Cardiology

Packer, M. (2020). “Role of Impaired Nutrient and Oxygen Deprivation Signaling and Deficient Autophagic Flux in Diabetic CKD Development: Implications for Understanding the Effects of Sodium-Glucose Cotransporter 2-Inhibitors.” J Am Soc Nephrol 31(5): 907-919.

Full text of this article.

Growing evidence indicates that oxidative and endoplasmic reticular stress, which trigger changes in ion channels and inflammatory pathways that may undermine cellular homeostasis and survival, are critical determinants of injury in the diabetic kidney. Cells are normally able to mitigate these cellular stresses by maintaining high levels of autophagy, an intracellular lysosome-dependent degradative pathway that clears the cytoplasm of dysfunctional organelles. However, the capacity for autophagy in both podocytes and renal tubular cells is markedly impaired in type 2 diabetes, and this deficiency contributes importantly to the intensity of renal injury. The primary drivers of autophagy in states of nutrient and oxygen deprivation-sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia-inducible factors (HIF-1alpha and HIF-2alpha)-can exert renoprotective effects by promoting autophagic flux and by exerting direct effects on sodium transport and inflammasome activation. Type 2 diabetes is characterized by marked suppression of SIRT1 and AMPK, leading to a diminution in autophagic flux in glomerular podocytes and renal tubules and markedly increasing their susceptibility to renal injury. Importantly, because insulin acts to depress autophagic flux, these derangements in nutrient deprivation signaling are not ameliorated by antihyperglycemic drugs that enhance insulin secretion or signaling. Metformin is an established AMPK agonist that can promote autophagy, but its effects on the course of CKD have been demonstrated only in the experimental setting. In contrast, the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors may be related primarily to enhanced SIRT1 and HIF-2alpha signaling; this can explain the effects of SGLT2 inhibitors to promote ketonemia and erythrocytosis and potentially underlies their actions to increase autophagy and mute inflammation in the diabetic kidney. These distinctions may contribute importantly to the consistent benefit of SGLT2 inhibitors to slow the deterioration in glomerular function and reduce the risk of ESKD in large-scale randomized clinical trials of patients with type 2 diabetes.

Packer, M. (2020). “Interplay of adenosine monophosphate-activated protein kinase/sirtuin-1 activation and sodium influx inhibition mediates the renal benefits of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: A novel conceptual framework.” Diabetes Obes Metab 22(5): 734-742.

Full text of this article.

Long-term treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors slows the deterioration of renal function in patients with diabetes. This benefit cannot be ascribed to an action on blood glucose, ketone utilization, uric acid or systolic blood pressure. SGLT2 inhibitors produce a striking amelioration of glomerular hyperfiltration. Although initially ascribed to an action of these drugs to inhibit proximal tubular glucose reabsorption, SGLT2 inhibitors exert renoprotective effects, even in patients with meaningfully impaired levels of glomerular function that are sufficient to abolish their glycosuric actions. Instead, the reduction in intraglomerular pressures may be related to an action of SGLT2 inhibitors to interfere with the activity of sodium-hydrogen exchanger isoform 3, thereby inhibiting proximal tubular sodium reabsorption and promoting tubuloglomerular feedback. Yet, experimentally, such an effect may not be sufficient to prevent renal injury. It is therefore noteworthy that the diabetic kidney exhibits an important defect in adenosine monophosphate-activated protein kinase (AMPK) and sirtuin-1 (SIRT1) signalling, which may contribute to the development of nephropathy. These transcription factors exert direct effects to mute oxidative stress and inflammation, and they also stimulate autophagy, a lysosomally mediated degradative pathway that maintains cellular homeostasis in the kidney. SGLT2 inhibitors induce both AMPK and SIRT1, and they have been shown to stimulate autophagy, thereby ameliorating cellular stress and glomerular and tubular injury. Enhanced AMPK/SIRT1 signalling may also contribute to the action of SGLT2 inhibitors to interfere with sodium transport mechanisms. The dual effects of SGLT2 inhibitors on AMPK/SIRT1 activation and renal tubular sodium transport may explain the protective effects of these drugs on the kidney in type 2 diabetes.

Packer, M. (2020). “Are the benefits of SGLT2 inhibitors in heart failure and a reduced ejection fraction influenced by background therapy? Expectations and realities of a new standard of care.” Eur Heart J Apr 29. pii: ehaa344. [Epub ahead of print].

Full text of this article.

With the completion of two large-scale trials of SGLT2 inhibitors in patients with chronic heart failure and a reduced ejection fraction, we are poised to add yet another drug to our portfolio of cardioprotective agents. These disease-modifying drugs target important, but distinct, pathways that promote cardiomyocyte dysfunction and demise, and it is critical that physicians prescribe all of them in combination to all appropriate patients who do not have demonstrable intolerance. Yet, <1% of patients with chronic heart failure are receiving currently recommended drugs at doses that have been shown to prolong life.1 According to modelling estimates, when compared with no neurohormonal blockade, the use of a broad-based combination of disease-modifying drugs at target doses may reduce the risk of death by as much as 75%. It is time that physicians who treat patients with heart failure took notice. (Excerpt from text; no abstract available.)

McCullough, P. A. (2020). “Prevention Guidelines as Failed Minimal Standards of Care.” Am J Cardiol 125(9): 1441-1442.

Full text of this article.

The 2019 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease had the major focus of primary prevention defined as the outcomes of atherosclerotic cardiovascular disease (ASCVD) including acute coronary syndromes, myocardial infarction, stable or unstable angina, arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease of atherosclerotic origin. 1 Although there is attention to use of coronary artery calcium scoring to identify risk and in the absence of calcium selecting away from the use of lipid lowering therapy, there is a lack of impetus to leverage the body of information on lipid-lowering to prevent the development of atherosclerotic plaques. Thus, for physicians reading these guidelines, do they represent an adequate minimum standard of care for patients in community practice?

Mack, M. (2020). “Commentary: Bundled payment models in value-based care: A toe in the (Colombian) water!” J Thorac Cardiovasc Surg 159(5): 1931-1932.

Full text of this article.

Value in healthcare delivery is increased by improving quality, decreasing cost, or, optimally, both. Alternative payment models in which all costs associated with a procedure are “bundled,” with a focus on decreasing the variability of care, has demonstrated some success. (Excerpt from text; no abstract available.)