Addressing the Missing Links in Cardiovascular Aging

Figures & data

Table 1 Manipulating the Microbiome on CVD Risk

Species	Study Type	Subjects	Findings	Citation
Human	RCT	36	Supplementation with Lactobacillus plantarum produced a significant decrease in systolic BP, leptin, and fibrinogen in heavy smokers	Naruszewicz M, Johansson ML, Zapolska-Downar D, Bukowska H. Effect of Lactobacillus plantarum 299v on cardiovascular disease risk factors in smokers. Am J Clin Nutr. 2002 Dec;76(6):1249–55. doi: 10.1093/ajcn/76.6.1249. PMID: 12450890^Citation31
Human	Controlled clinical trial	24	Fermented milk with L. plantarum showed more favorable results in relation to cardiovascular risk factors such as glucose and homocysteine in postmenopausal women with MetS.	Barreto FM, Colado Simão AN, Morimoto HK, Batisti Lozovoy MA, Dichi I, Helena da Silva Miglioranza L. Beneficial effects of Lactobacillus plantarum on glycemia and homocysteine levels in postmenopausal women with metabolic syndrome. Nutrition. 2014 Jul-Aug;30(7–8):939–42. doi: 10.1016/j.nut.2013.12.004. Epub 2013 Dec 14. PMID: 24613434^Citation32
Human	Meta analysis	641	Probiotic consumption significantly decreased systolic, diastolic BP, low density lipoprotein, total cholesterol and triglycerides, compared with placebo in T2DM	Hendijani F, Akbari V. Probiotic supplementation for management of cardiovascular risk factors in adults with type II diabetes: A systematic review and meta-analysis. Clin Nutr. 2018 Apr;37(2):532–541. doi: 10.1016/j.clnu.2017.02.015. Epub 2017 Feb 24. PMID: 28318686^Citation33
Human	RCT	46	Fiber induced probiotics negative correlation with HgA1c	Zhao L, Zhang F, Ding X, Wu G, Lam YY, Wang X, Fu H, Xue X, Lu C, Ma J, Yu L, Xu C, Ren Z, Xu Y, Xu S, Shen H, Zhu X, Shi Y, Shen Q, Dong W, Liu R, Ling Y, Zeng Y, Wang X, Zhang Q, Wang J, Wang L, Wu Y, Zeng B, Wei H, Zhang M, Peng Y, Zhang C. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science. 2018 Mar 9;359(6380):1151–1156. doi: 10.1126/science.aao5774. PMID: 29,590,046.^Citation34
Human	Observational study	21	Lp299v strain of probiotic improved vascular endothelial function and decreased systemic inflammation in men with CAD.	Malik M, Suboc TM, Tyagi S, Salzman N, Wang J, Ying R, Tanner MJ, Kakarla M, Baker JE, Widlansky ME. Lactobacillus plantarum 299v Supplementation Improves Vascular Endothelial Function and Reduces Inflammatory Biomarkers in Men With Stable Coronary Artery Disease. Circ Res. 2018 Oct 12;123(9):1091–1102. doi: 10.1161/CIRCRESAHA.118.313565. PMID: 30,355,158; PMCID: PMC6205737.^Citation35
Human	Systematic review	115	Lactobacillus rhamnosus GG most reduced plasma TMAO concentration	Cantero MA, Guedes MRA, Fernandes R, Lollo PCB. Trimethylamine N-oxide reduction is related to probiotic strain specificity: A systematic review. Nutr Res. 2022 Aug;104:29–35. doi: 10.1016/j.nutres.2022.04.001. Epub 2022 Apr 10. PMID: 35,588,611.^Citation36

Abbreviations: RCT, Randomized Controlled Trial; MetS, Metabolic Syndrome; T2DM, Type 2 Diabetes Mellitus; HgA1c, Hemoglobin A1c; BP, Blood pressure; TMAO, Trimethylamine N-oxide.

Table 2 Addressing Toxic Metals on CVD Risk

Species	Study Type	Subjects	Findings	Citation
Human	RCT	24	Consumption of probiotic yogurt had a protective effect against further increases in mercury and arsenic	Bisanz JE, Enos MK, Mwanga JR, Changalucha J, Burton JP, Gloor GB, Reid G. Randomized open-label pilot study of the influence of probiotics and the gut microbiome on toxic metal levels in Tanzanian pregnant women and school children. mBio. 2014 Oct 7;5(5):e01580–e01594. doi: 10.1128/mBio.01580–14. PMID: 25,293,764; PMCID: PMC4196227.^Citation51
Human	Meta analysis of RCT	1983	17 studies including 1 RCT, TACT, suggested improved outcomes which may provide more benefit to patients with diabetes and severe peripheral arterial disease	Ravalli F, Vela Parada X, Ujueta F, Pinotti R, Anstrom KJ, Lamas GA, Navas-Acien A. Chelation Therapy in Patients With metal toxicity and Cardiovascular Disease: A Systematic Review. J Am Heart Assoc. 2022 Mar 15;11(6):e024648. doi: 10.1161/JAHA.121.024648. Epub 2022 Mar 1. PMID: 35,229,619; PMCID: PMC9075296.^Citation52
Human	Meta analysis	968	Sauna treatment LVEF, 6-min walk distance, and flow-mediated dilation increased along with BNP decrease	Li Z, Jiang W. Acute and short-term efficacy of sauna treatment on cardiovascular function: a meta-analysis: reply. Eur J Cardiovasc Nurs. 2021 Oct 27;20(7):730. doi: 10.1093/eurjcn/zvab050. PMID: 34,329,397.^Citation53
Human	Multi-arm RCT	47	Greater improvements in CRF, SBP, and Cholesterol were noted in Sauna intervention when compared to exercise alone.	Lee E, Kolunsarka I, Kostensalo J, Ahtiainen JP, Haapala EA, Willeit P, Kunutsor SK, Laukkanen JA. Effects of regular sauna bathing in conjunction with exercise on cardiovascular function: a multi-arm, randomized controlled trial. Am J Physiol Regul Integr Comp Physiol. 2022 Sep 1;323(3):R289-R299. doi: 10.1152/ajpregu.00076.2022. Epub 2022 Jul 4. PMID: 35,785,965; PMCID: PMC9394774.^Citation54

Abbreviations: CRF, Cardio Respiratory Fitness; SBP, Systolic Blood Pressure; LVEF, Left Ventricular Ejection Fraction; BNP, Brain Natriuretic Peptide.

Table 3 Transdermal Hormone Replacement on CVD Risk

Species	Study Type	Subjects	Findings	Citation
Human	RCT	172	TE + IMP tended to improve cardiac autonomic control and prevented age-related changes in endothelial function in postmenopausal women.	Gordon JL, Rubinow DR, Watkins L, Hinderliter AL, Caughey MC, Girdler SS. The Effect of Perimenopausal Transdermal Estradiol and Micronized Progesterone on Markers of Risk for Arterial Disease. J Clin Endocrinol Metab. 2020 May 1;105(5):e2050–60. doi: 10.1210/clinem/dgz262. PMID: 31,838,497; PMCID: PMC7096310.^Citation75
Human	Randomized pilot trial	57	MP + t-E2 demonstrated a positive effect on traditional CVD markers cardiac output, reduction in diastolic blood pressure, and total peripheral resistance after 12 months	Mittal et al. Impact of micronised progesterone and medroxyprogesterone acetate in combination with transdermal oestradiol on cardiovascular markers in women diagnosed with premature ovarian insufficiency or an early menopause: a randomised pilot trial. Maturitas. 2022.^Citation76
Human	RCT	596	HT with estradiol plus topical progesterone reduced atherogenic progression of arterial wall composition in healthy postmenopausal women who were within 6 years from menopause	Karim R, Xu W, Kono N, Sriprasert I, Li Y, Yan M, Stanczyk FZ, Shoupe D, Mack WJ, Hodis HN. Effect of menopausal hormone therapy on arterial wall echomorphology: Results from the Early versus Late Intervention Trial with Estradiol (ELITE). Maturitas. 2022 Aug;162:15–22. doi: 10.1016/j.maturitas.2022.02.007. Epub 2022 Mar 17. PMID: 35,474,254; PMCID: PMC9232990.^Citation77
Human	RCT	5359	Transdermal HRT had a positive effect on flow-mediated dilatation trend towards benefit in non-fatal M.I.	Bontempo S, Yeganeh L, Giri R, Vincent AJ. Use of MHT in women with cardiovascular disease: a systematic review and meta-analysis. Climacteric. 2024 Feb;27(1):93–103. doi: 10.1080/13,697,137.2023.2273524. Epub 2024 Jan 15. PMID: 37,933,495.^Citation78

Abbreviations: RCT, Randomized Controlled Trial; MP, Micronized Progesterone; t-E2, Transdermal Estradiol; HT, hormone Therapy; TE, Transdermal Estradiol; IMP, Intermitent Micronized Progesterone; M.I, Myocardial Infarction.

Naruszewicz M, Johansson ML, Zapolska-Downar D, Bukowska H. Effect of Lactobacillus plantarum 299v on cardiovascular disease risk factors in smokers. Am J Clin Nutr. 2002;76(6):1249–1255. PMID: 12450890. doi:10.1093/ajcn/76.6.1249

 PubMed Web of Science ®Google Scholar

Barreto FM, Colado Simão AN, Morimoto HK, Batisti Lozovoy MA, Dichi I, Helena da Silva Miglioranza L. Beneficial effects of Lactobacillus plantarum on glycemia and homocysteine levels in postmenopausal women with metabolic syndrome. Nutrition. 2014;30(7–8):939–942. PMID: 24613434. doi:10.1016/j.nut.2013.12.004

 PubMed Web of Science ®Google Scholar

Hendijani F, Akbari V. Probiotic supplementation for management of cardiovascular risk factors in adults with type II diabetes: a systematic review and meta-analysis. Clin Nutr. 2018;37(2):532–541. PMID: 28318686. doi:10.1016/j.clnu.2017.02.015

 PubMed Web of Science ®Google Scholar

Zhao L, Zhang F, Ding X, et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science. 2018;359(6380):1151–1156. PMID: 29590046. doi:10.1126/science.aao5774

 PubMed Web of Science ®Google Scholar

Malik M, Suboc TM, Tyagi S, et al. Lactobacillus plantarum 299v supplementation improves vascular endothelial function and reduces inflammatory biomarkers in men with stable coronary artery disease. Circ Res. 2018;123(9):1091–1102. PMID: 30355158; PMCID: PMC6205737. doi:10.1161/CIRCRESAHA.118.313565

 PubMed Web of Science ®Google Scholar

Cantero MA, Guedes MRA, Fernandes R, Lollo PCB. Trimethylamine N-oxide reduction is related to probiotic strain specificity: a systematic review. Nutr Res. 2022;104:29–35. PMID: 35588611. doi:10.1016/j.nutres.2022.04.001

 PubMed Web of Science ®Google Scholar

Bisanz JE, Enos MK, Mwanga JR, et al. Randomized open-label pilot study of the influence of probiotics and the gut microbiome on toxic metal levels in Tanzanian pregnant women and school children. mBio. 2014;5(5):e01580–14. PMID: 25293764; PMCID: PMC4196227. doi:10.1128/mBio.01580-14

 PubMed Web of Science ®Google Scholar

Ravalli F, Vela Parada X, Ujueta F, et al. Chelation therapy in patients with cardiovascular disease: a systematic review. J Am Heart Assoc. 2022;11(6):e024648. PMID: 35229619; PMCID: PMC9075296. doi:10.1161/JAHA.121.024648

 PubMed Web of Science ®Google Scholar

Li Z, Jiang W. Acute and short-term efficacy of sauna treatment on cardiovascular function: a meta-analysis: reply. Eur J Cardiovasc Nurs. 2021;20(7):730. PMID: 34329397. doi:10.1093/eurjcn/zvab050

 PubMed Web of Science ®Google Scholar

Lee E, Kolunsarka I, Kostensalo J, et al. Effects of regular sauna bathing in conjunction with exercise on cardiovascular function: a multi-arm, randomized controlled trial. Am J Physiol Regul Integr Comp Physiol. 2022;323(3):R289–R299. PMID: 35785965; PMCID: PMC9394774. doi:10.1152/ajpregu.00076.2022

 PubMed Web of Science ®Google Scholar

Gordon JL, Rubinow DR, Watkins L, Hinderliter AL, Caughey MC, Girdler SS. The effect of perimenopausal transdermal estradiol and micronized progesterone on markers of risk for arterial disease. J Clin Endocrinol Metab. 2020;105(5):e2050–60. PMID: 31838497; PMCID: PMC7096310. doi:10.1210/clinem/dgz262

 PubMed Web of Science ®Google Scholar

Mittal M, McEniery C, Supramaniam PR. Impact of micronised progesterone and medroxyprogesterone acetate in combination with transdermal oestradiol on cardiovascular markers in women diagnosed with premature ovarian insufficiency or an early menopause: a randomised pilot trial. Maturitas. 2022;161:18–26.

 PubMed Web of Science ®Google Scholar

Karim R, Xu W, Kono N, et al. Effect of menopausal hormone therapy on arterial wall echomorphology: results from the Early versus Late Intervention Trial with Estradiol (ELITE). Maturitas. 2022;162:15–22. PMID: 35474254; PMCID: PMC9232990. doi:10.1016/j.maturitas.2022.02.007

 PubMed Web of Science ®Google Scholar

Bontempo S, Yeganeh L, Giri R, Vincent AJ. Use of MHT in women with cardiovascular disease: a systematic review and meta-analysis. Climacteric. 2024;27(1):93–103. PMID: 37933495. doi:10.1080/13697137.2023.2273524

 PubMed Web of Science ®Google Scholar