Browsing by keyword "dilated cardiomyopathy"
Now showing items 1-4 of 4
-
Dilated cardiomyopathy mutation E525K in human beta-cardiac myosin stabilizes the interacting-heads motif and super-relaxed state of myosinThe auto-inhibited, super-relaxed (SRX) state of cardiac myosin is thought to be crucial for regulating contraction, relaxation, and energy conservation in the heart. We used single ATP turnover experiments to demonstrate that a dilated cardiomyopathy (DCM) mutation (E525K) in human beta-cardiac myosin increases the fraction of myosin heads in the SRX state (with slow ATP turnover), especially in physiological ionic strength conditions. We also utilized FRET between a C-terminal GFP tag on the myosin tail and Cy3ATP bound to the active site of the motor domain to estimate the fraction of heads in the closed, interacting-heads motif (IHM); we found a strong correlation between the IHM and SRX state. Negative stain electron microscopy and 2D class averaging of the construct demonstrated that the E525K mutation increased the fraction of molecules adopting the IHM. Overall, our results demonstrate that the E525K DCM mutation may reduce muscle force and power by stabilizing the auto-inhibited SRX state. Our studies also provide direct evidence for a correlation between the SRX biochemical state and the IHM structural state in cardiac muscle myosin. Furthermore, the E525 residue may be implicated in crucial electrostatic interactions that modulate this conserved, auto-inhibited conformation of myosin.
-
Effect of type of diet on blood and plasma taurine concentrations, cardiac biomarkers, and echocardiograms in 4 dog breedsBACKGROUND: Associations of diet with dilated cardiomyopathy are under investigation. OBJECTIVES: That cardiac assessment would show abnormalities in healthy dogs eating grain-free (GF) diets or diets with Food and Drug Administration (FDA)-listed ingredients of concern (peas, lentils, or potatoes) as top 10 ingredients (FDA-PLP), but not in dogs eating grain-inclusive (GI) diets or diets without FDA-listed ingredients of concern (PLP) in the top 10 ingredients (NoFDA-PLP). ANIMALS: One hundred eighty-eight healthy Doberman Pinschers, Golden Retrievers, Miniature Schnauzers, and Whippets. METHODS: This study was an observational cross-sectional study. Echocardiograms, cardiac biomarkers, and blood and plasma taurine concentrations were compared between dogs eating GF (n = 26) and GI (n = 162) diets, and between FDA-PLP (n = 39) and NoFDA-PLP (n = 149) diets, controlling for age and breed. Demographic characteristics, murmurs, genetic status, and ventricular premature complexes (VPCs) during examination were compared between dogs eating different diet types. RESULTS: No differences in echocardiographic variables, N-terminal pro-B-type natriuretic peptide or whole blood taurine were noted between dogs eating different diet types. Dogs eating GF diets had higher median high-sensitivity cardiac troponin I (hs-cTnI) (GF 0.076 ng/mL [Interquartile range (IQR), 0.028-0.156] vs. GI 0.048 [IQR, 0.0026-0.080]; P < .001) and higher median plasma taurine (GF 125 nmol/mL [IQR, 101-148] vs GI 104 [IQR, 86-123]; P = .02) than dogs eating GI diets. Dogs eating FDA-PLP diets had higher median hs-cTnI (0.059 ng/mL [IQR, 0.028-0.122]) than dogs eating NoFDA-PLP diets (0.048 [IQR, 0.025-0.085]; P = .006). A greater proportion of dogs eating FDA-PLP diets (10%) had VPCs than dogs eating NoFDA-PLP diets (2%; P = .04). CONCLUSIONS AND CLINICAL IMPORTANCE: Higher hs-cTnI in healthy dogs eating GF and FDA-PLP diets might indicate low-level cardiomyocyte injury.
-
mTOR-activating mutations in RRAGD cause kidney tubulopathy and cardiomyopathy (KICA) syndrome [preprint]Background Over the last decaces, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, ±20% of all tubulopathy patients remain without genetic diagnosis. Here, we explore a large multicentric patient cohort with a novel inherited salt-losing tubulopathy, hypomagnesemia and dilated cardiomyopathy (DCM). Methods Whole exome and genome sequencings were performed with various subsequent functional analyses of identified RRAGD variants in vitro. Results In 8 children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt-wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients additionally suffered from DCM requiring heart transplantation in 3 of them. An additional dominant variant in RRAGD was simultaneously identified in eight members of a large family with a similar renal phenotype. RRAGD encodes GTPase RagD mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron include the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro, Conclusions Our findings establish a novel disease phenotype combining kidney tubulopathy and cardiomyopathy (KICA) caused by an activation of mTOR signaling suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.
-
Validation and preliminary data from a health-related quality of life questionnaire for owners of dogs with cardiac diseaseBACKGROUND: Cardiac disease in dogs impacts the quality of life (QoL) of their owners, but owners' QoL has not been comprehensively assessed in this population. OBJECTIVES: To develop, validate, and provide preliminary data from a health-related QoL (hrQoL) questionnaire for owners of dogs with cardiac disease. SUBJECTS: A total of 141 owners of dogs with cardiac disease were studied. METHODS: An owner hrQoL (O-hrQoL) questionnaire containing 20 items related to areas of a person's life that could be impacted by caring for a dog with cardiac disease was developed and administered to owners of dogs with cardiac disease. The highest possible total score was 100, with higher scores indicating a worse hrQoL. Readability, internal consistency, face and construct validity, and item-total correlations were assessed. RESULTS: Median O-hrQoL score was 35 (range, 0-87). The questionnaire had good internal consistency (Cronbach's alpha = 0.933), construct validity (Spearman's r = 0.38-0.53; Kendall's tau = 0.30-0.43; P < .001), and item-total correlation (Spearman's r = 0.44-0.79; Kendall's tau = 0.34-0.66; all P < .001). Fifty percent of owners indicated a negative effect of dogs' cardiac disease on their own QoL, but all owners responded that caring for their dogs either had strengthened (n = 76; 53.9%) or had no effect on their relationship with their dog (n = 65; 46.1%). CONCLUSIONS AND CLINICAL IMPORTANCE: The O-hrQoL questionnaire had good validity, and results suggest that owners' QoL is significantly impacted by caring for dogs with cardiac disease. Additional research on effective approaches to minimizing the negative effects of a dog's cardiac disease on the owner is warranted.
