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• Empagliflozin and Elderly Patients With Preserved Ejection Fraction Heart Failure: Is Age Just a Number? - Medscape, 10/17/22 - "Major molecular regulators of cellular lifespan are sirtuin-1 (SIRT1) and mammalian target of rapamycin complex 1 (mTORC1). In a nutrient-deficient or calorie-restricted state, SIRT1 activation, along with adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) set forth a cascade of downstream target activations culminating in deceleration of cell aging. Suppression of the mTORC1 pathway further augments SIRT1-activated autophagy, the lysosome-utilizing process of clearing misfolded proteins from the cytosol. Without healthy autophagy, oxidative stress contributes to impaired endothelial nitric oxide (NO) pathways, inflammation, cell death, fibrosis, and cardiomyopathy (adapted from Gevaert et al1). SGLT2 inhibitors are hypothesized to contribute to activation of SIRT1 and suppression of mTORC1 pathways.10 Akt = protein kinase B; HFpEF = heart failure with preserved ejection fraction; ROS = reactive oxygen species ... Aside from the obvious bedside clinical implications, the findings of Bohm et al[7] cause us to wonder more about the mechanistic impact of SGLT2 inhibition on multiple cardiovascular and noncardiovascular therapeutic targets. SGLT2 inhibitors induce glycosuria and reduce insulin levels, which promotes a ketogenic and fatty acid oxidation state, mimicking calorie restriction physiology, which has been associated with cellular stress resistance, attenuation of cellular senescence, and reduced oxidative stress-induced tissue damage.[9] Such pathway activation is hypothesized to assuage metabolic disease, alleviate endothelial and vascular inflammation, and mitigate the clinically observed arterial stiffness associated with the HFpEF syndrome" - See empagliflozin inhousepharmacy.vu.
• Dose-Response to Sacubitril/Valsartan in Patients With Heart Failure and Reduced Ejection Fraction - J Am Coll Cardiol 2022 Oct 18 - "The average daily dose was 112 mg in Tertile 1 (low dose), 342 mg in Tertile 2 (moderate dose), and 379 mg in Tertile 3 (high dose). Similar changes in prognostic biomarkers were observed in all dose tertiles. Gains in Kansas City Cardiomyopathy Questionnaire-23 scores were comparable regardless of dose category. Consistent reverse cardiac remodeling in all dose categories occurred; the median absolute left ventricular EF improvement across HF dose groups was 9.3%, 8.7%, and 10.2%, for low, moderate, and high doses, respectively; similar improvements in left atrial and ventricular volumes and E/e' were also observed across dose categories"
• Early Signal of Benefit for Empagliflozin in Acute MI: EMMY - Medscape, 9/2/22 - "SGLT2 inhibitors have shown benefits in patients with heart failure (HF) across the spectrum of left ventricular function, reducing the risk for HF hospitalization and cardiovascular death in low ejection fraction (EF) in last year's EMPEROR-Preserved and the newly reported DELIVER trial. SGLT2 inhibitors also lower the risk for incident HF in such high-risk groups as those with type 2 diabetes or chronic kidney disease ... Left ventricular EF improved in both groups, with those assigned to empagliflozin having a 1.5% absolute higher EF at week 26 (P = .029). The E/e′ ratio was significantly improved, being 6.8% lower than placebo ... The structural markers of left ventricular end systolic volume (–7.5 mL; P = .0003) and LV end diastolic volume (–9.7 mL; P = .0015) improved as well, and were smaller in the empagliflozin group" - See empagliflozin inhousepharmacy.vu.
• Effects of Ubiquinol and/or D-ribose in Patients With Heart Failure With Preserved Ejection Fraction - Am J Cardiol 2022 May 26 - "Patients with heart failure with preserved ejection fraction (HFpEF) have few pharmacologic therapies, and it is not known if supplementing with ubiquinol and/or d-ribose could improve outcomes ... Group 1 received placebo ubiquinol capsules and d-ribose powder, Group 2 received ubiquinol capsules (600 mg/d) and placebo d-ribose powder, Group 3 received placebo ubiquinol capsules with d-ribose powder (15 g/d), and Group 4 received ubiquinol capsules and d-ribose powder ... Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score ... Treatment with ubiquinol and/or d-ribose significantly improved the KCCQ clinical summary score (17.30 to 25.82 points), vigor score (7.65 to 8.15 points), and EF (7.08% to 8.03%) and reduced B-type natriuretic peptides (-72.02 to -47.51) and lactate/adenosine triphosphate ratio (-4.32 to -3.35 × 10-4). There were no significant increases in the septal E/e' or the 6-minute walk test. In conclusion, ubiquinol and d-ribose reduced the symptoms of HFpEF and increased the EF. These findings support the use of these supplements in addition to standard therapeutic treatments for patients with HFpEF" - See ubiquinol products at Amazon.com and D-ribose at Amazon.com.
• Effects of Sacubitril/Valsartan on clinical symptoms, echocardiographic parameters, and outcomes in HFrEF and HFmrEF patients with coronary heart disease and chronic kidney disease - Curr Med Res Opin 2021 Mar 25 - "To compare the effects of Angiotensin Receptor-Neprilysin inhibitor (ARNI) on the clinical symptoms, echocardiographic parameters, and outcomes (cardiovascular death and hospitalization) in heart failure with reduced ejection fraction (HFrEF) and heart failure with mid-range ejection fraction (HFmrEF) patients with coronary heart disease and chronic kidney disease ... A statistically significant increase of 68.8% was observed in left ventricular ejection fraction (LVEF) in HFrEF patients compared to that in HFmrEF patients, with an increase of 27.2% at 8 months of follow-up. Sacubitril/valsartan significantly reduced left ventricular end-systolic volumes (LVESV) in HFrEF patients unlike in HFmrEF patients. The decrease in LVESV was 28.8% in HFrEF patients and 17.1% in HFmrEF patients. A significant reduction in the prevalence of severe secondary mitral regurgitation (EROA >0.4cm2) was observed in HFrEF compared to that in HFmrEF patients with the use of sacubitril/valsartan. A reduction of 15.6% was observed in HFrEF patients, whereas a reduction of 7.1% was observed in HFmrEF patients. Improvement in functional classification (NYHA) was observed during follow-up. The prevalence of (NYHA III) reduced from 50% to 15.7% in HFrEF patients, whereas a reduction from 21.1% to 8.8% was observed in HFmrEF patients. There was a significant reduction in NT-proBNP in HFrEF patients compared to that in HFmrEF patients. A reduction of 52% was observed in HFrEF patients, whereas a reduction of 28.7% was observed in HFmrEF pateints. Sacubitril/valsartan reduced primary endpoint events in both groups. The prevalence of HF-related hospitalization was higher in HFrEF than in HFmrEF patients: 12.1% vs 7.5%, respectively. The prevalence of CV death in HFrEF vs HFmrEF patients was 3.7% vs 0.5%, respectively. Cardiovascular (CV) was higher in patients with atrial fibrillation in both groups"
• Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction - J Am Coll Cardiol 2021 Jan 26 - "Empagliflozin was associated with a significant reduction of LV end-diastolic volume (-25.1 ± 26.0 ml vs. -1.5 ± 25.4 ml for empagliflozin vs. placebo, respectively; p < 0.001) and LV end-systolic volume (-26.6 ± 20.5 ml vs. -0.5 ± 21.9 ml for empagliflozin vs. placebo; p < 0.001). Empagliflozin was associated with reductions in LV mass (-17.8 ± 31.9 g vs. 4.1 ± 13.4 g, for empagliflozin vs. placebo, respectively; p < 0.001) and LV sphericity, and improvements in LV ejection fraction (6.0 ± 4.2 vs. -0.1 ± 3.9; p < 0.001). Patients who received empagliflozin had significant improvements in peak O2 consumption (1.1 ± 2.6 ml/min/kg vs. -0.5 ± 1.9 ml/min/kg for empagliflozin vs. placebo, respectively; p = 0.017), oxygen uptake efficiency slope (111 ± 267 vs. -145 ± 318; p < 0.001), as well as in 6-min walk test (81 ± 64 m vs. -35 ± 68 m; p < 0.001) and quality of life (Kansas City Cardiomyopathy Questionnaire-12: 21" - See empagliflozin inhousepharmacy.vu.
• Tolerability and efficacy of Sacubitril/ Valsartan in clinical practice - Intern Med J. 2020 Jan 6 - "Heart failure is a major cause of morbidity and mortality. Sacubitril/Valsartan has demonstrated reductions in HF hospitalisation, and all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF) ... 14% of patients were able to able to achieve maximal dose (97/103 mg twice daily) whilst 37% remained on 49/51 mg and 23% on 24/26 mg. The mean SBP reduced from 118 ± 18 mmHg to 109 ± 15 mmHg with symptomatic hypotension (30%) being the most common side effect leading to dose reduction or drug cessation. Left ventricular ejection fraction (LVEF) improved from 29.1 ± 9.7% to 33.8 ± 9.9% (p < 0.05) on drug. There was also a significant improvement in quality of life scores; EQ5D-VAS 40 pre vs 67 post Sacubitril/Valsartan (p < 0.05), and New York Heart Association class (p < 0.05). Importantly, ten patients lost an existing indication for device based therapy after treatment with Sacubitril/Valsartan ... Sacubitril/Valsartan is a much needed therapeutic advancement in the treatment of HF. Our study indicates it is well tolerated with improvements in cardiac function and symptoms. Sacubitril/Valsartan could redefine the definition of "optimal medical therapy' when assessing patients for device based therapies"
• Combination therapy using tafamidis and neurohormonal blockers for cardiac amyloidosis and a reduced ejection fraction: a case report - J Int Med Res 2022 Jul - "We report a 77-year-old man who was diagnosed with wild-type cardiac amyloidosis and systolic dysfunction with a left ventricular ejection fraction of 27%. Following 6-month medical therapy of tafamidis 80 mg and neurohormonal blockers (carvedilol 5.0 mg, enalapril 2.5 mg, and spironolactone 25 mg), the left ventricular ejection fraction improved to 55%. Tafamidis-incorporated neurohormonal blocker therapy might be a promising strategy to facilitate cardiac reverse remodeling in patients with cardiac amyloidosis and systolic dysfunction"
  • Pfizer's blockbuster-to-be Vyndaqel is too costly for heart patients, study suggests - fiercepharma.com, 6/19/20 - "Pfizer’s tafamidis arrived in the U.S. in 2019 with a vastly discounted list price over rival transthyretin amyloidosis drugs. But its $225,000-a-year tag still seems too much for many heart patients"

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