humans, machine-learning-based analysis of high-resolution cardiac imaging showed TTNtv to be associated with eccentric cardiac remodeling. These data show that TTNtv have molecular and physiological effects on the heart across species, with a continuum of expressivity in health and disease.

The pattern of myocardial fibrosis differs significantly between different cardiomyopathies. Fibrosis in hypertrophic cardiomyopathy (HCM) is characteristically as patchy and regional but in dilated cardiomyopathy (DCM) as diffuse and global. We sought to investigate if texture analyses on myocardial native T.sub.1 mapping can differentiate between fibrosis patterns in patients with HCM and DCM. We prospectively acquired native myocardial T.sub.1 mapping images for 321 subjects (55±15 years, 70% male): 65 control, 116 HCM, and 140 DCM patients. To quantify different fibrosis patterns, four sets of texture descriptors were used to extract 152 texture features from native T.sub.1 maps. Seven features were sequentially selected to identify HCM- and DCM-specific patterns in 70% of data (training dataset). Pattern reproducibility and generalizability were tested on the rest of data (testing dataset) using support vector machines (SVM) and regression models. Pattern-derived texture features were capable to identify subjects in HCM, DCM, and controls cohorts with 202/237(85.2%) accuracy of all subjects in the training dataset using 10-fold cross-validation on SVM (AUC = 0.93, 0.93, and 0.93 for controls, HCM and DCM, respectively), while pattern-independent global native T.sub.1 mapping was poorly capable to identify those subjects with 121/237(51.1%) accuracy (AUC = 0.78, 0.51, and 0.74) (P<0.001 for all). The pattern-derived features were reproducible with excellent intra- and inter-observer reliability and generalizable on the testing dataset with 75/84(89.3%) accuracy. Texture analysis of myocardial native T.sub.1 mapping can characterize fibrosis patterns in HCM and DCM patients and provides additional information beyond average native T.sub.1 values.

Dilated cardiomyopathy is characterised by left ventricular dilation that is associated with systolic dysfunction. Diastolic dysfunction and impaired right ventricular function can develop. Affected individuals are at risk of left or right ventricular failure, or both. Heart failure symptoms can be exercise-induced or persistent at rest. Many patients are asymptomatic. Chronically treated patients sometimes present acutely with decompensated heart failure. Other life-threatening risks are ventricular arrhythmias and atrioventricular block, syncope, and sudden death. Genetic inheritance arises in 30–48% of patients, and inflammatory disorders such as myocarditis or toxic effects from medications, alcohol, or illicit drugs also result in dilated cardiomyopathy. Genes that cause dilated cardiomyopathy generally encode cytoskeletal and sarcomeric (contractile apparatus) proteins, although disturbance of calcium homeostasis also seems to be important. In children, disrupted mitochondrial function and metabolic abnormalities have a causal role. Treatments focus on improvement of cardiac efficiency and reduction of mechanical stress. Arrhythmia therapy and prevention of sudden death continue to be mainstays of treatment. Despite progress over the past 10 years, outcomes need to be improved.

Background Branched chain amino acids (BCAA) can impair insulin signaling, and cardiac insulin resistance can occur in the failing heart. We, therefore, determined if cardiac BCAA accumulation occurs in patients with dilated cardiomyopathy (DCM), due to an impaired catabolism of BCAA, and if stimulating cardiac BCAA oxidation can improve cardiac function in mice with heart failure. Method For human cohorts of DCM and control, both male and female patients of ages between 22 and 66 years were recruited with informed consent from University of Alberta hospital. Left ventricular biopsies were obtained at the time of transplantation. Control biopsies were obtained from non-transplanted donor hearts without heart disease history. To determine if stimulating BCAA catabolism could lessen the severity of heart failure, C57BL/6J mice subjected to a transverse aortic constriction (TAC) were treated between 1 to 4-week post-surgery with either vehicle or a stimulator of BCAA oxidation (BT2, 40 mg/kg/day). Result Echocardiographic data showed a reduction in ejection fraction (54.3 ± 2.3 to 22.3 ± 2.2%) and an enhanced formation of cardiac fibrosis in DCM patients when compared to the control patients. Cardiac BCAA levels were dramatically elevated in left ventricular samples of patients with DCM. Hearts from DCM patients showed a blunted insulin signalling pathway, as indicated by an increase in P-IRS1ser636/639 and its upstream modulator P-p70S6K, but a decrease in its downstream modulators P-AKT ser473 and in P-GSK3β ser9. Cardiac BCAA oxidation in isolated working hearts was significantly enhanced by BT2, compared to vehicle, following either acute or chronic treatment. Treatment of TAC mice with BT2 significantly improved cardiac function in both sham and TAC mice (63.0 ± 1.8 and 56.9 ± 3.8% ejection fraction respectively). Furthermore, P-BCKDH and BCKDK expression was significantly decreased in the BT2 treated groups. Conclusion We conclude that impaired cardiac BCAA catabolism and insulin signaling occur in human heart failure, while enhancing BCAA oxidation can improve cardiac function in the failing mouse heart.

A surge in Food and Drug Administration (FDA) consumer complaints identified concerns that legume-rich, grain-free diets were associated with nutritionally-mediated dilated cardiomyopathy (DCM). Golden retrievers represent the most reported breed affected by this condition and previous studies documented the disease is responsive to dietary change and taurine supplementation. Although dietary findings across cases are compelling, prospective studies with control groups are lacking. The role of diet in developing taurine deficiency and echocardiographic changes consistent with DCM in healthy dogs is unknown. We hypothesized that golden retrievers eating non-traditional diets are at a higher risk of having taurine deficiency and nutritionally-mediated DCM compared with those eating traditional commercial diets. We aimed to compare taurine concentrations and echocardiographic indices of systolic function between golden retrievers in each diet group and elucidate associations between diet and these variables. Additionally, we aimed to generate breed-specific reference intervals for whole blood and plasma taurine concentrations. 86 golden retrievers. Golden retrievers eating traditional or non-traditional diets were evaluated and diet history, taurine concentrations and echocardiographic data were collected. Dietary features, taurine concentrations and echocardiographic findings were compared between diet groups. Relative risks were calculated for the likelihood of echocardiographic abnormalities and taurine deficiency in each diet group. Breed-specific reference intervals were constructed for taurine concentrations in dogs from the traditional diet group. Golden retrievers eating non-traditional diets had significantly lower taurine concentrations and more frequent systolic dysfunction. Breed specific reference intervals are higher than previously reported across breeds. Non-traditional diets, which were typically grain-free and contained legumes in this study, were significantly associated with and have increased relative risk for the identification of taurine deficiency and echocardiographic abnormalities consistent with nutritionally-mediated DCM. These findings were identifiable in the absence of clinical signs and support the findings of multiple previous studies and the ongoing FDA investigation.

Chagas cardiomyopathy (CDC) is associated with a poor prognosis compared to other cardiomyopathies. Speckle tracking echocardiography (STE), which provides direct assessment of myocardial fiber deformation, may be useful in predicting prognosis. This study assessed STE in CDC and compared with idiopathic cardiomyopathy (IDC), and also examined the incremental prognostic information of STE over left ventricular ejection fraction (LVEF) in these patients. We enrolled 112 patients, age of 56.7 ± 11.8 years, 81 with CDC and 31 with IDC. STE indices were obtained at baseline in all patients. The endpoint was a composite of death, hospitalization for heart failure, or need for heart transplantation. Patients with IDC had worse LV systolic function compared to CDC, with LVEF of 34.5% vs 41.3%, p = 0.004, respectively. After adjustment for LVEF, there were no differences in STE values between CDC and IDC. During a median follow-up of 18.2 months (range, 11 to 22), 26 patients met the composite end point (24%). LV longitudinal strain was a strong predictor of adverse events, incremental to LVEF and E/e' ratio (HR 1.463, 95% CI 1.130-1.894; p = 0.004). The risk of cardiac events increased significantly in patients with GLS > - 12% (log-rank p = 0.035). STE indices were abnormal in patients with dilated cardiomyopathy, without differences between CDC and IDC. LV longitudinal strain was a powerful predictor of outcome, adding prognostic information beyond that provided by LVEF and E/e' ratio.

Calcium (Ca2+) dysregulation is a hallmark of heart failure and is characterized by impaired Ca2+ sequestration into the sarcoplasmic reticulum (SR) by the SR-Ca2+-ATPase (SERCA). We recently discovered a micropeptide named DWORF (DWarf Open Reading Frame) that enhances SERCA activity by displacing phospholamban (PLN), a potent SERCA inhibitor. Here we show that DWORF has a higher apparent binding affinity for SERCA than PLN and that DWORF overexpression mitigates the contractile dysfunction associated with PLN overexpression, substantiating its role as a potent activator of SERCA. Additionally, using a well-characterized mouse model of dilated cardiomyopathy (DCM) due to genetic deletion of the muscle-specific LIM domain protein (MLP), we show that DWORF overexpression restores cardiac function and prevents the pathological remodeling and Ca2+ dysregulation classically exhibited by MLP knockout mice. Our results establish DWORF as a potent activator of SERCA within the heart and as an attractive candidate for a heart failure therapeutic. The heart is a muscular organ that contracts regularly to pump blood around the body, ensuring that nutrients and oxygen are carried to the cells and organs. Heart failure is a disease where the heart muscle becomes weakened, does not beat as strongly, and cannot pump blood as well as it should. Eventually, the heart can no longer deliver enough blood to meet the body’s needs. Although heart failure is a widespread disease, we still do not fully understand its underlying causes and the molecular machinery driving its progression. However, one common feature in many cases of heart failure is a problem with the supply of calcium to the heart muscle. Calcium is the molecule responsible for the process of muscle contraction; the strength of contraction depends on the amount of calcium available. Movement of calcium within heart cells is in turn controlled by an enzyme pump called SERCA. In 2016, researchers identified a small protein, DWORF, which increased the activity of SERCA. Makarewich et al. – including many of the researchers involved in the 2016 study – therefore wanted to find out more about how DWORF and SERCA worked together. They also wanted to test if DWORF could be used to boost the heart’s ability to pump blood efficiently, and if so, whether it could treat heart failure. Genetically modified mice that produced larger than normal amounts of DWORF had more available calcium in the heart muscle, which made it contract more strongly. This was true even when the same mice were treated with an excessive amount of a specific protein (phospholamban) that can lower the activity of SERCA, suggesting that DWORF might have a protective effect on the heart. Experiments using mice engineered to show symptoms of heart disease confirmed that DWORF treatment did indeed help their hearts beat normally, and, crucially, prevented them from developing heart failure. This work has shown for the first time that DWORF can restore the heart’s ability to pump normally in an experimental model of heart disease. In the future, Makarewich et al. hope that DWORF could be a useful target for new, more effective drugs to treat heart failure.

Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM. 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value<0.01). The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01) demonstrated significant association for TTN variants only (P = 0.0085). All candidate genes but one (SLC39A8) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033) or common (n = 36, P = 0.019) variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here. We identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.

The dog provides a large animal model of familial dilated cardiomyopathy for the study of important aspects of this common familial cardiovascular disease. We have previously demonstrated a form of canine dilated cardiomyopathy in the Doberman pinscher breed that is inherited as an autosomal dominant trait and is associated with a splice site variant in the pyruvate dehydrogenase kinase 4 (PDK4) gene, however, genetic heterogeneity exists in this species as well and not all affected dogs have the PDK4 variant. Whole genome sequencing of a family of Doberman pinchers with dilated cardiomyopathy and sudden cardiac death without the PDK4 variant was performed. A pathologic missense variant in the titin gene located in an immunoglobulin-like domain in the I-band spanning region of the molecule was identified and was highly associated with the disease (p < 0.0001). We demonstrate here the identification of a variant in the titin gene highly associated with the disease in this spontaneous canine model of dilated cardiomyopathy. This large animal model of familial dilated cardiomyopathy shares many similarities with the human disease including mode of inheritance, clinical presentation, genetic heterogeneity and a pathologic variant in the titin gene. The dog is an excellent model to improve our understanding of the genotypic phenotypic relationships, penetrance, expression and the pathophysiology of variants in the titin gene.