The co-primary objectives of this study were to determine the human pharmacokinetics (PK) of oral NR and the effect of NR on whole blood nicotinamide adenine dinucleotide (NAD+) levels.
Though ...mitochondrial dysfunction plays a critical role in the development and progression of heart failure, no mitochondria-targeted therapies have been translated into clinical practice. Recent murine studies have reported associations between imbalances in the NADH/NAD+ ratio with mitochondrial dysfunction in multiple tissues, including myocardium. Moreover, an NAD+ precursor, nicotinamide mononucleotide, improved cardiac function, while another NAD+ precursor, nicotinamide riboside (NR), improved mitochondrial function in muscle, liver and brown adipose. Thus, PK studies of NR in humans is critical for future clinical trials.
In this non-randomized, open-label PK study of 8 healthy volunteers, 250 mg NR was orally administered on Days 1 and 2, then uptitrated to peak dose of 1000 mg twice daily on Days 7 and 8. On the morning of Day 9, subjects completed a 24-hour PK study after receiving 1000 mg NR at t = 0. Whole-blood levels of NR, clinical blood chemistry, and NAD+ levels were analyzed.
Oral NR was well tolerated with no adverse events. Significant increases comparing baseline to mean concentrations at steady state (Cave,ss) were observed for both NR (p = 0.03) and NAD+ (p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R2 = 0.72, p = 0.008).
Because NR increases circulating NAD+ in humans, NR may have potential as a therapy in patients with mitochondrial dysfunction due to genetic and/or acquired diseases.
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•Boosting NAD+ by NR has been shown to blunt worsening of cardiac function in murine cardiomyopathy models and suggested to have anti-inflammatory effects a small, nonrandomized ...clinical trial.•In in this study, NR at 2 g/d over 12 weeks was safe, well tolerated, and significantly increased whole blood NAD+ levels in ambulatory stage C HFrEF patients.•The whole blood NAD+ response to NR correlated with increased respiration and decreased proinflammatory cytokine expression in PBMCs, providing evidence that boosting NAD+ acts on peripheral immune cells to reduce systemic inflammation.
The mitochondrial dysfunction characteristic of heart failure (HF) is associated with changes in intracellular nicotinamide adenine dinucleotide (NAD+) and NADH levels. Raising NAD+ levels with the NAD+ precursor, nicotinamide riboside (NR), may represent a novel HF treatment. In this 30-participant trial of patients with clinically stable HF with reduced ejection fraction, NR, at a dose of 1,000 mg twice daily, appeared to be safe and well tolerated, and approximately doubled whole blood NAD+ levels. Intraindividual NAD+ increases in response to NR correlated with increases in peripheral blood mononuclear cell basal (R2 = 0.413, P = 0.003) and maximal (R2 = 0.434, P = 0.002) respiration, and with decreased NLRP3 expression (R2 = 0.330, P = 0.020). (Nicotinamide Riboside in Systolic Heart Failure; NCT03423342)
The treatment, genotyping, and phenotyping of patients with World Health Organization Group 1 pulmonary arterial hypertension (PAH) have evolved dramatically in the last decade.
The United States ...Pulmonary Hypertension Scientific Registry was established as the first US PAH patient registry to investigate genetic information, reproductive histories, and environmental exposure data in a contemporary patient population.
Investigators at 15 US centers enrolled consecutively screened adults diagnosed with Group 1 PAH who had enrolled in the National Biological Sample and Data Repository for PAH (PAH Biobank) within 5 years of a cardiac catheterization demonstrating qualifying hemodynamic criteria. Exposure and reproductive histories were collected by using a structured interview and questionnaire. The biobank provided genetic data.
Between 2015 and 2018, a total of 499 of 979 eligible patients with clinical diagnoses of idiopathic PAH (IPAH) or familial PAH (n = 240 48%), associated PAH (APAH; n = 256 51%), or pulmonary venoocclusive disease/pulmonary capillary hemangiomatosis (n = 3 1%) enrolled. The mean age was 55.8 years, average BMI was 29.2 kg/m
, and 79% were women. Mean duration between symptom onset and diagnostic catheterization was 1.9 years. Sixty-six percent of patients were treated with more than one PAH medication at enrollment. Past use of prescription weight loss drugs (16%), recreational drugs (27%), and oral contraceptive pills (77%) was common. Women often reported miscarriage (37%), although PAH was rarely diagnosed within 6 months of pregnancy (1.9%). Results of genetic testing identified pathogenic or suspected pathogenic variants in 13% of patients, reclassifying 18% of IPAH patients and 5% of APAH patients to heritable PAH.
Patients with Group 1 PAH remain predominately middle-aged women diagnosed with IPAH or APAH. Delays in diagnosis of PAH persist. Treatment with combinations of PAH-targeted medications is more common than in the past. Women often report pregnancy complications, as well as exposure to anorexigens, oral contraceptives, and/or recreational drugs. Results of genetic tests frequently identify unsuspected heritable PAH.
Context:
Excessive cardiac long-chain fatty acid (LCFA) metabolism/storage causes cardiomyopathy in animal models of type 2 diabetes. Medium-chain fatty acids (MCFAs) are absorbed and oxidized ...efficiently. Data in animal models of diabetes suggest MCFAs may benefit the heart.
Objective:
Our objective was to test the effects of an MCFA-rich diet vs an LCFA-rich diet on plasma lipids, cardiac steatosis, and function in patients with type 2 diabetes.
Design:
This was a double-blind, randomized, 2-week matched-feeding study.
Setting:
The study included ambulatory patients in the general community.
Patients:
Sixteen patients, ages 37–65 years, with type 2 diabetes, an ejection fraction greater than 45%, and no other systemic disease were included.
Intervention:
Fourteen days of a diet rich in MCFAs or LCFAs, containing 38% as fat in total, was undertaken.
Main Outcome Measures:
Cardiac steatosis and function were the main outcome measures, with lipidomic changes considered a secondary outcome.
Results:
The relatively load-independent measure of cardiac contractility, S′, improved in the MCFA group (P < .05). Weight-adjusted stroke volume and cardiac output decreased in the LCFA group (both P < .05). The MCFA, but not the LCFA, diet decreased several plasma sphingolipids, ceramide, and acylcarnitines implicated in diabetic cardiomyopathy, and changes in several sphingolipids correlated with improved fasting insulins.
Conclusions:
Although a diet high in MCFAs does not change cardiac steatosis, our findings suggest that the MCFA-rich diet alters the plasma lipidome and may benefit or at least not harm cardiac function and fasting insulin levels in humans with type 2 diabetes. Larger, long-term studies are needed to further evaluate these effects in less-controlled settings.
The treatment, genotyping, and phenotyping of patients with World Health Organization Group 1 pulmonary arterial hypertension (PAH) have evolved dramatically in the last decade.
The United States ...Pulmonary Hypertension Scientific Registry was established as the first US PAH patient registry to investigate genetic information, reproductive histories, and environmental exposure data in a contemporary patient population.
Investigators at 15 US centers enrolled consecutively screened adults diagnosed with Group 1 PAH who had enrolled in the National Biological Sample and Data Repository for PAH (PAH Biobank) within 5 years of a cardiac catheterization demonstrating qualifying hemodynamic criteria. Exposure and reproductive histories were collected by using a structured interview and questionnaire. The biobank provided genetic data.
Between 2015 and 2018, a total of 499 of 979 eligible patients with clinical diagnoses of idiopathic PAH (IPAH) or familial PAH (n = 240 48%), associated PAH (APAH; n = 256 51%), or pulmonary venoocclusive disease/pulmonary capillary hemangiomatosis (n = 3 1%) enrolled. The mean age was 55.8 years, average BMI was 29.2 kg/m2, and 79% were women. Mean duration between symptom onset and diagnostic catheterization was 1.9 years. Sixty-six percent of patients were treated with more than one PAH medication at enrollment. Past use of prescription weight loss drugs (16%), recreational drugs (27%), and oral contraceptive pills (77%) was common. Women often reported miscarriage (37%), although PAH was rarely diagnosed within 6 months of pregnancy (1.9%). Results of genetic testing identified pathogenic or suspected pathogenic variants in 13% of patients, reclassifying 18% of IPAH patients and 5% of APAH patients to heritable PAH.
Patients with Group 1 PAH remain predominately middle-aged women diagnosed with IPAH or APAH. Delays in diagnosis of PAH persist. Treatment with combinations of PAH-targeted medications is more common than in the past. Women often report pregnancy complications, as well as exposure to anorexigens, oral contraceptives, and/or recreational drugs. Results of genetic tests frequently identify unsuspected heritable PAH.
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