Baylor Heart and Vascular Institute

Packer, M. (2020). “Mechanisms Leading to Differential Hypoxia Inducible Factor Signaling in the Diabetic Kidney: Modulation by SGLT2 Inhibitors and Hypoxia Mimetics.” Am J Kidney Dis Jul 22;S0272-6386(20)30849-0. [Epub ahead of print.].

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert important renoprotective effects in the diabetic kidney, which cannot be readily explained by their actions to lower blood glucose, blood pressure or glomerular filtration pressures. Their effects to promote erythrocytosis suggests that these drugs act on hypoxia inducible factors (specifically, HIF-1α and HIF-2α), which may underlie their ability to reduce the progression of nephropathy. Type 2 diabetes is characterized by renal hypoxia, oxidative and endoplasmic reticulum stress, and defective nutrient deprivation signaling, which (acting in concert) are poised to cause both activation of HIF-1α and suppression of HIF-2α. This shift in the balance of HIF-1α/HIF-2α activities promotes proinflammatory and profibrotic pathways in glomerular and renal tubular cells. SGLT2 inhibitors alleviate renal hypoxia and cellular stress and enhance nutrient deprivation signaling, which collectively may explain their actions to suppress HIF-1α and activate HIF-2α, and thereby, augment erythropoiesis, while muting organellar dysfunction, inflammation and fibrosis. Cobalt chloride, a drug conventionally classified as a hypoxia-mimetic, has a profile of molecular and cellular actions in the kidney that is similar to those of SGLT2 inhibitors. Therefore, many of renoprotective benefits of SGLT2 inhibitors may be related to their effect to promote oxygen deprivation signaling in the diabetic kidney.

Packer, M. (2020). “Beth Levine In Memoriam.” Eur Heart J 41(28): 2617.

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Beth Levine was widely recognized as a world leader in the field of autophagy research. Over a span of two decades, her findings repeatedly deciphered the mysteries of the molecular pathways that were essential to cellular health and survival. Her laboratory identified conserved mechanisms underlying the regulation of autophagy and provided the first evidence that autophagy genes are important in antiviral host defence, tumour suppression, lifespan extension, apoptotic corpse clearance, metazoan development, and the beneficial metabolic effects of exercise. In addition, she developed a potent autophagy-inducing cell permeable peptide, Tat-beclin 1, which has been shown to have numerous potential therapeutic applications in a range of human diseases. [No abstract; excerpt from article].

Roberts, W. C. (2020). “Importance of Acquiring Financial Security for Physicians.” Am J Med Jul 16;S0002-9343(20)30601-X. [Epub ahead of print.].

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This review tries to make the case that physicians should be adequately rewarded financially so that they can have a clear fiduciary responsibility to do only what is best for their patients without unseemly personal financial gain. To develop financial security physicians need to save a portion of their income regularly to invest. The stock market is the best place to increase one’s monetary worth over a long period.

Roberts, W. C. and S. Ilyas (2020). “Examining One’s Own Heart.” Am J Cardiol 127: 41-51.

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At Baylor University Medical Center (BUMC) in Dallas, we began showing heart transplantation recipients their hearts in 2010. Since that time, we have shown 157 patients their own hearts (through March 2020). The exercise was initiated not by me or another physician but by a heart transplant recipient, Mr. Marvin Jones. I was walking in the corridor near the cardiac catheterization waiting room and next to me was Mr. Jones. He leaned over and asked if I was Dr. Roberts. “Yes,” I answered. He said, “I understand that you have my heart.” I invited him to our weekly cardiovascular pathology conference so that several physicians could observe a person examining their own heart.1 Subsequently, the heart transplant cardiologists, surgeons, their nurses and coordinators have gotten on board to encourage their heart transplant patients to “Call Dr. Roberts” to make the arrangements to view their own hearts. Some of the patients had their heart transplants many years earlier. Fortunately, BUMC has provided us with a heart storage facility and all transplant and autopsy hearts have resided there since 1993. Thus, all heart transplant recipients who want to see their hearts since that time can have their requests fulfilled. [No abstract; excerpt from article].

Vaduganathan, M., B. L. Claggett, P. S. Jhund, J. W. Cunningham, J. Pedro Ferreira, F. Zannad, M. Packer, G. C. Fonarow, J. J. V. McMurray and S. D. Solomon (2020). “Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials.” Lancet May 21;S0140-6736(20)30748-0. [Epub ahead of print].

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BACKGROUND: Three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor-neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF. METHODS: In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker). FINDINGS: The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30-0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 [95% CI 0·37-0·67]), hospital admission for heart failure alone (0·32 [0·24-0·43]), and all-cause mortality (0·53 [0·40-0·70]). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy. INTERPRETATION: Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard.