Cardiology

Packer, M. (2020). “Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure.” Eur Heart J May 27;ehaa360. [Epub ahead of print].

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The two primary molecular regulators of lifespan are sirtuin-1 (SIRT1) and mammalian target of rapamycin complex 1 (mTORC1). Each plays a central role in two highly interconnected pathways that modulate the balance between cellular growth and survival. The activation of SIRT1 [along with peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) and adenosine monophosphate-activated protein kinase (AMPK)] and the suppression of mTORC1 (along with its upstream regulator, Akt) act to prolong organismal longevity and retard cardiac ageing. Both activation of SIRT1/PGC-1α and inhibition of mTORC1 shifts the balance of cellular priorities so as to promote cardiomyocyte survival over growth, leading to cardioprotective effects in experimental models. These benefits may be related to direct actions to modulate oxidative stress, organellar function, proinflammatory pathways, and maladaptive hypertrophy. In addition, a primary shared benefit of both SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 inhibition is the enhancement of autophagy, a lysosome-dependent degradative pathway, which clears the cytosol of dysfunctional organelles and misfolded proteins that drive the ageing process by increasing oxidative and endoplasmic reticulum stress. Autophagy underlies the ability of SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 suppression to extend lifespan, mitigate cardiac ageing, alleviate cellular stress, and ameliorate the development and progression of cardiomyopathy; silencing of autophagy genes abolishes these benefits. Loss of SIRT1/PGC-1α/AMPK function or hyperactivation of Akt/mTORC1 is a consistent feature of experimental cardiomyopathy, and reversal of these abnormalities mitigates the development of heart failure. Interestingly, most treatments that have been shown to be clinically effective in the treatment of chronic heart failure with a reduced ejection fraction have been reported experimentally to exert favourable effects to activate SIRT1/PGC-1α/AMPK and/or suppress Akt/mTORC1, and thereby, to promote autophagic flux. Therefore, the impairment of autophagy resulting from derangements in longevity gene signalling is likely to represent a seminal event in the evolution and progression of cardiomyopathy.

Packer, M. (2020). “Autophagy-dependent and -independent modulation of oxidative and organellar stress in the diabetic heart by glucose-lowering drugs.” Cardiovasc Diabetol 19(1): 62.

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Autophagy is a lysosome-dependent intracellular degradative pathway, which mediates the cellular adaptation to nutrient and oxygen depletion as well as to oxidative and endoplasmic reticulum stress. The molecular mechanisms that stimulate autophagy include the activation of energy deprivation sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). These enzymes not only promote organellar integrity directly, but they also enhance autophagic flux, which leads to the removal of dysfunctional mitochondria and peroxisomes. Type 2 diabetes is characterized by suppression of SIRT1 and AMPK signaling as well as an impairment of autophagy; these derangements contribute to an increase in oxidative stress and the development of cardiomyopathy. Antihyperglycemic drugs that signal through insulin may further suppress autophagy and worsen heart failure. In contrast, metformin and SGLT2 inhibitors activate SIRT1 and/or AMPK and promote autophagic flux to varying degrees in cardiomyocytes, which may explain their benefits in experimental cardiomyopathy. However, metformin and SGLT2 inhibitors differ meaningfully in the molecular mechanisms that underlie their effects on the heart. Whereas metformin primarily acts as an agonist of AMPK, SGLT2 inhibitors induce a fasting-like state that is accompanied by ketogenesis, a biomarker of enhanced SIRT1 signaling. Preferential SIRT1 activation may also explain the ability of SGLT2 inhibitors to stimulate erythropoiesis and reduce uric acid (a biomarker of oxidative stress)-effects that are not seen with metformin. Changes in both hematocrit and serum urate are the most important predictors of the ability of SGLT2 inhibitors to reduce the risk of cardiovascular death and hospitalization for heart failure in large-scale trials. Metformin and SGLT2 inhibitors may also differ in their ability to mitigate diabetes-related increases in intracellular sodium concentration and its adverse effects on mitochondrial functional integrity. Differences in the actions of SGLT2 inhibitors and metformin may reflect the distinctive molecular pathways that explain differences in the cardioprotective effects of these drugs.

Milligan, G. P., A. Alam and C. Guerrero-Miranda (2020). “Recognizing Right Ventricular Dysfunction in Coronavirus Disease-2019-Related Respiratory Illness.” J Card Fail May 11;S1071-9164(20)30497-8. [Epub ahead of print].

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We have read the article by Tersalvi and colleagues1 detailing mechanisms of elevated troponin in patients with coronavirus disease 2019 (COVID-19), and we write to encourage recognition of acute right ventricular (RV) strain as an additional possibility. [No abstract; excerpt from article].

Kim, K. H., L. She, K. L. Lee, R. Dabrowski, P. A. Grayburn, M. Rajda, D. L. Prior, P. Desvigne-Nickens, W. A. Zoghbi, M. Senni, G. Stefanelli, C. Beghi, T. Huynh, E. J. Velazquez, J. K. Oh and G. Lin (2020). “Incremental prognostic value of echocardiography of left ventricular remodeling and diastolic function in STICH trial.” Cardiovasc Ultrasound 18(1): 17.

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AIMS: We sought to determine which echocardiographic markers of left ventricular (LV) remodeling and diastolic dysfunction can contribute as incremental and independent prognostic information in addition to current clinical risk markers of ischemic LV systolic dysfunction in the Surgical Treatment for Ischemic Heart Failure (STICH) trial. METHODS AND RESULTS: The cohort consisted of 1511 of 2136 patients in STICH for whom baseline transmitral Doppler (E/A ratio) could be measured by an echocardiographic core laboratory blinded to treatment and outcomes, and prognostic value of echocardiographic variables was determined by a Cox regression model. E/A ratio was the most significant predictor of mortality amongst diastolic variables with lowest mortality for E/A closest 0.8, although mortality was consistently low for E/A 0.6 to 1.0. Mortality increased for E/A < 0.6 and > 1.0 up to approximately 2.3, beyond which there was no further increase in risk. Larger LV end-systolic volume index (LVESVI) and E/A < 0.6 and > 1.0 had incremental negative effects on mortality when added to a clinical multivariable model, where creatinine, LVESVI, age, and E/A ratio accounted for 74% of the prognostic information for predicting risk. LVESVI and E/A ratio were stronger predictors of prognosis than New York Heart Association functional class, anemia, diabetes, history of atrial fibrillation, and stroke. CONCLUSIONS: Echocardiographic markers of advanced LV remodeling and diastolic dysfunction added incremental prognostic value to current clinical risk markers. LVESVI and E/A ratio outperformed other markers and should be considered as standard in assessing risks in ischemic heart failure. E/A closest to 0.8 was the most optimal filling pattern.

Holmes, D. R., Jr., M. J. Mack, M. Alkhouli and S. Vemulapalli (2020). “Racial disparities and democratization of health care: A focus on TAVR in the United States.” Am Heart J 224: 166-170.

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What can be said with certainty is that there are real and documented disparities in care involving TAVR in the increasing population of patients with aortic stenosis.1–8,28–32These disparities may become more prominent as TAVR becomes the standard of care. There are multiple issues relating to this disparity including socioeconomic,genetic, personal valuations and expectations, access to care, and follow-up. Approaches to resolution need to take into consideration of these multiple issues from many angles and include multiple stakeholders – hospital systems to promote culturally competent team based care, reimbursement agencies, patient education, family support systems access to community based educational programs, industry resources working to develop trials with specific focus and recruitment goals to include racialand ethnic groups, and social services.29-32The CMS Accountable Health Communities Model project has been implemented and could potentially be used by the centers involved to focus on one limb of unmet needs. [No abstract; excerpt from article p.169-170].