Research Spotlight

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.

Packer, M. (2020). “Characterization, Pathogenesis, and Clinical Implications of Inflammation-Related Atrial Myopathy as an Important Cause of Atrial Fibrillation.” J Am Heart Assoc Apr 7;9(7):e015343. [Epub 2020 Apr 3].

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Historically, atrial fibrillation has been observed in clinical settings of prolonged hemodynamic stress, eg, hypertension and valvular heart disease. However, recently, the most prominent precedents to atrial fibrillation are metabolic diseases that are associated with adipose tissue inflammation (ie, obesity and diabetes mellitus) and systemic inflammatory disorders (ie, rheumatoid arthritis and psoriasis). These patients typically have little evidence of left ventricular hypertrophy or dilatation; instead, imaging reveals abnormalities of the structure or function of the atria, particularly the left atrium, indicative of an atrial myopathy. The left atrium is enlarged, fibrotic and noncompliant, potentially because the predisposing disorder leads to an expansion of epicardial adipose tissue, which transmits proinflammatory mediators to the underlying left atrium. The development of an atrial myopathy not only leads to atrial fibrillation, but also contributes to pulmonary venous hypertension and systemic thromboembolism. These mechanisms explain why disorders of systemic or adipose tissue inflammation are accompanied an increased risk of atrial fibrillation, abnormalities of left atrium geometry and an enhanced risk of stroke. The risk of stroke exceeds that predicted by conventional cardiovascular risk factors or thromboembolism risk scores used to guide the use of anticoagulation, but it is strongly linked to clinical evidence and biomarkers of systemic inflammation.

Naesens, M., J. Friedewald, V. Mas, B. Kaplan and M. M. Abecassis (2020). “A Practical Guide to the Clinical Implementation of Biomarkers for Subclinical Rejection Following Kidney Transplantation.” Transplantation 104(4): 700-707.

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Noninvasive biomarkers are needed to monitor stable patients following kidney transplantation (KT), as subclinical rejection, currently detectable only with invasive surveillance biopsies, can lead to chronic rejection and graft loss. Several biomarkers have recently been developed to detect rejection in KT recipients, using different technologies as well as varying clinical monitoring strategies defined as “context of use (COU).” The various metrics utilized to evaluate the performance of each biomarker can also vary, depending on their intended COU. As the use of molecular biomarkers in transplantation represents a new era in patient management, it is important for clinicians to better understand the process by which the incremental value of each biomarkers is evaluated to determine its potential role in clinical practice. This process includes but is not limited to an assessment of clinical validity and utility, but to define these, the clinician must first appreciate the trajectory of a biomarker from bench to bedside as well as the regulatory and other requirements needed to navigate this course successfully. This overview summarizes this process, providing a framework that can be used by clinicians as a practical guide in general, and more specifically in the context of subclinical rejection following KT. In addition, we have reviewed available as well as promising biomarkers for this purpose in terms of the clinical need, COU, assessment of biomarker performance relevant to both the need and COU, assessment of biomarker benefits and risks relevant to the COU, and the evidentiary criteria of the biomarker relevant to the COU compared with the current standard of care. We also provide an insight into the path required to make biomarkers commercially available once they have been developed and validated so that they used by clinicians outside the research context in every day clinical practice.