Cardiology

Ronco, F., G. Tarantini and P. A. McCullough (2020). “Contrast induced acute kidney injury in interventional cardiology: an update and key guidance for clinicians.” Rev Cardiovasc Med 21(1): 9-23.

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Contrast-induced acute kidney injury (CI-AKI) is a serious complication that can affect outcome and prognosis of patients undergoing percutaneous diagnostic and interventional procedures in catheterization laboratories. There have been advancements in case definition and epidemiology. Additionally strategies have emerged that are positioned to have impact in the catheterization laboratory for patients undergoing cardiovascular procedures. The aim of this review is to provide the state-of-the-art of diagnosis, prevention and management of CI-AKI in interventional cardiology.

Roberts, C. S. and W. C. Roberts (2020). “The Layer Where the Coronary Arterial “Endarterectomy” Specimen Separates from the Underlying Artery.” Am J Cardiol 125(6): 999-1000.

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Described herein is a patient who had a coronary endarterectomy at the time of coronary artery bypass grafting. Histologic study of cross-sections of the endarterectomy specimen disclosed that the layer of separation of the endarterectomy specimen from the underlying native artery was in the media. This layer or plane of excision is virtually always the media irrespective of the artery having the endarterectomy. The procedure might better be called “endomediaectomy?”

Vaduganathan, M., P. S. Jhund, B. L. Claggett, M. Packer, J. Widimsky, P. Seferovic, A. Rizkala, M. Lefkowitz, V. Shi, J. J. V. McMurray and S. D. Solomon (2020). “A putative placebo analysis of the effects of sacubitril/valsartan in heart failure across the full range of ejection fraction.” Eur Heart J Mar 28. pii: ehaa184. [Epub ahead of print].

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AIMS: The PARADIGM-HF and PARAGON-HF trials tested sacubitril/valsartan against active controls given renin-angiotensin system inhibitors (RASi) are ethically mandated in heart failure (HF) with reduced ejection fraction and are used in the vast majority of patients with HF with preserved ejection fraction. To estimate the effects of sacubitril/valsartan had it been tested against a placebo control, we made indirect comparisons of the effects of sacubitril/valsartan with putative placebos in HF across the full range of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: We analysed patient-level data from the PARADIGM-HF and PARAGON-HF trials (n = 13 194) and the CHARM-Alternative and CHARM-Preserved trials (n = 5050, candesartan vs. placebo). The rate ratio (RR) of sacubitril/valsartan vs. putative placebo was estimated by the product of the RR for sacubitril/valsartan vs. RASi and the RR for RASi vs. placebo. Total HF hospitalizations and cardiovascular death were analysed using the negative binomial method. Treatment effects were estimated using cubic spline methods by ejection fraction as a continuous measure. Across the range of LVEF, sacubitril/valsartan was associated with a RR 0.54 [95% confidence interval (CI) 0.45-0.65] for the recurrent primary endpoint compared with putative placebo (P < 0.001). Treatment benefits of sacubitril/valsartan vs. putative placebo varied non-linearly with LVEF with attenuation of effects observed at LVEF above 60%. When analyzing data from PARADIGM-HF and CHARM-Alternative, the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 48% (95% CI 35-58%); P < 0.001. When analyzing data from PARAGON-HF and CHARM-Preserved (with LVEF >/= 45%), the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 29% (95% CI 7-46%); P = 0.013. Across the full range of LVEF, consistent effects were observed for time-to-first endpoints: first primary endpoint (RR 0.72, 95% CI 0.64-0.82), first HF hospitalization (RR 0.67, 95% CI 0.58-0.78), cardiovascular death (RR 0.76, 95% CI 0.64-0.89), and all-cause death (RR 0.83, 95% CI 0.71-0.96); all P < 0.02. CONCLUSION: This putative placebo analysis reinforces the treatment benefits of sacubitril/valsartan on risk of adverse cardiovascular events across the full range of LVEF, with most pronounced effects observed at a LVEF up to 60%.

Packer, M. (2020). “Role of Deranged Energy Deprivation Signaling in the Pathogenesis of Cardiac and Renal Disease in States of Perceived Nutrient Overabundance.” Circulation Mar 13. [Epub ahead of print].

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Sodium-glucose cotransporter 2 inhibitors reduce the risk of serious heart failure and adverse renal events, but the mechanisms that underlie this benefit are not understood. Treatment with SGLT2 inhibitors is distinguished by two intriguing features – ketogenesis and erythrocytosis. Both reflect the induction of a fasting-like and hypoxia-like transcriptional paradigm that is capable of restoring and maintaining cellular homeostasis and survival. In the face of perceived nutrient and oxygen deprivation, cells activate low-energy sensors, which include sirtuin-1 (SIRT1), adenosine monophosphate-activated protein kinase (AMPK) and hypoxia inducible factors (especially HIF-2alpha); these enzymes and transcription factors are master regulators of hundreds of genes and proteins that maintain cellular homeostasis. The activation of SIRT1 (through its effects to promote gluconeo-genesis and fatty acid oxidation) drives ketogenesis, and working in concert with AMPK, it can directly inhibit inflammasome activation and maintain mitochondrial capacity and stability. Hypoxia inducible factors act to promote oxygen delivery (by stimulating erythropoietin and erythrocytosis) and decrease oxygen consumption. Most importantly, the activation of SIRT1, AMPK and HIF-2alpha enhances autophagy, a lysosome-dependent degradative pathway that removes dangerous constituents, particularly damaged mitochondria and peroxisomes, which are major sources of oxidative stress and triggers of cellular dysfunction and death. SIRT1 and AMPK also act on sodium transport mechanisms to reduce intracellular sodium concentrations. Interestingly, type 2 diabetes, obesity, chronic heart failure and chronic kidney failure are characterized by the accumulation of intracellular glucose and lipid intermediates that are perceived by cells as indicators of energy overabundance. The cells respond by down-regulating SIRT1, AMPK and HIF-2alpha, thus leading to an impairment of autophagic flux and acceleration of cardiomyopathy and nephropathy. SGLT2 inhibitors reverse this maladaptive signaling by triggering a state of fasting and hypoxia mimicry, which includes activation of SIRT1, AMPK and HIF-2alpha, enhanced autophagic flux, reduced cellular stress, decreased sodium influx into cells, and restoration of mitochondrial homeostasis. This mechanistic framework clarifies the findings of large-scale randomized trials and the close association of ketogenesis and erythrocytosis with the cardioprotective and renoprotective benefits of these drugs.

Packer, M. (2020). “Critical Examination of Mechanisms Underlying the Reduction in Heart Failure Events With SGLT2 Inhibitors: Identification of a Molecular Link Between Their Actions to Stimulate Erythrocytosis and to Alleviate Cellular Stress.” Cardiovasc Res Apr 3. pii: cvaa064. [Epub ahead of print].

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of serious heart failure events, even though SGLT2 is not expressed in the myocardium. This cardioprotective benefit is not related to an effect of these drugs to lower blood glucose, promote ketone body utilization or enhance natriuresis, but it is linked statistically with their action to increase hematocrit. SGLT2 inhibitors increase both erythropoietin and erythropoiesis, but the increase in red blood cell mass does not directly prevent heart failure events. Instead, erythrocytosis is a biomarker of a state of hypoxia mimicry, which is induced by SGLT2 inhibitors in manner akin to cobalt chloride. The primary mediators of the cellular response to states of energy depletion are sirtuin-1 (SIRT1) and hypoxia inducible factors (HIF-1alpha/HIF-2alpha). These master regulators promote the cellular adaptation to states of nutrient and oxygen deprivation, promoting mitochondrial capacity and minimizing the generation of oxidative stress. Activation of SIRT1 and HIF-1alpha/HIF-2alpha also stimulates autophagy, a lysosome-mediated degradative pathway that maintains cellular homeostasis by removing dangerous constituents (particularly unhealthy mitochondria and peroxisomes), which are a major source of oxidative stress and cardiomyocyte dysfunction and demise. SGLT2 inhibitors can activate SIRT-1 and and stimulate autophagy in the heart, and thereby, favorably influence the course of cardiomyopathy. Therefore, the linkage between erythrocytosis and the reduction in heart failure events with SGLT2 inhibitors may be related to a shared underlying molecular mechanism that is triggered by the action of these drugs to induce a perceived state of oxygen and nutrient deprivation.