Your Cheating HeartOn
Atrial fibrillation (AF), like a bad moon, is on the rise. Nutritional standards have fallen so low that within a single generation the age-adjusted prevalence of AF has quadrupled (1), a worrying trend that appears to be continuing (2-4). Even more concerning, the disease itself may be becoming more malignant.
Students of medical history and ethnobotany will know something about the Cinchona or fever tree, which provides the closely related alkaloids quinine and quinidine. Their pharmacological properties overlap; quinine is the more effective anti-malarial and quinidine is the more effective anti-arrhythmic.
Quinidine fell out of favour in the mid-60’s (5) and was largely replaced by synthetic analogues which are more effective and somewhat safer (although see 6). Its main use today is to treat and prevent electrical storms in patients with Brugada syndrome (7), a rare genetic condition which carries a high risk of fatal ventricular arrhythmias and the name of the three cardiologist brothers who characterized it.
My old anatomy professor was not entirely thrilled by the burgeoning pharmaceutical industry, and often talked about medicine past. A proponent of quinidine, he had served in WW2 and told us of veterans from the Great War he knew who took the natural compound to treat intermittent atrial fibrillation, and had done so for decades. The implication was that their arrythmias were stable over time.
Fast forward fifty years and the picture is rather different. AF is now seen as an inherently and often rapidly progressive condition, with between 9 and 30% of patients moving from paroxysmal (intermittent) to persistent and finally permanent fibrillation within a year of diagnosis (8); requiring increasing doses of anti-arrhythmic drugs and moving on, where indicated, to cardiac ablation (9, 10).
Given the rapidly increasing numbers of cases and the apparent worsening in disease profile, discovering the risk factors which promote AF and its progression has become a priority in cardiovascular research. If this search is successful, it should help to provide strategies for better patient management.
Hypertension, obesity, diabetes and age are all risk factors for developing AF. The first three are increasing due to the modern diet and lifestyle, and this helps to explain the increasing incidence of fibrillation.
Reducing them would result in fewer cases of AF. But there is more.
The comorbidities most likely to signal progression include hypertension, obesity and diabetes (as before), but also coronary artery disease, sleep apnea and age (10-14). While there are many confounding variables (ie diet, smoking, physical activity, psychological factors), the above mix signals that chronic inflammatory stress is involved in the pathoaetiology and progression of AF (ie 15, 16).
Other inflammatory conditions can also trigger fibrillation.
These range from local inflammation caused by myocarditis (17) to systemic diseases such as sepsis (18), pneumonia (19), and autoimmune conditions (20-22); with higher inflammatory biomarkers in blood predicting a higher risk of developing or progressing AF (23-26). Inflammatory changes can be seen in the atria themselves (ie 27).
To summarise, atrial fibrillation is increasingly being seen as an inflammatory condition, with inflammation a key factor driving its progression (27, 28).
This explains why the commonly used anti-arrhythmic drugs, while they improve the acute symptoms of AF, have relatively little effect on slowing progression (29) or on overall mortality (10, 30, 31). They treat symptoms but are not dealing with the underlying pathology. The anticoagulants, in contrast, are highly protective (32) because they correctly target intra-atrial thrombus formation.
Let us progress to a very basic overview of the pathophysiology of AF progression.
There is evidence that recurrent AF episodes promote the inducibility and stability of AF (ie progression) via an interaction between electrical and structural re-modelling (33, 34); with subsequent changes in the ongoing conversations between myocytes, fibroblasts and endothelial cells (35).
Chronic inflammation is a central part of this process. Chronic inflammation in the atria (and in any other tissue) degrades the extracellular matrix, a 3-D mesh of microfibers which acts as a soft skeleton for the myocytes and is involved in extra-cellular channeling of electrical and physical signals.
The inflammatory process drives fibrosis in the heart, involving fibroblast proliferation and the subsequent deposition of amyloid and improperly orientated bundles of microfibers (36-39). As these deposits grow they impede normal electrical flow and facilitate re-entry (36-39) in a process which resembles kindling. Activation of the inflammasome in immune cells infiltrating the myocardium is integral to this process (39), and therefore to atrial fibrillation (40, 41).
If this model is even partly accurate, anti-inflammatory drugs should provide some degree of protection – but the data are not very encouraging.
The nonsteroidal anti-inflammatory drugs are associated with a slightly increased risk of developing AF (42). This relationship is probably not directly causative. It is thought to be a sequel to these drug’s more familiar adverse effects, which include raising the risk of heart attacks. Prednisone and colchicine have anti-inflammatory and anti-arrhythmic effects (43-45), but are too toxic for long-term use.
Are the anti-inflammatory nutrients any better?
Key anti-inflammatory nutrients include the omega 3 HUFA’s and the polyphenols. The omega 3’s (46-48) and many polyphenols (49-55) including the amphiphilic polyphenols in marine algae (53) and olives (54, 55), down-regulate the inflammasome very effectively.
Intakes of these important anti-inflammatory compounds have steadily declined since the late 19th century (56), due to our increasing reliance on ultra-processed foods (57). This has left us more vulnerable to chronic inflammation and all of its manifestations; and it is logical to suppose that this has contributed to the increasing incidence of atrial fibrillation, and an increasing tendency to progression.
Might replacing the omega 3’s and the polyphenols in our diet be protective?
The omega 3’s stabilise cardiomyocyte membranes and offer protection against ventricular arrhythmias (58, 59), but their effect on A-fib is unclear. Omega 3 HUFA’s in commercial fish oil supplements have either no effect at all (60) or a tendency to increase AF in individuals with cardiovascular disease (61), depending on which paper you prefer.
As the inflammasome / inflammatory stress is profoundly involved in the development and progression of AF, and the omega 3’s are one of the key nutrient groups which have the ability to down-grade the inflammasome, these results appear paradoxical. But there is another way of looking at this.
Given that commercial and pharmaceutical fish oils do NOT confer the documented benefits of oily fish or omega 3’s combined with amphiphile polyphenols (ie 62-68), I suspect that the null / negative results reflect the fish oil industry’s decision to replace the phlorotannin chaperones originally contained in fish oil with the inappropriate antioxidant, d-alpha-tocopherol.
This formulation error leaves ingested omega 3’s prone to oxidation in the body, manifested as lower secondary bioavailability (69) and implying increased formation of lipid peroxidation products – some of which appear to be profibrillatory (70-72).
The polyphenols have anti-arrhythmic properties of their own (ie 73) which may extend to the alleviation of atrial fibrillation (74). Extra virgin olive oil, a rich source of amphiphile polyphenols, was found in the PREDIMED trial to reduce the risk of AF developing (75) and PREDIMAR, a follow-up study designed to look at the effects of olive oil on AF progression (76), will be reporting in late 2023.
I will continue to take Balance oil, which combines fish oil and extra-virgin olive oil, to manage my own AF. Originally triggered by Grave’s Disease and documented by the good doctors at Epsom Hospital in the UK, my AF has not progressed in 13 years.
It is controlled by the same low dose of flecainide (50 mg b.i.d.) that was originally prescribed.
This is not the whole story. Chronic and/or severe psychological stress is pro-inflammatory (77), and extreme stress, which re-wires circuitry in the hippocampus, parahippocampus and limbic system, is known to trigger Takotsuba syndrome (78, 79) which can cause AF directly. Psychological stress also increases the secretion of aldosterone (80), another factor implicated in AF (81).
Declining intakes of anxiolytic phytonutrients make us more vulnerable to stress (82, 83), and even to the memory of stress (84). Is loss of resilience, caused by the ultra-processed diet, contributing to the increase in AF? Here is another potential problem to lay at the doors of the food industry, and another avenue worth exploring.
A hat tip to the surgeons who developed maze and then closed chest maze surgery. This beautiful and very often curative technique has transformed many lives, and is still developing. And finally, my heartfelt gratitude for the healing power of music (85).
Next week: Only the Lonely. Hearts, minds and gut feelings.
- Schnabel RB, Yin X, Levy D. Fifty-year Trends in Atrial Fibrillation Prevalence, Incidence, Risk Factors and Mortality in the Community. Lancet (2015) Jul 11: 386(9899):154-162
- Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. 2001;285:2370–5.
- Stefansdottir H, Aspelund T, Gudnason V, Arnar DO. Trends in the incidence and prevalence of atrial fibrillation in Iceland and future projections.2011;13:1110–7.
- Williams BA, Chamberlain AM, Blankenship JC, Hylek EM, Voyce S. Trends in Atrial Fibrillation Incidence Rates Within an Integrated Health Care Delivery System, 2006 to 2018. JAMA Netw Open. 2020 Aug 3;3(8):e2014874
- Selzer A. Wray HW. Quinidine syncope. Paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias.Circulation 1964, 30, 17–26.
- Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. Engl. J. Med. 1991, 324, 781–788.
- Sieira J, Dendramis G, Brugada P. Pathogenesis and management of Brugada syndrome. Rev. Cardiol.2016, 13, 744–756.
- Shukla A, Curtis AB. Avoiding permanent atrial fibrillation: treatment approaches to prevent disease progression. Vasc Health Risk Manag. 2014;10:1-12.
- Shah AJ, Hocini M, Komatsu Y, Daly M, Zellerhoff S, Jesel L, Amaroui S, Ramoul K, Denis A, Derval N, Sacher F, Jais P, Haissaguerre M. The Progressive Nature of Atrial Fibrillation:A Rationale for Early Restoration and Maintenance of Sinus Rhythm. J Atr Fibrillation. 2013 Aug 31;6(2):849.
- Holmqvist F, Kim S, Steinberg BA, Reiffel JA, Mahaffey KW, Gersh BJ, Fonarow GC, Naccarelli GV, Chang P, Freeman JV, Kowey PR, Thomas L, Peterson ED, Piccini JP; ORBIT-AF Investigators. Heart rate is associated with progression of atrial fibrillation, independent of rhythm. 2015 Jun;101(11):894-9.
- Park WC, Seo I, Kim SH, Lee YJ, Ahn SV. Association between Resting Heart Rate and Inflammatory Markers (White Blood Cell Count and High-Sensitivity C-Reactive Protein) in Healthy Korean People. Korean J Fam Med. 2017 Jan;38(1):8-13.
- Whelton SP, Narla V, Blaha MJ, Nasir K, Blumenthal RS, Jenny NS, Al-Mallah MH, Michos ED. Association between resting heart rate and inflammatory biomarkers (high-sensitivity C-reactive protein, interleukin-6, and fibrinogen) (from the Multi-Ethnic Study of Atherosclerosis). Am J Cardiol. 2014 Feb 15;113(4):644-9.
- Sajadieh A, Nielsen OW, Rasmussen V, Hein HO, Abedini S, Hansen JF. Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease. Eur Heart J. 2004 Mar;25(5):363-70.
- Wang L, Zhang N, Sun BG, Wang Z, Cao ZY. Elevated Resting Heart Rate Is Associated with Carotid Atherosclerosis in Middle-Aged and Elderly Chinese Population. J Stroke Cerebrovasc Dis. 2016 Jan;25(1):34-40.
- Ahmadi, SS, Svensson AM, Pivodic A, Rosengren A, Lind M. Risk of atrial fibrillation in persons with type 2 diabetes and the excess risk in relation to glycaemic control and renal function: a Swedish cohort study. Cardiovasc Diabetol19, 9 (2020).
- Karam BS, Chavez-Moreno A, Koh W, Akar JG, Akar FG. Oxidative stress and inflammation as central mediators of atrial fibrillation in obesity and diabetes. Cardiovasc Diabetol. 2017;16(1):120.
- Morgera T, Di Lenarda A, Dreas L, Pinamonti B, Humar F, Bussani R, Silvestri F, Chersevani D, CameriniF. Electrocardiography of myocarditis revisited: clinical and prognostic significance of electrocardiographic changes.Am Heart J. (1992) 124:455–67.
- Kuipers S, Klein Klouwenberg PM, Cremer OL. Incidence, risk factors and outcomes of new-onset atrial fibrillation in patients with sepsis: a systematic review.Crit Care. (2014) 18:688.
- Musher DM, Alexandraki I, Graviss EA, Yanbeiy N, Eid A, Inderias LA, Phan HM, Solomon E. Bacteremic and nonbacteremic pneumococcal pneumonia. A prospective study.Medicine. (2000) 79:210–21.
- Ungprasert P, Srivali N, Kittanamongkolchai W. Risk of incident atrial fibrillation in patients with rheumatoid arthritis: a systematic review and meta-analysis.Int J Rheum Dis. (2017) 20:434–41.
- Ahlehoff O, Gislason GH, Jørgensen CH, Lindhardsen J, Charlot M, Olesen JB, Abildstrøm SZ, Skov L, Torp-Pedersen C, Hansen PR. Psoriasis and risk of atrial fibrillation and ischaemic stroke: a danish nationwide cohort study.Eur Heart J. (2012) 33:2054–64.
- Seferović PM, Ristić AD, Maksimović R, Simeunović DS, Ristić GG, Radovanović G, Seferović D, Maisch B, Matucci-Cerinic M. Cardiac arrhythmias and conduction disturbances in autoimmune rheumatic diseases.Rheumatology. (2006) 45:iv39–42.
- Jabati S, Fareed J, Liles J, Otto A, Hoppensteadt D, Bontekoe J, Phan T, Walborn A, Syed M. Biomarkers of inflammation, thrombogenesis, and collagen turnover in patients with atrial fibrillation.Clin Appl Thromb Hemost. (2018) 24:718–23.
- Hijazi Z, Aulin J, Andersson U, Alexander JH, Gersh B, Granger CB, Hanna M, Horowitz J, Hylek EM, Lopes RD, Siegbahn A, Wallentin L; ARISTOTLE Investigators. Biomarkers of inflammation and risk of cardiovascular events in anticoagulated patients with atrial fibrillation.Heart. (2016) 102:508–17.
- Bhat T, Teli S, Rijal J, Bhat H, Raza M, Khoueiry G, Meghani M, Akhtar M, Costantino T. Neutrophil to lymphocyte ratio and cardiovascular diseases: a review. Expert Rev Cardiovasc Ther. (2013) 11:55–9.
- Richter B, Gwechenberger M, Socas A, Zorn G, Albinni S, Marx M, Bergler-Klein J, Binder T, Wojta J, Gössinger HD. Markers of oxidative stress after ablation of atrial fibrillation are associated with inflammation, delivered radiofrequency energy and early recurrence of atrial fibrillation. Clin Res Cardiol. (2012) 101:217–25.
- Scott L J, Li N, Dobrev D. Role of inflammatory signaling in atrial fibrillation. Int J Cardiol. (2019) 287:195–200.
- Zhou X, Dudley SC Jr. Evidence for Inflammation as a Driver of Atrial Fibrillation. Front Cardiovasc Med. 2020 Apr 29;7:62.
- De Vos CB, Breithardt G, Camm AJ, Dorian P, Kowey PR, Le Heuzey JY, Naditch-Brûlé L, Prystowsky EN, Schwartz PJ, Torp-Pedersen C, Weintraub WS, Crijns HJ. Progression of atrial fibrillation in the REgistry on Cardiac rhythm disORDers assessing the control of Atrial Fibrillation cohort: clinical correlates and the effect of rhythm-control therapy.Am Heart J. 2012;163(5):887–893.
- Larsen JA, Kadish AH, Schwartz JB. Proper use of antiarrhythmic therapy for reduction of mortality after myocardial infarction. Drugs Aging. 2000 May;16(5):341-50.
- Krishnamoorthy S, Lip GYH. How safe is the antiarrhythmic drug therapy in atrial fibrillation? EP Europace2009: 11( 7), 837–839
- Arbel R, Sergienko R, Hammerman A, Dotan-Greenberg S, Batat E, Avnery O, Greenberg D, Ellis MH. Direct oral anticoagulation and mortality in moderate to high-risk atrial fibrillation. 2019 Oct;105(19):1487-1492.
- Capucci A, Compagnucci P. (2020). Is delayed cardioversion the better approach in recent-onset atrial fibrillation? No. Emerg. Med. 15, 5–7.
- Nattel S, Heijman J, Zhou L, Dobrev D. Molecular Basis of Atrial Fibrillation Pathophysiology and Therapy: A Translational Perspective. Circ Res. 2020 Jun 19;127(1):51-72.
- Segers VFM, De Keulenaer GW. Autocrine Signaling in Cardiac Remodeling: A Rich Source of Therapeutic Targets. J Am Heart Assoc. 2021 Feb 2;10(3):e019169.
- Rog-Zielinska EA, Norris RA, Kohl P and Markwald R. The living scar-cardiac fibroblasts and the injured heart. Trends Mol Med. 22:99–114. 2016.
- Frangogiannis NG. The extracellular matrix in myocardial injury, repair, and remodeling. J Clin Invest. 127:1600–1612. 2017.
- Bruins P, te Velthuis H, Yazdanbakhsh AP, Jansen PG, van Hardevelt FW, de Beaumont EM, Wildevuur CR, Eijsman L, Trouwborst A. Hack CE: Activation of the complement system during and after cardiopulmonary bypass surgery: Postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia. 96:3542–3548. 1997.
- Smorodinova N, Bláha M, Melenovský V, Rozsívalová K, Přidal J, Ďurišová M, Pirk J, Kautzner J, Kučera T. Analysis of immune cell populations in atrial myocardium of patients with atrial fibrillation or sinus rhythm. PLoS One. 2017 Feb 22;12(2):e0172691.
- Yao C, Veleva T, Scott L Jr, Cao S, Li L, Chen G, Jeyabal P, Pan X, Alsina KM, Abu-Taha I Dr, Ghezelbash S, Reynolds CL, Shen YH, LeMaire SA, Schmitz W, Müller FU, El-Armouche A, Tony Eissa N, Beeton C, Nattel S, Wehrens XHT, Dobrev D, Li N. Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation. Circulation. 2018 Nov 13;138(20):2227-2242.
- Van Wagoner DR, Chung MK. Inflammation, Inflammasome Activation, and Atrial Fibrillation. 2018 Nov 13;138(20):2243-2246.
- Chuang SY, Hsu PF, Lin FJ, Huang YW, Wang GZ, Chang WC, Tsai HJ. Association between nonsteroidal anti-inflammatory drugs and atrial fibrillation among a middle-aged population: a nationwide population-based cohort. Br J Clin Pharmacol. 2018 Jun;84(6):1290-1300.
- Mohsen A. The anti-arrhythmic effects of prednisone in patients with sarcoidosis. Acta Cardiol. 2011 Dec;66(6):803-5.
- Won H, Kim JY, Shim J, Uhm JS, Pak HN, Lee MH, Joung B. Effect of a single bolus injection of low-dose hydrocortisone for prevention of atrial fibrillation recurrence after radiofrequency catheter ablation. Circ J. (2013) 77:53–9.
- Deftereos S, Giannopoulos G, Papoutsidakis N, Panagopoulou V, Kossyvakis C, Raisakis K, Raisakis K, Cleman MW, Stefanadis C. Colchicine and the heart: pushing the envelope. J Am Coll Cardiol. (2013) 62:1817–25.
- Shen L, Yang Y, Ou T, Key CC, Tong SH, Sequeira RC, Nelson JM, Nie Y, Wang Z, Boudyguina E, Shewale SV, Zhu X. Dietary PUFAs attenuate NLRP3 inflammasome activation via enhancing macrophage autophagy. J Lipid Res. 2017 Sep;58(9):1808-1821.
- Li G, Chen Z, Bhat OM, Zhang Q, Abais-Battad JM, Conley SM, Ritter JK, Li PL. NLRP3 inflammasome as a novel target for docosahexaenoic acid metabolites to abrogate glomerular injury. J Lipid Res. 2017 Jun;58(6):1080-1090.
- Lin C, Chao H, Li Z, Xu X, Liu Y, Bao Z, Hou L, Liu Y, Wang X, You Y, Liu N, Ji J. Omega-3 fatty acids regulate NLRP3 inflammasome activation and prevent behavior deficits after traumatic brain injury. Exp Neurol. 2017 Apr;290:115-122.
- Yao Y, Mao J, Xu S, Zhao L, Long L, Chen L, Li D, Lu S. Rosmarinic acid inhibits nicotine-induced C-reactive protein generation by inhibiting NLRP3 inflammasome activation in smooth muscle cells. J Cell Physiol. 2019 Feb;234(2):1758-1767.
- Liu S, Tian L, Chai G, Wen B, Wang B. Targeting heme oxygenase-1 by quercetin ameliorates alcohol-induced acute liver injury via inhibiting NLRP3 inflammasome activation. Food Funct. 2018 Aug 15;9(8):4184-4193.
- Yu W, Tao M, Zhao Y, Hu X, Wang M. 4′-Methoxyresveratrol Alleviated AGE-Induced Inflammation via RAGE-Mediated NF-κB and NLRP3 Inflammasome Pathway. 2018 Jun 14;23(6). pii: E1447.
- Jhang JJ, Lin JH, Yen GC. Beneficial Properties of Phytochemicals on NLRP3 Inflammasome-Mediated Gout and Complication. J Agric Food Chem. 2018 Jan 31;66(4):765-772.
- Yang K, Kim SY, Park JH, Ahn WG, Jung SH, Oh D, Park HC, Choi C. Topical Application of Phlorotannins from Brown Seaweed Mitigates Radiation Dermatitis in a Mouse Model. Mar Drugs. 2020 Jul 22;18(8):377.
- Al Rihani SB, Darakjian LI, Kaddoumi A. Oleocanthal-Rich Extra-Virgin Olive Oil Restores the Blood-Brain Barrier Function through NLRP3 Inflammasome Inhibition Simultaneously with Autophagy Induction in TgSwDI Mice. ACS Chem Neurosci. 2019 Aug 21;10(8):3543-3554.
- Kaneko Y, Sano M, Seno K, Oogaki Y, Takahashi H, Ohkuchi A, Yokozawa M, Yamauchi K, Iwata H, Kuwayama T, Shirasuna K. Olive Leaf Extract (OleaVita) Suppresses Inflammatory Cytokine Production and NLRP3 Inflammasomes in Human Placenta. 2019 Apr 28;11(5):970.
- Clayton P, Rowbotham J. How the mid-Victorians worked, ate and died. Int J Environ Res Public Health. 2009 Mar;6(3):1235-53.
- Monteiro CA, Moubarac JC, Cannon G, Ng SW, Popkin B. Ultra-processed products are becoming dominant in the global food system. Obes Rev.2013 Nov;14 Suppl 2:21-8.
- Lombardi M, Chiabrando JG, Vescovo GM, Bressi E, Del Buono MG, Carbone S, Koenig RA, Van Tassell BW, Abbate A, Biondi-Zoccai G, Dixon DL. Impact of Different Doses of Omega-3 Fatty Acids on Cardiovascular Outcomes: a Pairwise and Network Meta-analysis. Curr Atheroscler Rep. 2020 Jul 16;22(9):45.
- Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999 Aug 7;354(9177):447-55.
- Siscovick DS, Barringer TA, Fretts AM, Wu JH, Lichtenstein AH, Costello RB, Kris-Etherton PM, Jacobson TA, Engler MB, Alger HM, Appel LJ, Mozaffarian D; American Heart Association Nutrition Committee of the Council on Lifestyle and Cardiometabolic Health; Council on Epidemiology and Prevention; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology. Omega-3 Polyunsaturated Fatty Acid (Fish Oil) Supplementation and the Prevention of Clinical Cardiovascular Disease: A Science Advisory From the American Heart Association. 2017 Apr 11;135(15):e867-e884.
- Lombardi M, Carbone S, Del Buono MG, Chiabrando JG, Vescovo GM, Camilli M, Montone RA, Vergallo R, Abbate A, Biondi-Zoccai G, Dixon DL, Crea F. Omega-3 fatty acids supplementation and risk of atrial fibrillation: an updated meta-analysis of randomized controlled trials. Eur Heart J Cardiovasc Pharmacother. 2021 Jul 23;7(4):e69-e70.
- Clayton PR, Ladi S. From alga to omega; have we reached peak (fish) oil? J R Soc Med. 2015 Sep;108(9):351-7.
- Østerud B, Olvevoll EO. The combination of virgin olive oils and refined marine oils. Beneficial effects. Nutr. 2008, 10, 230-236.
- Eilertsen KE, Mæhre HK, Cludts K, Olsen JO, Hoylaerts MF. Dietary enrichment of apolipoprotein E-deficient mice with extra virgin olive oil in combination with seal oil inhibits atherogenesis. Lipids Health Dis. 2011 Mar 3;10:41.
- Streppel MT, Ocké MC, Boshuizen HC, Kok FJ, Kromhout D. Long-term fish consumption and n-3 fatty acid intake in relation to (sudden) coronary heart disease death: the Zutphen study. Eur Heart J. 2008 Aug;29(16):2024-30.
- Chrysohoou C, Panagiotakos DB, Pitsavos C, Skoumas J, Krinos X, Chloptsios Y, Nikolaou V, Stefanadis C. Long-term fish consumption is associated with protection against arrhythmia in healthy persons in a Mediterranean region–the ATTICA study. Am J Clin Nutr. 2007 May;85(5):1385-91.
- Mozaffarian D, Psaty BM, Rimm EB, Lemaitre RN, Burke GL, Lyles MF, Lefkowitz D, Siscovick DS. (2004). Fish intake and risk of incident atrial fibrillation. Circulation110, 368–373.
- Visioli F, Rise P, Barassi MC, Marangoni F, Galli C. Dietary Intake of Fish vs. Formulations Leads to Higher Plasma Concentrations of n-3 Fatty Acids. Lipids 2003, 38, 415-418.
- Ramlawi B, Otu H, Mieno S, Boodhwani M, Sodha NR, Clements RT, Bianchi C, Sellke FW. Oxidative stress and atrial fibrillation after cardiac surgery: a case-control study. Ann Thorac Surg. 2007 Oct;84(4):1166-72; discussion 1172-3.
- Prinsen JK, Kannankeril PJ, Sidorova TN, Yermalitskaya LV, Boutaud O, Zagol-Ikapitte I, Barnett JV, Murphy MB, Subati T, Stark JM, Christopher IL, Jafarian-Kerman SR, Saleh MA, Norlander AE, Loperena R, Atkinson JB, Fogo AB, Luther JM, Amarnath V, Davies SS, Kirabo A, Madhur MS, Harrison DG, Murray KT. Highly Reactive Isolevuglandins Promote Atrial Fibrillation Caused by Hypertension. JACC Basic Transl Sci. 2020 May 27;5(6):602-615.
- Zhao Q, Kebbati AH, Zhang Y, Tang Y, Okello E, Huang C. Effect of coenzyme Q10 on the incidence of atrial fibrillation in patients with heart failure. J Investig Med. 2015 Jun;63(5):735-9.
- Behl T, Bungau S, Kumar K, Zengin G, Khan F, Kumar A, Kaur R, Venkatachalam T, Tit DM, Vesa CM, Barsan G, Mosteanu DE. Pleotropic Effects of Polyphenols in Cardiovascular System. Biomed Pharmacother. 2020 Oct;130:110714.
- Baczkó I, Light PE. Resveratrol and derivatives for the treatment of atrial fibrillation. Ann N Y Acad Sci. 2015 Aug;1348(1):68-74.
- Martínez-González MÁ, Toledo E, Arós F, Fiol M, Corella D, Salas-Salvadó J, Ros E, Covas MI, Fernández-Crehuet J, Lapetra J, Muñoz MA, Fitó M, Serra-Majem L, Pintó X, Lamuela-Raventós RM, Sorlí JV, Babio N, Buil-Cosiales P, Ruiz-Gutierrez V, Estruch R, Alonso A; PREDIMED Investigators. Extravirgin olive oil consumption reduces risk of atrial fibrillation: the PREDIMED (Prevención con Dieta Mediterránea) trial. 2014 Jul 1;130(1):18-26.
- Barrio-Lopez MT, Ruiz-Canela M, Ramos P, Tercedor L, Ibañez Criado JL, Ortiz M, Goni L, Ibañez Criado A, Macías-Ruiz R, García-Bolao I, Martínez-González MA, Almendral J. PREvention of recurrent arrhythmias with Mediterranean diet (PREDIMAR) study in patients with atrial fibrillation: Rationale, design and methods. Am Heart J. 2020 Feb;220:127-136.
- Pitsavos C, Panagiotakos DB, Papageorgiou C, Tsetsekou E, Soldatos C, Stefanadis C. Anxiety in relation to inflammation and coagulation markers, among healthy adults: the ATTICA study. Atherosclerosis (2006). 185(2),320–326.
- Silva AR, Magalhães R, ArantesC, Moreira PS, Rodrigues M, Marques P, Marques J, Sousa N, Pereira VH. Brain functional connectivity is altered in patients with Takotsubo Syndrome. Sci Rep. 2019 Mar 12;9(1):4187.
- Templin C, Hänggi J, Klein C, Topka MS, Hiestand T, LevinsonRA, Jurisic S, Lüscher TF, Ghadri JR, Jäncke L. Altered limbic and autonomic processing supports brain-heart axis in Takotsubo syndrome. Eur Heart J. 2019 Apr 14;40(15):1183-1187.
- Kubzansky LD, Adler GK. Aldosterone: A forgotten mediator of the relationship between psychological stress and heart disease. Neurosci Biobehav 2010 Jan:34(1);80-86
- Seccia TM, Caroccia B, Maiolino G, Cesari M, Rossi GP. Arterial Hypertension, Aldosterone, and Atrial Fibrillation. Curr Hypertens Rep. 2019 Nov 18;21(12):94.
- Farzaei MH, Bahramsoltani R, Rahimi R, Abbasabadi F, Abdollahi M. A Systematic Review of Plant-Derived Natural Compounds for Anxiety Disorders. Curr Top Med Chem. 2016;16(17):1924-42.
- Nabavi SM, Daglia M, Braidy N, Nabavi SF. Natural products, micronutrients, and nutraceuticals for the treatment of depression: A short review. Nutr Neurosci. 2017 Apr;20(3):180-194.
- Koren T, Yifa R, Krot M, BZen-Shannan TL, Axulay-Debby H, Zalayat I, Hajjo H, Schiller M, Haykin H, Korin B, Farfara D, Hakim F, Kobiler O, Rosenbum K. Insular cortex neurons encode and retrieve specific immune responses. Cell 2021, https://doi.org/10.1016/j.cell.2021.10.013