Nicotinamide for the treatment of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD+ precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD+ precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans.

Impaired Myocardial Bioenergetics in HFpEF and the Role of Antioxidants

Heart failure with preserved ejection fraction (HFpEF) is a significant cardiovascular condition for more than 50% of patients with heart failure. Currently, there is no effective treatment to decrease morbidity and mortality rates associated with HFpEF because of its pathophysiological heterogeneity. Recent evidence shows that deficiency in myocardial bioenergetics is one of the key pathophysiological factors contributing to diastolic dysfunction in HFpEF. Another known mechanism for HFpEF is an overproduction of free radicals, specifically reactive oxygen species. To reduce free radical formation, antioxidants are often used. This article is a summative review of the recent relevant literature that addresses cardiac bioenergetics, deficiency in myocardial bioenergetics, and increased reactive oxygen species associated with HFpEF and the promising potential use of antioxidants in managing this condition.

Abstract 18663: Myocardial Heterogeneity in Heart With Postinfarction LV Remodeling and its Response to Cell Therapy

Rationale and Objective: Human induced pluripotent stem cells (hiPSCs) hold promise for myocardial repair following injury. Here, we investigated the functional impact and myocardial heterogeneity of bioenergetics using a porcine model of post infarction LV remodeling, and 2 dimensional chemical shift imaging (2D CSI) P-31 MR spectroscopy. Methods and Results: Ischemia-reperfusion (I/R) injury was surgically induced by occlusion distal LAD (OCCL) for 60 minutes in female Yorkshire farm swine (≈15kg), then randomly assigned to experimental groups: 1) 16 million human induced pluripotent stem cells (hiPSC) derived cardio myocytes (CMs), smooth muscle cells (SMC) and Endothelia cells (ECs) were directly myocardial injected through an epicardial fibrin patch (P+Cell, n= 4), 2) open patch (fibrin patch with no cell) were placed over the injury site (P w/o Cell, n=4). Size matched normal (n=9) and OCCL only (n=5) pigs were also studied. Four weeks after I/R, 2D CSI MRS studies were performed in a 9.4T/ 65 cm bore magnet. In vivo myocardial energetic mapping was achieved using 31 P 2D CSI. To measure the forward flux rate PCr to ATP, 2D CSI data were acquired with or without saturation on ATPγ resonance. I/R injury has a heterogeneous effect on LV myocardial bioenergetics. Myocardial creatine phosphate (PCr)/ATP ratio is significantly decreased in border zone (BZ) of the infarction than the myocardial areas remote from the scar (RZ) in cell treated and patch only groups (1.54+/- 0.05 vs 2.25 +/- 0.10, 1.49+/-0.07 vs 2.34 +/- 0.07, BZ vs RZ, p<0.05). The BZ PCr/ATP ratio is improved in the cell treated group compared with open patch group (1.71 +/- 0.05 vs. 1.54 +/- 0.05, p<0.05). The forward flux rate constant of PCr/ATP (k pcr→ATP ) in the border zone is slightly increased in cell treated group compared with patch only group (0.29 +/- 0.02 vs 0.22 +/- 0.04 , p<0.05) Conclusion: The approach of 2D CSI 31 P MRS can effectively map the heterogeneity of myocardial ATP flux rate via CK In Vivo porcine hearts. Postinfarction LV remodeling heart manifests pronounced heterogeneity in myocardial bioenergetics with most severe alterations in BZ. Cell therapy may effectively improve BZ myocardial bioenergetics.

Lipid Resuscitation of Bupivacaine Toxicity

Background The superiority of Intralipid, a long-chain triglyceride (LCT) emulsion versus Lipovenoes, a long- and medium-chain triglyceride (LCT/MCT) emulsion, in reversing local anesthetic-induced cardiac arrest is poorly defined and needs to be determined. Methods The study included two parts: in experiment A, bupivacaine (20 mg/kg) was injected to produce asystole. Either Intralipid 20% (LCT group, n = 30) or Lipovenoes 20% (LCT/MCT group, n = 30) with epinephrine was infused immediately. Return of spontaneous circulation and recurrence of asystole after resuscitation were recorded. In experiment B, 80 rats using the same model and resuscitation protocol were divided into 10 groups: LCT₀, LCT₁₅, LCT₃₀, LCT₆₀, and LCT₁₂₀ and LCT/MCT₀, LCT/MCT₁₅, LCT/MCT₃₀, LCT/MCT₆₀, and LCT/MCT₁₂₀ (n = 8 each; the subscripts represent respective observation period). LCT₁₅-LCT₁₂₀ and LCT/MCT₁₅-LCT/MCT₁₂₀ groups received Intralipid 20% or Lipovenoes 20%, respectively. Plasma and myocardial bupivacaine and triglyceride concentrations, as well as myocardial bioenergetics, were determined. Results In experiment A, 24 rats in LCT group and 23 in LCT/MCT group achieved return of spontaneous circulation (P = 0.754); among them, 2 (8.3%) and 8 (34.8%) rats suffered a repeated asystole, respectively (P = 0.027). In experiment B, plasma and myocardial bupivacaine concentrations in LCT₁₅ and LCT₆₀ groups were lower than LCT/MCT₁₅ and LCT/MCT₆₀ groups, respectively. Furthermore, the plasma bupivacaine level in LCT/MCT₆₀ group was higher than LCT/MCT₃₀ group (P = 0.003). Conclusions LCT emulsion may be superior to LCT/MCT emulsion in treating bupivacaine-related cardiotoxicity as it was associated with fewer recurrences of asystole after resuscitation and lower myocardial bupivacaine concentrations.

Abstract 5368: Igf +hgf Enhance Sca-1 + /cd31 − Cell Therapy in Hearts with Postinfarction Lv Remodeling

Insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are two potent cell survival factors in response to hypoxia and oxidative stress. We have previously shown that transplantation of Sca-1 + /CD31 − cells can improve LV function in hearts with acute myocardial infarction (AMI) although the engraftment rate was low. We hypothesized that supplementation of IGF-1 and HGF at delivery of cellular therapy can enhance the beneficial effects of Sca-1 + /CD31 − cells in the injured heart by increasing engraftment rate and endogenous cardiac cell survival. Adenovirus nuclear LacZ-labeled Sca-1 + /CD31 − cells (1x10 6 ) were injected into the ischemic area after LAD ligation in BalbC mice. Recombinant mouse IGF-1+HGF (100ng) was added to the cell suspension prior to the injection. The LV function (ECHO) and in vivo myocardial bioenergetics ( 31 P-NMR spectroscopy) were assessed 4 weeks after AMI and cell transplantation. Normal mice (Normal, n=6), and 2 control groups of LAD ligation (MI, n=6), and MI plus Sca-1 + /CD31 − cell transplantation (Cell, n=6), were compared to AMI mice with Sca-1 + /CD31 − cells transplantation plus IGF-1+HGF (Cell+IGF-1+HGF, n=6). Sca-1 + /CD31 − cells formed viable grafts and improved LV contractile function (EF: Control, 53.3+/−3.2; MI, 18.9+/−3.9; Cell, 29.1+/−5.1, p<0.05) and myocardial bioenergetics (PCr/ATP: Control, 2.13+/−0.09; MI, 1.21+/−0.09; Cell, 1.72+/−0.12; p<0.01). IGF+HGF significantly further enhanced the benefits of the cell transplantation as evidenced by significantly increased EF to 38.3+/−3.1% (p<0.05), which was accompanied by a higher cell engraftment rate (p<0.05). Using the in vitro co culture of Sca-1 + /CD31 − cells with HL-1 cells labeled by Vybrant CFDA SE cell tracer kit, we observed both IGF+HGF and Sca-1 + /CD31 − cells can inhibit TNFα and hypoxia induced HL-1 cell apoptosis (Control, 7+/−1%; TNFα, 24+/−1%; IGF+HGF+TNFα, 10+/−1%; n=6, P<0.001) and caspase 3 expression. These data demonstrate that IGF-1+HGF could serve as an adjuvant to cell transplantation for myocardial restoration.