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Ventricular arrhythmias can cause death in heart failure (HF). A trigger is the occurrence of Ca2+ waves which activate a Na+‐Ca2+ exchange (NCX) current, leading to delayed after‐depolarisations and triggered action potentials. Waves arise when sarcoplasmic reticulum (SR) Ca2+ content reaches a threshold and are commonly induced experimentally by raising external Ca2+, although the mechanism by which this causes waves is unclear and was the focus of this study. Intracellular Ca2+ was measured in voltage‐clamped ventricular myocytes from both control sheep and those subjected to rapid pacing to produce HF. Threshold SR Ca2+ content was determined by applying caffeine (10 mM) following a wave and integrating wave and caffeine‐induced NCX currents. Raising external Ca2+ induced waves in a greater proportion of HF cells than control. The associated increase of SR Ca2+ content was smaller in HF due to a lower threshold. Raising external Ca2+ had no effect on total influx via the L‐type Ca2+ current, ICa‐L, and increased efflux on NCX. Analysis of sarcolemmal fluxes revealed substantial background Ca2+ entry which sustains Ca2+ efflux during waves in the steady state. Wave frequency and background Ca2+ entry were decreased by Gd3+ or the TRPC6 inhibitor BI 749327. These agents also blocked Mn2+ entry. Inhibiting connexin hemi‐channels, TRPC1/4/5, L‐type channels or NCX had no effect on background entry. In conclusion, raising external Ca2+ induces waves via a background Ca2+ influx through TRPC6 channels. The greater propensity to waves in HF results from increased background entry and decreased threshold SR content. Key points: Heart failure is a pro‐arrhythmic state and arrhythmias are a major cause of death.At the cellular level, Ca2+ waves resulting in delayed after‐depolarisations are a key trigger of arrhythmias. Ca2+ waves arise when the sarcoplasmic reticulum (SR) becomes overloaded with Ca2+.We investigate the mechanism by which raising external Ca2+ causes waves, and how this is modified in heart failure.We demonstrate that a novel sarcolemmal background Ca2+ influx via the TRPC6 channel is responsible for SR Ca2+ overload and Ca2+ waves.The increased propensity for Ca2+ waves in heart failure results from an increase of background influx, and a lower threshold SR content.The results of the present study highlight a novel mechanism by which Ca2+ waves may arise in heart failure, providing a basis for future work and novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Cats with subclinical hypertrophic cardiomyopathy (sHCM) have elevated serum insulin and serum amyloid A concentrations correlating with the degree of cardiac hypertrophy. Diet might affect these and other cardiac variables. Objective: Evaluate the effect of a complete, balanced diet with restricted starch and supplemented with eicosapentaenoic acid + docosahexaenoic acid (EPA + DHA) on echocardiographic variables and cardiac biomarkers in cats with sHCM. Animals Forty‐four client‐owned cats with sHCM. Methods: A prospective, randomized, double‐blind, multicenter study enrolled cats with end‐diastole interventricular septum thickness (IVSd) or left ventricular wall thickness (LVWd) ≥6 mm, or both. Nonsedated, fasted cats were examined at baseline and after 6 and 12 months of Test (restricted starch and EPA + DHA supplements) (n = 23) or Control (unrestricted starch without EPA + DHA supplementation) (n = 21) diet. Assessments included auscultation, body weight, body condition score, echocardiography and blood analysis. Linear and generalized mixed models analyzed diet, time and diet * time interactions (5% significance level). Results: No differences between diet groups were significant for any variable at any timepoint. There were significant decreases in the Test but not Control group in maximum IVSd (P =.03), maximum LVWd (P =.02) and insulin‐like growth factor‐1 levels (P =.04) after 12 months, and in ultrasensitive cardiac troponin I (cTnI) (P =.001) after 6 months; effect sizes (95% confidence interval) were 0.53 (0.09; 0.99), 0.63 (0.18; 1.09), 0.61 (0.16; 1.07), and 0.37 (−0.06; 0.8), respectively. Conclusions and Clinical Importance: Cats with sHCM fed Test diet had significant decreases in echocardiographic variables of sHCM and in cTnI and IGF‐1. [ABSTRACT FROM AUTHOR]

Background: Left atrial (LA) function is an important determinant of the left ventricular (LV) filling, playing a key role in maintaining optimal cardiac performance. Pimobendan is a phosphodiesterase III inhibitor with positive inotropic and vasodilator effects. The present study aims to investigate the effects of pimobendan on LA function in dogs with stage B2 myxomatous mitral valve disease (MMVD). Aim: The aim of this investigation was to study the effects of pimobendan on LA function in dogs with preclinical MMVD. Methods: Twenty-seven dogs with stage B2 MMVD were retrospectively included. LA function was assessed before and 1-6 months following pimobendan initiation. For each dog, two-dimensional (2D) echocardiography was performed to assess LA diameter and volume for each phase of the LA cycle and to assess complete, passive, and active LA function. Pulsed-wave tissue Doppler imaging (TDI) of the left ventricular longitudinal myocardial velocity associated with atrial contraction (A'), both at the level of the interventricular septum and the LV free wall, was also used as an indicator of LA function. Results: There were no significant differences in any of the left atrial variables pre- and posttreatment. Conclusion: Echocardiographic estimates of LA function by 2D diameters and volumes and TDI A' in dogs with MMVD do not change after treatment with pimobendan. [ABSTRACT FROM AUTHOR]

Background: Transverse (t)-tubules drive the rapid and synchronous Ca 2+ rise in cardiac myocytes. The virtual complete atrial t-tubule loss in heart failure (HF) decreases Ca 2+ release. It is unknown if or how atrial t-tubules can be restored and how this affects systolic Ca 2+ ., Methods: HF was induced in sheep by rapid ventricular pacing and recovered following termination of rapid pacing. Serial block-face scanning electron microscopy and confocal imaging were used to study t-tubule ultrastructure. Function was assessed using patch clamp, Ca 2+ , and confocal imaging. Candidate proteins involved in atrial t-tubule recovery were identified by western blot and expressed in rat neonatal ventricular myocytes to determine if they altered t-tubule structure., Results: Atrial t-tubules were lost in HF but reappeared following recovery from HF. Recovered t-tubules were disordered, adopting distinct morphologies with increased t-tubule length and branching. T-tubule disorder was associated with mitochondrial disorder. Recovered t-tubules were functional, triggering Ca 2+ release in the cell interior. Systolic Ca 2+ , I Ca-L , sarcoplasmic reticulum Ca 2+ content, and sarcoendoplasmic reticulum Ca 2+ ATPase function were restored following recovery from HF. Confocal microscopy showed fragmentation of ryanodine receptor staining and movement away from the z-line in HF, which was reversed following recovery from HF. Acute detubulation, to remove recovered t-tubules, confirmed their key role in restoration of the systolic Ca 2+ transient, the rate of Ca 2+ removal, and the peak L-type Ca 2+ current. The abundance of telethonin and myotubularin decreased during HF and increased during recovery. Transfection with these proteins altered the density and structure of tubules in neonatal myocytes. Myotubularin had a greater effect, increasing tubule length and branching, replicating that seen in the recovery atria., Conclusions: We show that recovery from HF restores atrial t-tubules, and this promotes recovery of I Ca-L , sarcoplasmic reticulum Ca 2+ content, and systolic Ca 2+ . We demonstrate an important role for myotubularin in t-tubule restoration. Our findings reveal a new and viable therapeutic strategy., Competing Interests: None.

Ventricular arrhythmias can cause death in heart failure (HF). A trigger is the occurrence of Ca 2+ waves which activate a Na + -Ca 2+ exchange (NCX) current, leading to delayed after-depolarisations and triggered action potentials. Waves arise when sarcoplasmic reticulum (SR) Ca 2+ content reaches a threshold and are commonly induced experimentally by raising external Ca 2+ , although the mechanism by which this causes waves is unclear and was the focus of this study. Intracellular Ca 2+ was measured in voltage-clamped ventricular myocytes from both control sheep and those subjected to rapid pacing to produce HF. Threshold SR Ca 2+ content was determined by applying caffeine (10  mM) following a wave and integrating wave and caffeine-induced NCX currents. Raising external Ca 2+ induced waves in a greater proportion of HF cells than control. The associated increase of SR Ca 2+ content was smaller in HF due to a lower threshold. Raising external Ca 2+ had no effect on total influx via the L-type Ca 2+ current, I Ca-L , and increased efflux on NCX. Analysis of sarcolemmal fluxes revealed substantial background Ca 2+ entry which sustains Ca 2+ efflux during waves in the steady state. Wave frequency and background Ca 2+ entry were decreased by Gd 3+ or the TRPC6 inhibitor BI 749327. These agents also blocked Mn 2+ entry. Inhibiting connexin hemi-channels, TRPC1/4/5, L-type channels or NCX had no effect on background entry. In conclusion, raising external Ca 2+ induces waves via a background Ca 2+ influx through TRPC6 channels. The greater propensity to waves in HF results from increased background entry and decreased threshold SR content. KEY POINTS: Heart failure is a pro-arrhythmic state and arrhythmias are a major cause of death. At the cellular level, Ca 2+ waves resulting in delayed after-depolarisations are a key trigger of arrhythmias. Ca 2+ waves arise when the sarcoplasmic reticulum (SR) becomes overloaded with Ca 2+ . We investigate the mechanism by which raising external Ca 2+ causes waves, and how this is modified in heart failure. We demonstrate that a novel sarcolemmal background Ca 2+ influx via the TRPC6 channel is responsible for SR Ca 2+ overload and Ca 2+ waves. The increased propensity for Ca 2+ waves in heart failure results from an increase of background influx, and a lower threshold SR content. The results of the present study highlight a novel mechanism by which Ca 2+ waves may arise in heart failure, providing a basis for future work and novel therapeutic targets., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: Insulin, insulin-like growth factor-1 (IGF-1), and inflammation possibly are involved in cats with asymptomatic hypertrophic cardiomyopathy (aHCM)., Objectives: To evaluate echocardiography, morphology, cardiac and inflammatory markers, insulin and IGF-1 in cats with aHCM., Animals: Fifty-one client-owned cats with aHCM., Methods: Observational descriptive study. Variables (body weight [BW], body condition score [BCS], echocardiography, and serum concentrations of N-terminal pro-B-type natriuretic peptide [NT-proBNP], ultra-sensitive troponin-I [c-TnI], serum amyloid A [SAA], insulin, glucose and IGF-1) were evaluated for significant increases above echocardiography cutoff values and laboratory reference ranges, associations and effect of left atrial (LA) remodeling and generalized hypertrophy., Results: Cats with aHCM had BCS ≥6/9 (P = .01) and insulin (P < .001), NT-proBNP (P = .001) and cTn-I (P < .001) above laboratory reference ranges. Associations were present between NT-proBNP and maximum end-diastolic interventricular septum thickness (IVSd; ρ = .32; P = .05), maximum end-diastolic left ventricular free wall thickness;(ρ = .41; P = .01), LA/Aorta (ρ = .52; P = .001) and LA diameter (LA-max; ρ = .32; P = .05); c-TnI and LA/Aorta (ρ = .49; P = .003) and LA-max (ρ = .28; P = .05); and SAA and number of IVSd regions ≥6 mm thickness (ρ = .28; P = .05). Body weight and BCS were associated with IGF-1 (r = 0.44; P = .001), and insulin (ρ = .33; P = .02), glucose (ρ = .29; P = .04) and IGF-1 (ρ = .32; P = .02), respectively. Concentrations of NT-proBNP (P = .02) and c-TnI (P = .01), and SAA (P = .02), were higher in cats with LA remodeling, and generalized hypertrophy, respectively., Conclusions and Clinical Importance: Results suggest potential implications of insulin, IGF-1, and inflammation in cats with aHCM, but it remains to be confirmed whether these findings represent a physiological process or a part of the pathogenesis and development of disease., (© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Heart failure (HF) is predominantly a disease of older adults and characterized by extensive sympatho-vagal imbalance leading to impaired reflex control of heart rate (HR). However, whether aging influences the development or extent of the autonomic imbalance in HF remains unclear. To address this, we used an ovine model of aging with tachypacing-induced HF to determine whether aging affects the chronotropic and inotropic responses to autonomic stimulation and reduction in heart rate variability (HRV) in HF. We find that aging is associated with increased cardiac dimensions and reduced contractility before the onset of tachypacing, and these differences persist in HF. Additionally, the chronotropic response to β-adrenergic stimulation was markedly attenuated in HF, and this occurred more rapidly in aged animals. By measuring HR during sequential autonomic blockade, our data are consistent with a reduced parasympathetic control of resting HR in aging, with young HF animals having an attenuated sympathetic influence on HR. Time-domain analyses of HR show a reduction in HRV in both young and aged failing animals, although HRV is lowest in aged HF. In conclusion, aging is associated with altered autonomic control and β-adrenergic responsiveness of HR, and these are exacerbated with the development of HF., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America.)