Ketogenic diets (KDs), initially employed for alleviating symptoms of various diseases, have gained popularity among healthy individuals seeking to prevent overweight. However, emerging research suggests a potential link between prolonged KD exposure and adverse cardiovascular effects, specifically an increased risk of heart arrhythmia. This article explores the mechanisms behind this association, drawing upon recent studies and clinical observations.
The Ketogenic Diet: A Metabolic Shift
Consumption of a KD forces the body to use fats rather than carbohydrates to generate energy. During fatty acid oxidation in the liver, three major forms of ketone bodies are produced: acetoacetate (AcAc), β-hydroxybutyrate (β-OHB), and acetone. These ketone bodies are then transported to extrahepatic tissues via the circulatory system. In healthy adults, circulating total ketone body concentrations typically exhibit circadian oscillations of ~100-250 μM.
While β-OHB has been acknowledged for its beneficial effects, its safety concerning cardiovascular health has been questioned by certain clinical evidence.
KD Exposure Induces Cardiac Fibrosis
Studies in rats have revealed that prolonged KD exposure can induce cardiac fibrosis. Specifically, KD or frequent deep fasting decreased mitochondrial biogenesis, reduced cell respiration, and increased cardiomyocyte apoptosis and cardiac fibrosis.
After 16 weeks, besides a decrease in body weight, fat mass, and blood pressure in KD-fed rats, increased heart rates and impaired cardiac function were observed, as evaluated by echocardiography. The left ventricular posterior wall thickness (LVPWd) increased significantly compared with normal diet-fed rats, indicating a compensatory increase in cardiomyocytes, used to enhance cardiac contractility. If the left heart function was decompensated, the blood accumulated in the pulmonary circulation. The right ventricular anterior wall thickness (RVAW) also increased, indicating increased pulmonary circulation resistance and corresponding thickening of the right ventricular myocardium. Furthermore, the left atrial diameter (LAD), left ventricular dimension in diastole (LVDd), and left ventricular dimension in systole (LVDs) increased in KD-fed rats, indicating that cardiac function was decompensated and entered a state of failure.
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Cardiac fibrosis, characterized by increased levels of type I collagen, type III collagen, and α-smooth muscle actin (α-SMA), was observed in the atrial tissues of KD-fed rats. This finding aligns with the fact that increased cardiac fibrosis is associated with cardiac hypertrophy, dilatation, and the onset of atrial fibrillation (AF). Significantly increased ketone bodies were also observed in the cardiac tissues of patients with AF.
Interestingly, caloric restriction (CR) did not induce cardiac fibrosis or cardiac function impairment in rats, suggesting that the adverse effects are specific to the KD and not solely due to energy restriction. The KD caused increased levels of β-OHB and AcAc, the predominant forms of ketone bodies, in both plasma and heart tissues, whereas CR only induced a mild elevation of these ketone bodies.
The Role of β-OHB in Cardiac Fibrosis and Arrhythmia
Further investigation revealed that increased levels of β-OHB, but not AcAc, resulted in impaired cardiac function and cardiac fibrosis. Rats injected with β-OHB exhibited similar cardiac changes to those observed in KD-fed rats, including increased LAD, LVDs, LVDd, LVPWd, and RVAW, as well as the occurrence of cardiac fibrosis.
Mechanistically, increased levels of the ketone body β-OHB, an HDAC2 inhibitor, promoted histone acetylation of the Sirt7 promoter and activated Sirt7 transcription. This, in turn, inhibited the transcription of mitochondrial ribosome-encoding genes and mitochondrial biogenesis, leading to cardiomyocyte apoptosis and cardiac fibrosis.
Notably, increased β-OHB levels and SIRT7 expression, decreased mitochondrial biogenesis, and increased cardiac fibrosis were detected in human atrial fibrillation heart tissues.
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In cultured human cardiomyocytes (HCM), rat cardiomyoblasts (H9C2), and mouse cardiac muscle cells (HL-1), increased levels of β-OHB led to elevated rates of apoptosis; however, β-OHB did not induce significant increases in apoptosis in fibroblasts, such as mouse embryonic fibroblasts (MEFs) and 3T3 cells. In primary cells isolated from neonatal mice, β-OHB treatment also led to an increase in apoptosis in primary mouse cardiomyocytes, but not in primary mouse cardiac fibroblast. In accordance with increased apoptosis, elevated β-OHB led to increases in the levels of cleaved caspase 3 in HCM and H9C2 cells, but not in MEFs. Moreover, in rat atrial tissue, high β-OHB levels, induced by either KD feeding or β-OHB injection, led to increased rates of apoptosis, as evidenced by in situ TUNEL assays and detection of the levels of cleaved caspase 3 in rat atrial tissue.
β-OHB Impairs Mitochondrial Metabolism and Biogenesis
The mechanism by which β-OHB induces cardiomyocyte apoptosis involves the impairment of mitochondrial metabolism and biogenesis. Increased input of ketone bodies did not enhance ketolysis. Instead, increased β-OHB may lead to reduced mitochondrion numbers because the levels of some mitochondrial enzymes decreased.
β-OHB treatment decreased MitoTracker Green staining levels and decreased the ratio of mitochondrial (mt) DNA to nucleic DNA in HCM, H9C2, and HL-1 cells, in a concentration-dependent manner. In primary mouse cardiomyocytes isolated from neonatal mice, β-OHB treatment also led to a decrease in mitochondrion mass, as determined by measuring the ratio of mtDNA to nucleic DNA. In rats fed a KD or injected intraperitoneally with β-OHB, significant decreases in cardiac mitochondrion mass were observed compared with those in untreated animals, as determined by measuring the ratio of mtDNA to nucleic DNA.
Mitochondrial respiration was significantly reduced after β-OHB treatment in both H9C2 and HL-1 cells. Decreased mitochondrial respiration was also observed in primary cardiomyocytes isolated from KD-fed or β-OHB-injected rats. These results were consistent with the hypothesis that a decrease in mitochondrion numbers may lead to cardiomyocyte apoptosis, which has been shown to be induced by hypoxia.
β-OHB decreased protein levels of mitochondrial ribosomal protein L16 (MRPL16), mitochondrial ribosomal protein L24 (MRPL24), and G elongation factor mitochondrial 2 (GFM2), markers of mitochondrial biogenesis. β-OHB also decreased GFM2, MRPL16, and MRPL24 mRNA levels.
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Clinical Implications and Considerations
The findings discussed above highlight the potential risks associated with prolonged KD consumption, particularly concerning heart health. Several clinical observations further support this concern:
- The concentration of β-OHB in heart tissues is significantly higher in patients with atrial fibrillation (AF).
- Increased circulating β-OHB is independently associated with major adverse cardiovascular events in patients undergoing hemodialysis.
- Diabetes, often associated with high levels of ketone bodies, is an independent risk factor for cardiovascular diseases, including AF, coronary heart disease, and stroke.
While KDs may offer short-term benefits for weight loss and metabolic control, the long-term cardiovascular consequences warrant careful consideration. It is crucial for individuals considering or currently following a KD to consult with healthcare professionals to assess their individual risk factors and monitor their cardiovascular health.
Broader Perspective on Keto Diets and Heart Health
The review summarized the current evidence on how keto diets may raise heart disease risk. While the diet may dramatically reduce fat mass and weight over the short term, there is scarce evidence for any long-term benefit. Ketogenic diets appear to lower blood levels of triglycerides but raise levels of artery-clogging LDL cholesterol. The diet's extreme carbohydrate restrictions may lead people to shun most vegetables and fruits and consume large amounts of leafy greens. But the vitamin K in these foods may interfere with the anti-clotting drug warfarin taken by some heart patients.