Cardiology

Ferreira, J.P., Mogensen, U.M., Jhund, P.S., Desai, A.S., Rouleau, J.L., Zile, M.R., Rossignol, P., Zannad, F., Packer, M., Solomon, S.D. and McMurray, J.J.V. (2020). “Serum Potassium in the PARADIGM-HF trial.” Eur J Heart Fail Aug 18. [Epub ahead of print.].

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BACKGROUND: We studied the association between potassium and outcomes, the effect of sacubitril/valsartan on potassium, and whether potassium level modified the effect of sacubitril/valsartan in patients with heart failure and a reduced ejection fraction in PARADIGM-HF. AIMS: We examined several outcomes including cardiovascular death, sudden-death, pump-failure death, non-cardiovascular death and heart failure hospitalization. METHODS: 8399 patients were randomized to either enalapril or sacubitril/valsartan. Potassium at randomization and follow-up was examined as a continuous and categorical variable (≤3.5, 3.6-4.0, 4.1-4.9, 5.0-5.4, and ≥5.5mmol/L) in various statistical models. Hyperkalemia was defined as K(+) ≥5.5mmol/L and hypokalemia as K(+) ≤3.5mmol/L. RESULTS: Compared to potassium 4.1-4.9mmol/L, both hypokalemia (HR 2.40, 95%CI 1.84-3.14) and hyperkalemia (HR 1.42, 1.10-1.83) were associated with a higher risk of cardiovascular death. However, potassium abnormalities were similarly associated with sudden death and pump failure death, as well as non-cardiovascular death and heart failure hospitalization. Sacubitril/valsartan had no effect on potassium overall. The benefit of sacubitril/valsartan over enalapril was consistent across the range of baseline potassium. CONCLUSIONS: Although both higher and lower potassium were independent predictors of cardiovascular death, potassium abnormalities may mainly be markers rather than mediators of risk of death.

Packer, M. (2020). “Uric Acid Is a Biomarker of Oxidative Stress in the Failing Heart: Lessons Learned from Trials With Allopurinol and SGLT2 Inhibitors.” J Card Fail Sep 2;S1071-9164(20)30948-9 [Epub ahead of print.].

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Hyperuricemia increases the risk of heart failure, and higher levels of serum uric acid are seen in patients who have worse ventricular function, functional capacity and prognosis. Heart failure is also accompanied by upregulation of xanthine oxidase, the enzyme that catalyzes the formation of uric acid and a purported source of reactive oxygen species. However, the available evidence does not support the premise that either uric acid or the activation of xanthine oxidase has direct injurious effects on the heart in the clinical setting. Xanthine oxidase inhibitors (allopurinol and oxypurinol) have had little benefit and may exert detrimental effects in patients with chronic heart failure in randomized controlled trials, and the more selective and potent inhibitor febuxostat increases the risk of cardiovascular death more than allopurinol. Instead, the available evidence indicates that changes in xanthine oxidase and uric acid are biomarkers of oxidative stress (particularly in heart failure) and that xanthine oxidase may provide an important source of nitric oxide that quenches the injurious effects of reactive oxygen species. A primary determinant of the cellular redox state is nicotinamide adenine dinucleotide (NAD+), whose levels drive an inverse relationship between xanthine oxidase and sirtuin-1 (SIRT1), a nutrient deprivation sensor that exerts important antioxidant and cardioprotective effects. Interestingly, sodium-glucose cotransporter 2 (SGLT2) inhibitors induce a state of nutrient deprivation that includes activation of sirtuin-1, suppression of xanthine oxidase and lowering of serum uric acid. The intermediary role of sirtuin-1 in both uric acid-lowering and cardioprotection may explain why, in mediation analyses of large-scale cardiovascular trials, the effect of SGLT2 inhibitors to decrease serum uric acid is a major predictor of the ability of these drugs to reduce serious heart failure events.

Mc Causland, F.R., Lefkowitz, M.P., Claggett, B., Anavekar, N.S., Senni, M., Gori, M., Jhund, P.S., McGrath, M.M., Packer, M., Shi, V., van Veldhuisen, D.J., Zannad, F., Comin-Colet, J., Pfeffer, M.A., McMurray, J.J.V. and Solomon, S.D. (2020). “Angiotensin-Neprilysin Inhibition and Renal Outcomes in Heart Failure with Preserved Ejection Fraction.” Circulation Aug 17. [Epub ahead of print.].

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Background: In patients with heart failure, chronic kidney disease (CKD) is common and associated with a higher risk of renal events than in patients without CKD. We assessed the renal effects of angiotensin/neprilysin inhibition in patients with heart failure and preserved ejection fraction (HFpEF) enrolled in PARAGON-HF. Methods: In this randomized, double-blind, event-driven trial, we assigned 4,822 patients with HFpEF to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein we present the results of the pre-specified renal composite outcome (time to first occurrence of either: ≥50% reduction in eGFR, end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope. Results: At randomization, eGFR was 63±19 ml/min/1.73m(2). At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio [HR], 0.50; 95%CI, 0.33 to 0.77; P=0.001). The treatment effect on the composite renal endpoint did not differ according to the baseline eGFR (<60 vs ≥ 60 ml/min/1.73 m(2) (P-interaction=0.92). The decline in eGFR was less for sacubitril/valsartan compared with valsartan (-1.8 [95%CI, -2.0 to -1.6] vs. -2.4 [95%CI, -2.6 to - 2.2] ml/min/1.73m(2)/year). Conclusions: In patients with HFpEF, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, compared with valsartan.

Packer, M. (2020). “Molecular, Cellular, and Clinical Evidence That Sodium-Glucose Cotransporter 2 Inhibitors Act as Neurohormonal Antagonists When Used for the Treatment of Chronic Heart Failure.” J Am Heart Assoc 9(16): e016270.

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure. Initially, these drugs were believed to have a profile similar to diuretics or hemodynamically active drugs, but they do not rapidly reduce natriuretic peptides or cardiac filling pressures, and they exert little early benefit on symptoms, exercise tolerance, quality of life, or signs of congestion. Clinically, the profile of SGLT2 inhibitors resembles that of neurohormonal antagonists, whose benefits emerge gradually during sustained therapy. In experimental models, SGLT2 inhibitors produce a characteristic pattern of cellular effects, which includes amelioration of oxidative stress, mitigation of mitochondrial dysfunction, attenuation of proinflammatory pathways, and a reduction in myocardial fibrosis. These cellular effects are similar to those produced by angiotensin converting enzyme inhibitors, β-blockers, mineralocorticoid receptor antagonists, and neprilysin inhibitors. At a molecular level, SGLT2 inhibitors induce transcriptional reprogramming of cardiomyocytes that closely mimics that seen during nutrient deprivation. This shift in signaling activates the housekeeping pathway of autophagy, which clears the cytosol of dangerous cytosolic constituents that are responsible for cellular stress, thereby ameliorating the development of cardiomyopathy. Interestingly, similar changes in cellular signaling and autophagic flux have been seen with inhibitors of the renin-angiotensin system, β-blockers, mineralocorticoid receptor antagonists, and neprilysin inhibitors. The striking parallelism of these molecular, cellular, and clinical profiles supports the premise that SGLT2 inhibitors should be regarded as neurohormonal antagonists when prescribed for the treatment of heart failure with a reduced ejection fraction.

Packer, M. (2020). “Role of ketogenic starvation sensors in mediating the renal protective effects of SGLT2 inhibitors in type 2 diabetes.” J Diabetes Complications 34(9): 107647.

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors ameliorate the progression of diabetic chronic kidney disease, but the mechanisms underlying this nephroprotective effect have not been fully elucidated. These drugs induce a fasting-like transcriptional paradigm, which includes activation of sirtuin-1 (SIRT1) and its downstream effectors, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and fibroblast growth factor 21 (FGF21). This triad of enzymes and transcription factors serve as master regulators of nutrient and cellular homeostasis, and each acts to enhance gluconeogenesis, fatty acid oxidation and ketogenesis, the hallmarks of treatment with SGLT2 inhibitors. At the same time, SIRT1/PGC-1α/FGF21 signaling also promotes autophagy, a lysosome-dependent degradative pathway that cleanses the cytosol of dysfunctional organelles. This action alleviates cellular stress, ameliorates inflammation, and is strikingly nephroprotective. Interestingly, type 2 diabetes is characterized by both a deficiency of SIRT1/PGC-1α signaling and an impairment of autophagic flux, thus explaining the high levels of oxidative stress in the diabetic kidney. SIRT1 gene polymorphisms have been linked with an increased risk of diabetic nephropathy in several epidemiological studies. Importantly, there is an inverse relationship between the activity of SGLT2 and signaling through the SIRT1/PGC-1α/FGF21 pathway, and SGLT2 inhibition leads to activation of these ketogenic nutrient deprivation sensors. Therefore, activation of SIRT1/PGC-1α/FGF21 may explain the effect of SGLT2 inhibitors not only to promote ketogenesis, but also to preserve renal function in type 2 diabetes.