Cardiology

Packer, M. (2020). “Mutual Antagonism of Hypoxia-Inducible Factor Isoforms in Cardiac, Vascular, and Renal Disorders.” JACC Basic Transl Sci 5(9): 961-968.

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Hypoxia-inducible factor (HIF)-1α and HIF-2α promote cellular adaptation to acute hypoxia, but during prolonged activation, these isoforms exert mutually antagonistic effects on the redox state and on proinflammatory pathways. Sustained HIF-1α signaling can increase oxidative stress, inflammation, and fibrosis, actions that are opposed by HIF-2α. Imbalances in the interplay between HIF-1α and HIF-2α may contribute to the progression of chronic heart failure, atherosclerotic and hypertensive vascular disorders, and chronic kidney disease. These disorders are characterized by activation of HIF-1α and suppression of HIF-2α, which are potentially related to mitochondrial and peroxisomal dysfunction and suppression of the redox sensor, sirtuin-1. Hypoxia mimetics can potentiate HIF-1α and/or HIF-2α; ideally, such agents should act preferentially to promote HIF-2α while exerting little effect on or acting to suppress HIF-1α. Selective activation of HIF-2α can be achieved with drugs that: 1) inhibit isoform-selective prolyl hydroxylases (e.g., cobalt chloride and roxadustat); or 2) promote the actions of the redox sensor, sirtuin-1 (e.g., sodium-glucose cotransporter 2 inhibitors). Selective HIF-2α signaling through sirtuin-1 activation may explain the effect of sodium-glucose cotransporter 2 inhibitors to simultaneously promote erythrocytosis and ameliorate the development of cardiomyopathy and nephropathy.

Packer, M. (2020). “Cardioprotective Effects of Sirtuin-1 and Its Downstream Effectors: Potential Role in Mediating the Heart Failure Benefits of SGLT2 (Sodium-Glucose Cotransporter 2) Inhibitors.” Circ Heart Fail 13(9): e007197.

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The cardioprotective effects of SGLT2 (sodium-glucose cotransporter 2) inhibitors may be related to their ability to induce a fasting-like paradigm, which triggers the activation of nutrient deprivation pathways to promote cellular homeostasis. The most distinctive metabolic manifestations of this fasting mimicry are enhanced gluconeogenesis and ketogenesis, which are not seen with other antihyperglycemic drugs. The principal molecular stimulus to gluconeogenesis and ketogenesis is activation of SIRT1 (sirtuin-1) and its downstream mediators: PGC-1α (proliferator-activated receptor gamma coactivator 1-alpha) and FGF21 (fibroblast growth factor 21). These three nutrient deprivation sensors exert striking cardioprotective effects in a broad range of experimental models. This benefit appears to be related to their actions to alleviate oxidative stress and promote autophagy-a lysosome-dependent degradative pathway that disposes of dysfunctional organelles that are major sources of cellular injury. Nutrient deprivation sensors are suppressed in states of perceived energy surplus (ie, type 2 diabetes mellitus and chronic heart failure), but SGLT2 inhibitors activate SIRT1/PGC-1α/FGF21 signaling and promote autophagy. This effect may be related to their action to trigger the perception of a system-wide decrease in environmental nutrients, but SGLT2 inhibitors may also upregulate SIRT1, PGC-1α, and FGF21 by a direct effect on the heart. Interestingly, metformin-induced stimulation of AMP-activated protein kinase (a nutrient deprivation sensor that does not promote ketogenesis) has not been shown to reduce heart failure events in clinical trials. Therefore, promotion of ketogenic nutrient deprivation signaling by SGLT2 inhibitors may explain their cardioprotective effects, even though SGLT2 is not expressed in the heart.

Ranganath, P., Moore, A., Guerrero, M., Collins, J., Foley, T., Williamson, E. and Rajiah, P. (2020). “CT for Pre- and Postprocedural Evaluation of Transcatheter Mitral Valve Replacement.” Radiographics 40(6): 1528-1553.

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Transcatheter mitral valve replacement (TMVR) is a catheter-based interventional technique for treating mitral valve disease in patients who are at high risk for open mitral valve surgery and with unfavorable anatomy for minimally invasive edge-to-edge transcatheter mitral valve repair. There are several TMVR devices with different anchoring mechanisms, delivered by either transapical or transseptal approaches. Transthoracic echocardiography is the first-line imaging modality used for characterization and quantification of mitral valve disorders. CT is complementary to echocardiography and has several advantages, including high isotropic spatial resolution, good temporal resolution, large field of view, multiplanar reconstruction capabilities, and rapid turnaround time. CT is essential for multiple aspects of preprocedural planning. Accurate and reproducible techniques to prescribe the mitral annulus at CT have been described from which important measurements such as the area, perimeter, trigone-trigone distance, intercommissural distance, and septolateral distance are obtained. The neo-left ventricular outflow tract (LVOT) can be simulated by placing a virtual prosthesis in the CT data to predict the risk of TMVR-induced LVOT obstruction. The anatomy of the landing zone and subvalvular apparatus as well as the relationship of the virtual device to adjacent structures such as the coronary sinus and left circumflex coronary artery can be evaluated. CT also stimulates procedural fluoroscopic angles. CT can be used to evaluate the chest wall for transapical access and the atrial septum for transseptal access. Follow-up CT is useful in identifying complications such as LVOT obstruction, paravalvular leak, pseudoaneurysm, and valve embolization. Online supplemental material is available for this article.

Goyal, A., Lo, K.B., Chatterjee, K., Mathew, R.O., McCullough, P.A., Bangalore, S. and Rangaswami, J. (2020). “Acute coronary syndromes in the peri-operative period after kidney transplantation in United States.” Clin Transplant Sep 18;e14083. [Epub ahead of print.].

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INTRODUCTION: Chronic kidney disease is an independent risk factor for cardiovascular disease. Despite careful preoperative evaluation, there is a risk of acute coronary syndromes after kidney transplant. METHODS: The National Inpatient Sample for the years 2004-2013 was used for this retrospective cohort study. All adult patients undergoing kidney transplantation were identified using the appropriate ICD-9-CM codes. Multivariate logistic regression was used to identify predictors of acute coronary syndromes in the peri-operative period after kidney transplantation. RESULTS: A total of 147 431 kidney transplants were performed from 2004 through 2013 in the United States. The average peri-operative in-hospital mortality was 0.5%. Acute coronary syndrome occurred in 1.3% patients in the peri-operative period. Half of patients with acute coronary syndromes had pre-existing coronary artery disease. The strongest predictors of acute coronary syndromes included older age: 45-64 years. OR 3.28 95% CI (1.85-5.83), ≥65 years. OR 4.84 (2.59-9.05), race: African American, OR 0.66 (0.47-0.93) and pre-existing coronary artery disease OR 3.83 (2.84-5.15). The case fatality rates were 16.9% and 5.3% for STEMI and NSTEMI, respectively. The overall mortality for any ACS event was 7.1%. CONCLUSION: Acute coronary syndrome in the immediate peri-operative period after kidney transplantation is rare but is associated with high rates of mortality.

Lo, K.B., Bhargav, R., Salacup, G., Pelayo, J., Albano, J., McCullough, P.A. and Rangaswami, J. (2020). “Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers and outcomes in patients with COVID-19: a systematic review and meta-analysis.” Expert Rev Cardiovasc Ther Oct 5;1-12. [Epub ahead of print.].

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BACKGROUND: The use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in patients with coronavirus disease 2019 (COVID-19) given their interaction with the angiotensin-converting enzyme-2 (ACE-2) receptor remains controversial. . OBJECTIVE: To investigate the impact of ACEI/ARB on COVID-19 disease severity and mortality through a systematic review and meta-analysis. METHODS: We searched PubMed and CINAHL databases as well as pre-print servers for studies investigating usage of ACEIs/ARBs in patients with COVID-19 compared to a control group of COVID-19 patients without ACEI/ARB use. COVID-19 related severity of disease, and death were identified as end points. Pooled odds ratios (OR) and their 95% confidence intervals (CI) were calculated using random-effects model. RESULTS: 21 studies were included in the meta-analysis. For mortality with ACEI/ARB use, the pooled odds ratio was 1.29 [0.89-1.87] p = 0.18 with heterogeneity of 91%, while the pooled OR for COVID-19 severity was 0.94 [0.59-1.50] p = 0.81 with heterogeneity of 89% (Figure 2). In combining both mortality and severe disease outcomes, the pooled odds ratio was 1.09 [0.80-1.48] p = 0.58 but with heterogeneity of 92%. EXPERT OPINION: Even on pooled analysis of both un-adjusted data, adjusted data(studies with matched controls) and taking into account factors such as risk of bias of studies via meta regression and sensitivity analyses, the results hold true that ACEI/ARB use is not associated with COVID-19 disease severity or mortality. To look for any potential beneficial effects, randomized controlled trials are needed. CONCLUSION: use of ACEI/ARB was not associated with increased mortality or severe COVID-19.