Abstract-Diurnal variation of cardiac function in vivo has been attributed primarily to changes in factors such as sympathetic activity. No study has investigated previously the intrinsic properties of the heart throughout the day. We therefore investigated diurnal variations in metabolic flux and contractile function of the isolated working rat heart and how this related to circadian expression of metabolic genes. Contractile performance, carbohydrate oxidation, and oxygen consumption were greatest in the middle of the night, with little variation in fatty acid oxidation. The expression of all metabolic genes investigated (including regulators of carbohydrate utilization, fatty acid oxidation, and mitochondrial function) showed diurnal variation, with a general peak in the night. In contrast, pressure overloadinduced cardiac hypertrophy completely abolished this diurnal variation of metabolic gene expression. Thus, over the course of the day, the normal heart anticipates, responds, and adapts to physiological alterations within its environment, a trait that is lost by the hypertrophied heart. We speculate that loss of plasticity of the hypertrophied heart may play a role in the subsequent development of contractile dysfunction. Key Words: function Ⅲ gene expression Ⅲ metabolism Ⅲ perfusions Ⅲ rat C ells are able to anticipate, respond, and adapt to fluctuations in their environment. Anticipation is achieved through self-sustained intracellular clocks, providing advantageous priming of the cell in preparation to a given stimulus. 1 The response of any cell is dictated by the level of the stimulus, as well as the sensitivity to that stimulus. The latter is affected by both intracellular (genotype, circadian clocks) and extracellular (eg, neuronal and humoral factors) influences. The resultant adaptation can be either immediate (alterations in preexisting proteins) or prolonged (changes in gene and protein expression) depending on the length of exposure to the stimulus.The heart, not unlike other organs, possesses both internal clocks and the ability to respond to external stimuli, both of which could potentially influence gene expression, metabolism, and function. [2][3][4] It is well known that the onset of heart failure, myocardial infarction, and sudden death is greatest in the early hours of the morning. 5-7 For this reason, several studies have investigated diurnal variation in cardiac function in vivo, in both rodents and humans, and have correlated findings with fluctuations in neurohumoral influences. 5,8 -11 However, to date, no study has either postulated or investigated whether the intrinsic properties of the heart fluctuate during the day, or whether loss of synchronization between the presence of a stimulus (eg, sympathetic activity) and responsiveness of the heart plays a role in the development of contractile dysfunction.We set out to characterize the diurnal variation in contractile function and metabolic flux of the heart in the absence of confounding extracardiac influences by using the isolat...

Myocardial phospholipids serve as primary reservoirs of arachidonic acid (AA), which is liberated through the rate-determining hydrolytic action of cardiac phospholipases A2 (PLA2s). A predominant PLA2 in myocardium is calcium-independent phospholipase A2beta (iPLA2beta), which, through its calmodulin (CaM) and ATP-binding domains, is regulated by alterations in local cellular Ca2+ concentrations and cardiac bioenergetic status, respectively. Importantly, iPLA2beta has been demonstrated to be activated by ischaemia through elevation of the concentration of myocardial fatty acyl-CoA, which abrogates Ca2+/CaM-mediated inhibition of iPLA2beta. AA released by PLA2-catalysed hydrolysis of phospholipids serves as a precursor for eicosanoids generated by pathways dependent on cyclooxygenases (COX), lipoxygenases (LOX), and cytochromes P450 (CYP). Eicosanoids initiate and propagate diverse signalling cascades, primarily through their interaction with cellular receptors and ion channels. However, during pathologic states such as ischaemia or congestive heart failure, eicosanoids contribute to multiple maladaptive changes including inflammation, alterations of cellular growth programmes, and activation of multiple transcriptional events leading to the deleterious sequelae of these pathologic states. This review summarizes the central roles of myocardial PLA(2)s in eicosanoid signalling in the heart, the major COX, LOX, and CYP pathways of eicosanoid generation in the myocardium, and the effects of important eicosanoids on receptor-, ion channel-, and transcription-mediated processes that facilitate cardiac hypertrophy, mediate ischaemic preconditioning, and precipitate arrhythmogenesis in response to pathologic stimuli.

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A dyshomeostasis of extra-and intracellular Ca 2+ and Zn 2+ occurs in rats receiving chronic aldosterone/salt treatment (ALDOST). Herein, we hypothesized the dyshomeostasis of intracellular Ca 2+ and Zn 2+ is intrinsically coupled that alters the redox state of cardiac myocytes and mitochondria, with Ca 2+ serving as a prooxidant and Zn 2+ as an antioxidant. Toward this end, we harvested hearts from rats receiving 4 wks ALDOST alone or cotreatment with either spironolactone (Spiro), an aldosterone receptor antagonist, or amlodipine (Amlod), an L-type Ca 2+ channel blocker (LTCC), and from age-/gender-matched untreated controls. , each of which could be prevented by Spiro and attenuated with Amlod; b) increased levels of 3-nitrotyrosine and 4-hydroxy-2-nonenal in cardiomyocytes, together with increased H 2 O 2 production, malondialdehyde and oxidized GSSG in mitochondria that were coincident with increased activities of Cu/Znsuperoxide dismutase and glutathione peroxidase; and c) increased expression of MT-1, Zip1 and ZnT-1, and MTF-1, attenuated by Spiro. Thus, an intrinsically coupled dyshomeostasis of intracellular Ca 2+ and Zn 2+ occurs in cardiac myocytes and mitochondria in rats receiving ALDOST, where it serves to alter their redox state through a respective induction of oxidative stress and generation of antioxidant defenses. The importance of therapeutic strategies that can uncouple these two divalent cations and modulate their ratio in favor of sustained antioxidant defenses is therefore suggested.

Background Adults with congenital heart disease (CHD) have been considered potentially high risk for novel coronavirus disease-19 (COVID-19) mortality or other complications. Objectives This study sought to define the impact of COVID-19 in adults with CHD and to identify risk factors associated with adverse outcomes. Methods Adults (age 18 years or older) with CHD and with confirmed or clinically suspected COVID-19 were included from CHD centers worldwide. Data collection included anatomic diagnosis and subsequent interventions, comorbidities, medications, echocardiographic findings, presenting symptoms, course of illness, and outcomes. Predictors of death or severe infection were determined. Results From 58 adult CHD centers, the study included 1,044 infected patients (age: 35.1 ± 13.0 years; range 18 to 86 years; 51% women), 87% of whom had laboratory-confirmed coronavirus infection. The cohort included 118 (11%) patients with single ventricle and/or Fontan physiology, 87 (8%) patients with cyanosis, and 73 (7%) patients with pulmonary hypertension. There were 24 COVID-related deaths (case/fatality: 2.3%; 95% confidence interval: 1.4% to 3.2%). Factors associated with death included male sex, diabetes, cyanosis, pulmonary hypertension, renal insufficiency, and previous hospital admission for heart failure. Worse physiological stage was associated with mortality (p = 0.001), whereas anatomic complexity or defect group were not. Conclusions COVID-19 mortality in adults with CHD is commensurate with the general population. The most vulnerable patients are those with worse physiological stage, such as cyanosis and pulmonary hypertension, whereas anatomic complexity does not appear to predict infection severity.

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