Oral ketone esters acutely improve myocardial contractility in post-hospitalized COVID-19 patients: A randomized placebo-controlled double-blind crossover study.

Background: COVID-19 is associated with subclinical myocardial injury. Exogenous ketone esters acutely improve left myocardial function in healthy participants and patients with heart failure, but the effects have not been investigated in participants previously hospitalized for COVID-19. Methods: This is a randomized placebo-controlled double-blind crossover study comparing a single oral ketone ester dose of 395 mg/kg with placebo. Fasting participants were randomized to either placebo in the morning and oral ketone ester in the afternoon or vice versa. Echocardiography was performed immediately after intake of the corresponding treatment. Primary outcome was left ventricular ejection fraction (LVEF). Secondary outcomes were absolute global longitudinal strain (GLS), cardiac output and blood oxygen saturation. Linear mixed effects models were used to assess differences. Results: We included 12 participants previously hospitalized for COVID-19 with a mean (±SD) age of 60 ± 10 years. The mean time from hospitalization was 18 ± 5 months. Oral ketone esters did not increase LVEF between placebo and oral ketone ester [mean difference: -0.7% (95% CI -4.0 to 2.6%), p = 0.66], but increased GLS [1.9% (95% CI: 0.1 to 3.6%), p = 0.04] and cardiac output [1.2 L/min (95% CI: -0.1 to 2.4 L/min), p = 0.07], although non-significant. The differences in GLS remained significant after adjustment for change in heart rate (p = 0.01). There was no difference in blood oxygen saturation. Oral ketone esters increased blood ketones over time (peak level 3.1 ± 4.9 mmol/L, p < 0.01). Ketone esters increased blood insulin, c-peptide, and creatinine, and decreased glucose and FFA (all p ≤ 0.01) but did not affect glucagon, pro-BNP, or troponin I levels (all p > 0.05). Conclusion: In patients previously hospitalized with COVID-19, a single oral dose of ketone ester had no effect on LVEF, cardiac output or blood oxygen saturation, but increased GLS acutely. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04377035.

Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue.

The increased metabolic activity of the heart as a pump involves a high demand of mitochondrial adenosine triphosphate (ATP) production for its mechanical and electrical activities accomplished mainly via oxidative phosphorylation, supplying up to 95% of the necessary ATP production, with the rest attained by substrate-level phosphorylation in glycolysis. In the normal human heart, fatty acids provide the principal fuel (40-70%) for ATP generation, followed mainly by glucose (20-30%), and to a lesser degree (<5%) by other substrates (lactate, ketones, pyruvate and amino acids). Although ketones contribute 4-15% under normal situations, the rate of glucose use is drastically diminished in the hypertrophied and failing heart which switches to ketone bodies as an alternate fuel which are oxidized in lieu of glucose, and if adequately abundant, they reduce myocardial fat delivery and usage. Increasing cardiac ketone body oxidation appears beneficial in the context of heart failure (HF) and other pathological cardiovascular (CV) conditions. Also, an enhanced expression of genes crucial for ketone break down facilitates fat or ketone usage which averts or slows down HF, potentially by avoiding the use of glucose-derived carbon needed for anabolic processes. These issues of ketone body utilization in HF and other CV diseases are herein reviewed and pictorially illustrated.

VLCKD in Combination with Physical Exercise Preserves Skeletal Muscle Mass in Sarcopenic Obesity after Severe COVID-19 Disease: A Case Report.

The prevalence of sarcopenic obesity is increasing worldwide, with a strong impact on public health and the national health care system. Sarcopenic obesity consists of fat depot expansion and associated systemic low-grade inflammation, exacerbating the decline in skeletal muscle mass and strength. Dietary approach and physical exercise represent essential tools for reducing body weight and preserving muscle mass and function in subjects with sarcopenic obesity. This case report describes the effects of a dietary intervention, based on a Very-Low-Calorie Ketogenic Diet (VLCKD) combined with physical exercise, on body composition, cardiometabolic risk factors, and muscle strength in a woman with sarcopenic obesity, two weeks after hospitalization for bilateral interstitial pneumonia due to COVID-19. To our knowledge, this is the first case report to describe the efficacy of a combined approach intervention including VLCKD along with physical exercise, in reducing fat mass, improving metabolic profile, and preserving skeletal muscle performance in a patient with obesity, soon after severe COVID-19 disease.

Can ketone bodies inactivate coronavirus spike protein? The potential of biocidal agents against SARS-CoV-2.

Biocidal agents such as formaldehyde and glutaraldehyde are able to inactivate several coronaviruses including SARS-CoV-2. In this article, an insight into one mechanism for the inactivation of these viruses by those two agents is presented, based on analysis of previous observations during electron microscopic examination of several members of the orthocoronavirinae subfamily, including the new virus SARS-CoV-2. This inactivation is proposed to occur through Schiff base reaction-induced conformational changes in the spike glycoprotein leading to its disruption or breakage, which can prevent binding of the virus to cellular receptors. Also, a new prophylactic and therapeutic measure against SARS-CoV-2 using acetoacetate is proposed, suggesting that it could similarly break the viral spike through Schiff base reaction with lysines of the spike protein. This measure needs to be confirmed experimentally before consideration. In addition, a new line of research is proposed to help find a broad-spectrum antivirus against several members of this subfamily.

Investigating Ketone Bodies as Immunometabolic Countermeasures against Respiratory Viral Infections.

Respiratory viral infections remain a scourge, with seasonal influenza infecting millions and killing many thousands annually and viral pandemics, such as COVID-19, recurring every decade. Age, cardiovascular disease, and diabetes mellitus are risk factors for severe disease and death from viral infection. Immunometabolic therapies for these populations hold promise to reduce the risks of death and disability. Such interventions have pleiotropic effects that might not only target the virus itself but also enhance supportive care to reduce cardiopulmonary complications, improve cognitive resilience, and facilitate functional recovery. Ketone bodies are endogenous metabolites that maintain cellular energy but also feature drug-like signaling activities that affect immune activity, metabolism, and epigenetics. Here, we provide an overview of ketone body biology relevant to respiratory viral infection, focusing on influenza A and severe acute respiratory syndrome (SARS)-CoV-2, and discuss the opportunities, risks, and research gaps in the study of exogenous ketone bodies as novel immunometabolic interventions in these diseases.