Cardiology

Packer, M. and P. A. Grayburn (2020). “New Evidence Supporting a Novel Conceptual Framework for Distinguishing Proportionate and Disproportionate Functional Mitral Regurgitation.” JAMA Cardiol Feb 19. [Epub ahead of print].

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Importance: Traditionally, physicians distinguished between mitral regurgitation (MR) as a determinant of outcomes and MR as a biomarker of left-ventricular (LV) dysfunction by designating the lesions as primary or secondary, respectively. In primary MR, leaflet abnormalities cause the MR, resulting in modest increases in LV end-diastolic volume over time, whereas in patients with classic secondary MR, LV dysfunction and dilatation lead to MR without structural leaflet abnormalities. However, certain patients with global LV disease (eg, those with left bundle branch block or regional wall motion abnormalities) have the features of primary MR and might respond favorably to interventions that aim to restore the proper functioning of the mitral valve apparatus. Observations: A novel conceptual framework is proposed, which classifies patients with meaningful LV disease based on whether the severity of MR is proportionate or disproportionate to the LV end-diastolic volume. Treatments that reduce LV volumes (eg, neurohormonal antagonists) are effective in proportionate MR but not disproportionate MR. Conversely, procedures that restore mitral valve function (eg, cardiac resynchronization and mitral valve repair) are effective in patients with disproportionate MR but not in those with proportionate MR. The proposed framework explains the discordant findings in the Multicentre Randomized Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation (MITRA-FR) and the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trials; differences in procedural success and medical therapy in the 2 studies cannot explain the different results. In addition, the small group of patients in the COAPT trial who had the features of proportionate MR and were similar to those enrolled in the MITRA-FR trial did not respond favorably to transcatheter mitral valve repair. Conclusions and Relevance: The characterization of patients with functional MR into proportionate and disproportionate subtypes may explain the diverse range of responses to drug and device interventions that have been observed.

Packer, M. (2020). “SGLT2 Inhibitors Produce Cardiorenal Benefits by Promoting Adaptive Cellular Reprogramming to Induce a State of Fasting Mimicry: A Paradigm Shift in Understanding Their Mechanism of Action.” Diabetes Care 43(3): 508-511.

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There is compelling evidence that sodium–glucose cotransporter 2 (SGLT2) inhibitors exert cardioprotective and renoprotective effects that are far greater than expected based on their effects on glycemia or glycosuria. In large-scale randomized controlled trials, SGLT2 inhibitors reduce the risk of hospitalizations for heart failure by ∼30% and often decrease the risk of cardiovascular death. This benefit is particularly striking in patients who have the most marked impairment of systolic function prior to treatment. In parallel, SGLT2 inhibitors also reduce the risk of end-stage renal events, including the occurrence of renal death and the need for dialysis or renal transplantation by ∼30%. This benefit is seen even when glomerular filtration rates are sufficiently low to abolish the glycosuric effect of these drugs. These cardiorenal benefits cannot be explained by an action of SGLT2 inhibitors to lower blood glucose, since similar effects are not seen with antidiabetes drugs that have greater antihyperglycemic actions. Additionally, they cannot be ascribed to a natriuretic action, since these drugs exert only a modest effect on plasma volume or on circulating natriuretic peptides . . . Three lines of clinical evidence support the hypothesis that SGLT2 inhibitors exert their effects by the activation of low-energy sensors, which are responsible for mimicking a fasting transcriptional paradigm. First, SGLT2 inhibitors induce a loss of calories in the urine, and glycosuria is accompanied by a decrease of glucagon synthesis (often with the promotion of glycolysis), increased fatty acid oxidation, and the shrinkage of adipose tissue depots, including the alleviation of organ steatosis. Viewed from this perspective, the ketonemia seen with these drugs is not the source of an efficient fuel but instead is a biomarker of a fasting-like transcriptional state. Second, SGLT2 inhibitors may not only deceive cells into believing that they are fasting but also that they are hypoxic. Oxygen deprivation (like nutrient deprivation) stimulates AMPK and SIRT1. The latter activates hypoxia-inducible factor-2α (HIF-2α) and possibly also hypoxia-inducible factor-1α (HIF-1α) under certain conditions; these represent the principal stimuli for erythropoietin synthesis. Thus, the erythrocytosis that is seen with SGLT2 inhibitors may represent a biomarker for enhanced SIRT1 signaling and its organ-protective effects. Such a relationship may explain why, in statistical mediation analyses, erythrocytosis has been the most powerful predictor of the action of SGLT2 inhibitors to reduce heart failure events in large-scale trials. Third, metformin also stimulates autophagy, primarily by activating AMPK and SIRT1 and suppressing Akt/mTOR. Metformin exerts both cardioprotective and renoprotective effects in experimental models, and it favorably influences the evolution of heart failure and nephropathy in cohort studies. The overlap in the mechanism of action between metformin and SGLT2 inhibitors (with respect to AMPK/SIRT1 activation and autophagy) may explain why the magnitude of the benefit of SGLT2 inhibitors in large-scale trials may be attenuated in patients receiving metformin. However, metformin suppresses HIF-1α, thus distinguishing its action from that of SGLT2 inhibitors; this effect may explain why metformin modestly decreases hematocrit, whereas SGLT2 inhibitors induce erythrocytosis. However, since both HIF-1α and HIF-2α appear to induce autophagy in a manner than is independent of AMPK, it is possible that enhanced HIF-1α/HIF-2α signaling by SGLT2 inhibitors may amplify the autophagic flux that is already augmented by AMPK/SIRT1, thereby contributing importantly to the striking cardiorenal benefits of these drugs, which are not seen with other glucose-lowering agents. (Excerpts from text, p. 508, 510; no abstract available.)

Packer, M. (2020). “Mitigation of the Adverse Consequences of Nutrient Excess on the Kidney: A Unified Hypothesis to Explain the Renoprotective Effects of Sodium-Glucose Cotransporter 2 Inhibitors.” Am J Nephrol Mar 3. [Epub ahead of print].

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The 2 most common causes of chronic kidney disease worldwide (type 2 diabetes and obesity) are states of nutrient excess, suggesting that fuel overabundance leads to deleterious effects on the structure and function of the kidneys. Three pathophysiological pathways may potentially explain this linkage. First, both obesity and type 2 diabetes are characterized by glomerular hyperfiltration, which may result from increased proximal tubular reabsorption of sodium (due to enhanced glucose and sodium transport) coupled with activation of the renin-angiotensin system. Second, both obesity and type 2 diabetes are characterized by adipose tissue expansion and inflammation, followed by the augmented synthesis and release of lipid intermediates and proinflammatory adipocytokines that can have deleterious effects on the kidney. Third, states of nutrient excess cause a diminution in the activation of the energy sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). The result is a suppression of autophagy, a lysosomal degradative pathway that is responsible for the clearance of damaged organelles that are an important source of oxidative and endoplasmic reticulum stress and inflammation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors induces a transcriptional paradigm that mimics fasting, which leads to the amelioration of glomerular hyperfiltration and adipose tissue inflammation as well as augmentation of AMPK/SIRT1 signaling and autophagy, thereby acting to mute organellar and cellular stress in the kidney. Therefore, SGLT2 inhibitors are positioned to antagonize all 3 pathways by which nutrient excess can lead to nephropathy.

Packer, M. (2020). “Epicardial Adipose Tissue Inflammation Can Cause the Distinctive Pattern of Cardiovascular Disorders Seen in Psoriasis.” Am J Med 133(3): 267-272.

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Psoriasis is a systemic inflammatory disorder that can target adipose tissue; the resulting adipocyte dysfunction is manifest clinically as the metabolic syndrome, which is present in approximately 20%-40% of patients. Epicardial adipose tissue inflammation is likely responsible for a distinctive pattern of cardiovascular disorders consisting of 1) accelerated coronary atherosclerosis leading to myocardial infarction, 2) atrial myopathy leading to atrial fibrillation and thromboembolic stroke, and 3) ventricular myopathy leading to heart failure with a preserved ejection fraction. If cardiovascular inflammation drives these risks, then treatments that focus on blood pressure, lipids, and glucose will not ameliorate the burden of cardiovascular disease in patients with psoriasis, especially in those who are young and have severe inflammation. Instead, interventions that alleviate systemic and adipose tissue inflammation may not only minimize the risks of atrial fibrillation and heart failure but may also have favorable effects on the severity of psoriasis. Viewed from this perspective, the known link between psoriasis and cardiovascular disease is not related to the influence of the individual diagnostic components of the metabolic syndrome.

Packer, M. (2020). “Does Metformin Interfere With the Cardiovascular Benefits of SGLT2 Inhibitors? Questions About Its Role as the Cornerstone of Diabetes Treatment.” Am J Med Feb 12. [Epub ahead of print].

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Metformin is widely used as first-line therapy to lower blood glucose in type 2 diabetes, because it is inexpensive and does not cause weight gain. However, the evidentiary basis for the primacy of metformin is not persuasive. A clinical trial performed >20 years ago reported that initial therapy with metformin reduced the risk of myocardial infarction when compared with other glucose-lowering drugs. However, this finding represented a subgroup analysis that relied only a small number of events, with confidence intervals that did not exclude a neutral effect. Furthermore, the benefit of metformin was not confirmed in a parallel trial in which the drug was used as second-line therapy. Importantly, there is little evidence to support a benefit of metformin to prevent the most serious cardiovascular complication of type 2 diabetes — heart failure. Observational studies have reported that metformin use is associated with a lower risk of heart failure and its adverse consequences; however, these reports are difficult to interpret, since it is likely that physicians selectively prescribed metformin to low-risk patients, due to fears that its use causes lactic acidosis in patients with left ventricular dysfunction. Furthermore, in these studies, metformin was compared with insulin-signaling antihyperglycemic drugs that have themselves been linked to an increased risk of heart failure; thus, the finding of a lower risk of heart failure in metformin users may have been due to an adverse effect of the comparator rather than a benefit of the biguanide. Importantly, in two large meta-analyses of randomized controlled trials, metformin did not did not influence the risk or consequences of heart failure, and the use of metformin with sulfonylureas has been accompanied by an increased risk of death both in observational studies and clinical trials. In light of these observations, there is no reliable evidence that metformin prevents or ameliorates the clinical course of heart failure in type 2 diabetes. (Excerpt from text, n.p.; no abstract available.)