The heart pumps blood through pulsatile contraction driven by its own electrical pacemaker system (the sinoatrial node). Resting pulse rate and rhythm are used on this wiki as practical markers of metabolic rate, see Roadmap/02 - Self diagnosis & markers.

Metabolic connections

In a UK Biobank cohort of roughly 400,000 adults, neither raw nor cooked vegetable intake was associated with reduced cardiovascular disease risk after adjusting for confounders, contradicting the standard dietary-guideline assumption that higher vegetable consumption itself protects the heart.[1]

Long working hours (≥49 hours/week) were associated with a higher prevalence of masked and sustained hypertension, chronic occupational stress driving cardiovascular risk that routine clinic blood-pressure checks can miss entirely.[2]

In adults over 60, higher LDL cholesterol did not predict cardiovascular death in a large systematic review; the highest LDL group showed survival comparable to or better than lower-LDL groups.[3] Therapeutically achieved aspirin concentrations downregulated endothelial AT1R expression and angiotensin II–driven neovascularization, overlapping the plaque-stabilizing biology of AT1R blockers such as losartan.[4] Sun-avoidant women in Sweden showed about twice the all-cause death rate of the most UV-exposed group; lower cardiovascular mortality was the dominant contributor to the sun-exposure survival benefit.[5] EPIC-Oxford found vegetarians and vegans had ~20% higher stroke incidence (including hemorrhagic stroke) despite lower coronary disease risk, versus meat eaters over 18 years of follow-up.[6] Inflammation-driven mitochondrial fragmentation in endothelial cells was reversed by salicylate through Drp1 and NF-κB pathways, linking antiplatelet therapy to preserved mitochondrial fusion in the vasculature.[7] Menaquinone supplementation has been associated with hypotension severe enough to require clinical attention in at least one published case, consistent with vitamin K's role in vascular calcification reversal and arterial stiffness.[8] Six months after myocardial infarction, recovered patients still showed elevated basal cortisol, low urinary androgens including DHEA, and exaggerated catecholamine responses to mild audiogenic stress.[9] Primate cardiovascular tissues selectively accumulate DHT and express androgen receptors that preferentially bind DHT over testosterone.[10] Long-term marine omega-3 fatty acid supplementation associated with higher incident atrial fibrillation across randomized cardiovascular trials.[11] In women over 70, lower testosterone and DHEA, but not lower estrone, doubled major cardiovascular-event risk across quartiles of blood androgen concentrations.[12] One month of bromocriptine improved central aortic stiffness and blood pressure in adolescents with type 1 diabetes, suggesting dopaminergic–serotonergic modulation can reverse early vascular disease.[13] Declining dihydrotestosterone with age tracked higher carotid stiffness, pulse-wave velocity, and CRP in men, supporting low androgens as a cardiovascular risk marker.[14] Five-year vitamin D3 supplementation (1600–3200 IU/day) in older adults lowered incident atrial fibrillation risk by 27–32% versus placebo in the Finnish FIND trial.[15] NAD+ depletion in hypertensive aorta correlated inversely with blood pressure; NAD+ precursor supplementation raised tissue NAD+ and reduced systolic pressure and vascular stiffness markers.[16] Long-term aspirin use correlated with slower abdominal aortic aneurysm expansion in serial ultrasound follow-up, suggesting antiplatelet therapy may delay aneurysm progression.[17] Prospective cohort data link low-carbohydrate eating patterns to increased risk of developing atrial fibrillation.[18]

Gut microbiota, LPS, and CHD with depression

Direct platelet-aggregating effects of unmodified PUFA and MUFA (independent of thromboxane synthesis) add a lipid-driven thrombotic pathway alongside LPS and serotonin mechanisms.[19] Blood LPS activates coagulation factors within minutes, offering a non-hormonal mechanism for meal-associated and sepsis-related thrombotic risk.[20] Serum LPS and IL-6 rise with myxomatous mitral valve disease severity in dogs, paralleling gastrointestinal signs and barrier dysfunction.[21] A high-fat diet plus chronic unpredictable mild stress produces coronary heart disease with depression in rats; fecal transfer from diseased animals elevates serum LPS and activates cardiac and hippocampal TLR4/MYD88/NF-κB signaling.[22] Cardiac muscle relies heavily on oxidative metabolism and is sensitive to thyroid status: hypothyroidism slows heart rate and contractility and can cause fluid accumulation around the heart, while excess Adrenaline-driven stimulation raises heart rate without reflecting true metabolic rate.

Lipolysis and mitochondrial distress signals

Stressed adipocytes release extracellular vesicles containing mitochondrial fragments that raise cardiac reactive oxygen species and prime the heart for ischemic stress, linking chronic lipolysis to long-term cardiac fibrosis risk.[23]

Serotonin and valve disease

Reduced serotonin-transporter activity in mitral-valve interstitial cells promoted degenerative mitral regurgitation through excess serotonergic signaling and myxomatous remodeling.[24] Pulmonary-heart patients with atherosclerosis showed corticosteronemia, hyperestrogenemia, testosterone deficiency, and elevated serotonin and noradrenaline alongside severe pulmonary hypertension.[25] In a large prospective cohort, regular fish-oil supplementation in initially healthy adults associated with higher risk of first cardiovascular disease and stroke.[26] Serotonin raises IL-6 production in human vascular smooth-muscle cells via 5-HT2A and PKC signaling, providing a direct serotonergic pathway for vascular inflammatory activation during atherogenesis.[27] SSRI drugs impair mitochondrial oxidative metabolism in human cardiomyocyte models, offering a non-valvular mechanism for antidepressant-associated cardiac toxicity.[28] Arterial injury-induced intimal hyperplasia is blunted when vascular smooth muscle expresses HIOMT, linking serotonin metabolism to post-injury vessel-wall thickening.[29] Patients on SSRIs undergo degenerative mitral-valve surgery at younger ages; serotonin overstimulates valve interstitial cells to deposit collagen, with parallel findings in SERT-deficient mice.[30]

Vitamin D and blood pressure

Vitamin D deficiency alone produced heart failure in rats with cardiac insulin resistance, impaired glucose and fatty-acid utilization, and inflammatory remodeling resembling high-calorie diet injury.[31] Low postmenopausal progesterone (and low male progesterone) may contribute to rising blood pressure and cardiovascular risk; physiological progesterone supplementation produced significant antihypertensive effects in a pilot trial.[32] Higher estradiol correlated with stiffer arteries in premenopausal, contraceptive-using, and hormone-treated women, supporting estrogen exposure as a contributor to age-related vascular rigidity.[33] In overweight elderly adults, vitamin D3 plus calcium lowered systolic and diastolic blood pressure over 12 months in hypertensive and BMI>30 subgroups, largely independent of dose (600 vs 3750 IU/day).[34]

Lipid peroxidation and 4-HNE

Extracellular poly(ADP-ribose) from PARP activation drove pathological matrix calcification in bone and vasculature; inhibiting PARP biosynthesis blocked biomineralization in vitro and in vivo.[35] High-dose α-tocopherol reduced advanced plaque thickness, necrotic core area, and intraplaque neovascularization while improving cardiac function in atherosclerosis-prone mice, without lowering lipid peroxidation markers, arguing against antioxidant mediation.[36] A lard-based high-fat diet diverted adipocyte-derived mitochondria away from macrophage clearance into circulation and heart tissue, whereas coconut-oil or high-carbohydrate feeding did not.[37] Higher serum lipopolysaccharide-binding protein predicted cardiovascular events in hemodialysis patients independently of traditional risk markers, linking gut-derived LPS exposure to uremic CVD.[38] Heart-failure-associated mitochondrial dysfunction raises 4-hydroxynonenal, which irreversibly inactivates Dicer and disrupts microRNA processing; activating mitochondrial ALDH2 with AD-9308 restores Dicer activity and reverses heart failure in rodent models.[39]

Iron and post-infarction remodeling

Peri-infarct RRR-alpha-tocopherol for three days (before, during, and after ischemia) preserved left-ventricular function and limited post-MI fibrosis in mice, with anti-inflammatory effects beyond classic antioxidant action.[40] In hemorrhagic myocardial infarction, iron from extravasated red blood cells drives replacement of scar with epicardial fat and progressive heart failure; removing myocardial iron reduces fat deposition in large-animal models.[41]

GLP-1 receptor agonists (semaglutide) reduce heart-muscle mass in obese and lean mice and in cultured human cardiomyocytes, paralleling skeletal-muscle loss from the same drug class.[42]

Post-CABG antiplatelet therapy

In the TACSI trial (2,201 ACS patients after coronary-artery bypass), aspirin alone matched dual antiplatelet therapy (ticagrelor plus aspirin) for major adverse cardiovascular events at 12 months while major bleeding was 2.5-fold higher with dual therapy.[43]

Cardiomyocyte fuel use and regeneration

Boosting mitochondrial unfolded-protein response with nicotinamide riboside mitigated stress-induced falls in cardiomyocyte mitochondrial respiration and contractile dysfunction in vitro and mouse models.[44] Thiamine 200 mg daily for three to six months improved left ventricular ejection fraction from about 30% to 45–53% in alcoholic cardiomyopathy with reduced ventricular dimensions.[45] Mitochondrial pyruvate import is required for cardiomyocyte (and neuronal) calcium handling; MPC loss raises free calcium, drives hyperexcitability, and worsens seizure lethality unless ketones restore mitochondrial buffering.[46] Chronic heart failure depleted cardiac succinyl-CoA through excess ketone and heme pathways, impairing oxidative phosphorylation; 5-aminolevulinate partially restored mitochondrial energetics in mice.[47] Loss of the mitochondrial pyruvate carrier and excess lactate export drive cardiomyocyte hypertrophy; restoring MPC activity or blocking MCT4 lactate efflux prevents and reverses pressure-overload hypertrophy in rodent models.[48] Mammalian hearts lose regenerative capacity shortly after birth when cardiomyocyte mitochondria switch from glucose to fatty-acid oxidation; genetic deletion of pyruvate dehydrogenase kinase 4 (PDK4) forces glucose oxidation in adult cardiomyocytes and improves functional recovery after experimental infarction, with gene-expression markers suggesting resumed cell division.[49] Low-fat maternal milk and post-weaning low-fat diets similarly prolong the neonatal regenerative window by delaying the fatty-acid metabolic switch.

Rising heart-failure mortality in younger US adults

Age-adjusted heart-failure-related cardiovascular mortality in the United States rose after decades of decline, with the increase concentrated in adults under 65 and pronounced racial/geographic disparities, pointing to worsening upstream metabolic health rather than acute-care failures.[50]

Artificial sweeteners and cardiovascular risk

The zero-calorie sweetener erythritol was associated with elevated platelet reactivity, clot formation, and higher incident risk of major adverse cardiovascular events in a large cohort plus mechanistic studies, undercutting its marketing as a metabolically inert sugar substitute.[51]

See also

References

  1. ↑ Feng Q, Kim JH, Omiyale W, et al. "Raw and cooked vegetable consumption and risk of cardiovascular disease: a study of 400,000 adults in UK Biobank," Front Nutr. 2022. doi:10.3389/fnut.2022.831470.
  2. ↑ Trudel X, Brisson C, Gilbert-Ouimet M, et al. "Long working hours and the prevalence of masked and sustained hypertension," Hypertension. 2020. doi:10.1161/HYPERTENSIONAHA.119.12926.
  3. ↑ Ravnskov U, et al. "LDL cholesterol and mortality in older adults," BMJ Open. 2016. doi:10.1136/bmjopen-2015-010401.
  4. ↑ Mitra S, et al. "Aspirin downregulates angiotensin type 1 receptor," J Cardiovasc Pharmacol. 2012. PMID 22561363.
  5. ↑ Lindqvist PG, et al. "Avoidance of sun exposure and mortality," J Intern Med. 2014. PMID 24697969.
  6. ↑ Tong TYN, et al. "Vegetarian diet and stroke risk," BMJ. 2019. doi:10.1136/bmj.l4897.
  7. ↑ Eguchi S, et al. "Mitochondrial fission and endothelial inflammation," Hypertension. 2020. doi:10.1161/HYPERTENSIONAHA.120.14686.
  8. ↑ Teperikidis E. "Hypotension associated with menaquinone," Am J Health Syst Pharm. 2012. PMID 22821789. doi:10.2146/ajhp110235.
  9. ↑ Mendelson GL, et al. "Hormonal status after myocardial infarction," J Clin Endocrinol Metab. 1974. PMID 4270621.
  10. ↑ Sheridan PJ, et al. "DHT receptors in baboon brain and CVS," Anat Rec. 1988. doi:10.1002/ar.1092200415.
  11. ↑ Gencer B, et al. "Marine omega-3 supplementation and atrial fibrillation," Circulation. 2021. doi:10.1161/CIRCULATIONAHA.121.055654.
  12. ↑ Islam RM, et al. "Associations between blood sex steroid concentrations and cardiovascular disease risk in older women," Lancet Healthy Longev. 2022. doi:10.1016/S2666-7568(22)00001-0.
  13. ↑ Schäfer M, et al. "Bromocriptine and aortic stiffness in type 1 diabetes," Hypertension. 2023. doi:10.1161/HYPERTENSIONAHA.122.19547.
  14. ↑ Grandys M, et al. "Age-related DHT decline and arterial stiffness," Exp Gerontol. 2023. PMID 36693531.
  15. ↑ Virtanen JK, et al. "Vitamin D and atrial fibrillation," Am Heart J. 2023. doi:10.1016/j.ahj.2023.05.024.
  16. ↑ Zhang Y, et al. "NMN lowers blood pressure in hypertension," Signal Transduct Target Ther. 2023. doi:10.1038/s41392-023-01577-3.
  17. ↑ Cameron SJ, et al. "Aspirin and abdominal aortic aneurysm progression," JAMA Netw Open. 2023. doi:10.1001/jamanetworkopen.2023.47296. PMID 38085542.
  18. ↑ Zhang S, et al. "Low-carbohydrate diets and atrial fibrillation," J Am Heart Assoc. 2019. PMID 31020911.
  19. ↑ Hashimoto Y, et al. "PUFA induce platelet aggregation and serotonin release," Biochim Biophys Acta. 1985;835(1):144-150. PMID 2992603.
  20. ↑ LPS drives blood clotting in sepsis, J Biol Chem. 2024. doi:10.1016/j.jbc.2024.108110.
  21. ↑ Jugan MC, et al. "LPS and mitral valve disease in dogs," PLoS One. 2025. doi:10.1371/journal.pone.0337580.
  22. ↑ Wang C, et al. "Gut microbiota and CHD comorbid with depression," BMC Microbiol. 2025. doi:10.1186/s12866-025-04302-y.
  23. ↑ Banfi C, et al. "Adipocyte mitochondrial fragments signal to the heart," Cell Metab. 2021;33(9):1743-1757.e12. doi:10.1016/j.cmet.2021.08.002.
  24. ↑ Castillero E, et al. "Serotonin transporter activity in mitral valve disease," Sci Transl Med. 2023. doi:10.1126/scitranslmed.adc9606.
  25. ↑ Pribylova NN, et al. "Steroid hormones and biogenic amines in atherosclerosis," Kardiologiia. 1983. PMID 6620818.
  26. ↑ Chen G, et al. "Regular fish oil and cardiovascular disease course," BMJ Med. 2024. doi:10.1136/bmjmed-2022-000451.
  27. ↑ Ito M, et al. "Serotonin and IL-6 in vascular smooth muscle," Circulation. 2000. doi:10.1161/01.CIR.102.20.2522. PMID 11076827.
  28. ↑ Shen Y, et al. "SSRI cardiac mitochondrial toxicity," Commun Biol. 2025. doi:10.1038/s42003-025-08168-8.
  29. ↑ Jiang Z, et al. "HIOMT in smooth muscle and intimal hyperplasia," J Biomed Sci. 2025. doi:10.1186/s12929-025-01172-4.
  30. ↑ Jain R, et al. "Serotonin and mitral valve disease," Sci Transl Med. 2023. PMID 36599005.
  31. ↑ Nizami ID, Banerjee SK, et al. "Vitamin D deficiency and cardiac dysfunction," Mol Nutr Food Res. 2019. doi:10.1002/mnfr.201900109.
  32. ↑ Heron J, et al. "Natural progesterone and blood pressure," Br J Obstet Gynaecol. 1985. PMID 3917316.
  33. ↑ Laakkonen EK, et al. "Associations of sex hormones and hormonal status with arterial stiffness in women," Front Endocrinol. 2021. doi:10.3389/fendo.2021.765916.
  34. ↑ Rahme M, et al. "Vitamin D3 and blood pressure in overweight elderly," J Endocr Soc. 2024. doi:10.1210/jendso/bvae168.
  35. ↑ Müller KH, et al. "Poly(ADP-ribose) links DNA damage and biomineralization," Cell Rep. 2019. PMID 31189100.
  36. ↑ Coornaert I, et al. "α-Tocopherol inhibits atherogenesis independently of antioxidant properties," Vasc Biol. 2024. PMID 38717284.
  37. ↑ Borcherding N, et al. "Dietary fat alters adipocyte mitochondrial transfer," Sci Signal. 2022. doi:10.1126/scisignal.adf2995.
  38. ↑ Lin S, et al. "LBP and cardiovascular events in hemodialysis," Nephrology (Carlton). 2022. doi:10.1111/nep.14107.
  39. ↑ Ferreira JCB, et al. "4-Hydroxynonenal inhibits Dicer and microRNA biogenesis in heart failure," Eur Heart J. 2023. doi:10.1093/eurheartj/ehad662.
  40. ↑ Wallert M, Peter K, et al. "Vitamin E after myocardial infarction," Redox Biol. 2019. doi:10.1016/j.redox.2019.101260.
  41. ↑ Dharmakumar R, et al. "Epicardial adipose tissue after myocardial infarction promotes cardiac dysfunction," Nat Commun. 2022;13:7116. doi:10.1038/s41467-022-33776-x.
  42. ↑ Dyck GJB, et al. "GLP-1 agonists reduce cardiac muscle mass," Curr Opin Cardiol. 2024. doi:10.1016/j.cors.2024.11.003.
  43. ↑ Jeppsson A, et al. "Ticagrelor and aspirin or aspirin alone after coronary surgery," N Engl J Med. 2025. doi:10.1056/NEJMoa2508026. PMID 40888737.
  44. ↑ Smyrnias I, Shah AM, et al. "Nicotinamide riboside and cardiac UPRmt," J Am Coll Cardiol. 2019. doi:10.1016/j.jacc.2019.04.085.
  45. ↑ Satish OS, et al. "Thiamine in alcoholic cardiomyopathy," Indian Heart J. 2021. doi:10.1016/j.ihj.2021.03.013.
  46. ↑ De La Rossa A, et al. "Paradoxical neuronal hyperexcitability in mitochondrial pyruvate carrier deficiency," eLife. 2022. doi:10.7554/eLife.72595.
  47. ↑ Takada S, et al. "Succinyl-CoA dysfunction in heart failure," Proc Natl Acad Sci U S A. 2022. doi:10.1073/pnas.2203628119.
  48. ↑ Merali S, et al. "Mitochondrial pyruvate metabolism in heart failure," Cell Metab. 2021. doi:10.1016/j.cmet.2020.12.003.
  49. ↑ Cardoso AC, et al. "Mitochondrial Substrate Utilization Regulates Cardiomyocyte Cell Cycle Progression," Nat Metab. 2020;2(2):104-114. PMID 32617517.
  50. ↑ Glynn P, Lloyd-Jones DM, Feinstein MJ, et al. "Disparities in cardiovascular mortality related to heart failure in the United States," J Am Coll Cardiol. 2019. doi:10.1016/j.jacc.2019.02.042.
  51. ↑ Witkowski M, Nemet I, Alamri H, et al. "The artificial sweetener erythritol and cardiovascular event risk," Nat Med. 2023. doi:10.1038/s41591-023-02223-9.