Why is Alcohol-Induced Atrial Arrhythmias and Sudden Cardiac Death Difficult to Prevent and Treat: Potential Roles of Unrecognized Ionized Hypomagnesemia and Release of Ceramides and Platelet-Activating Factor
Received Date: Jul 25, 2016 / Accepted Date: Aug 26, 2016 / Published Date: Oct 02, 2016
Heart failure is the leading worldwide cause of morbidity, myocardial infarctions and mortality whose causes impose staggering costs and often lengthy hospitalizations. The specific reasons (or mechanisms) to explain or predict atrial arrhythmias in alcoholics or” binge- drinkers” are not known. The authors present evidence for a novel, new hypothesis whereby low tissue and serum levels of ionized magnesium(Mg2+) coupled to release of ceramides and platelet-activating factor (PAF) act to increase risk for cardiac atrial arrhythmias in people who imbibe too much alcoholic spirits over a short-period of time(i.e., binge-drinkers) or are alcohol abusers. The authors discuss several mechanisms whereby low Mg2+ and the generation of PAF and ceramides produce a high probability for atrial arrhythmias in alcoholics. The importance of adequate water-borne and dietary levels of Mg is emphasized
Keywords: Alcohol abuse; Sphingolipids; PAF; Ionized magnesium; Microcirculation
Numerous epidemiological studies have suggested that ingestion of daily low concentrations of alcohol (e.g., 1-2 drinks) might be cardioprotective [1-3]. In contrast, high doses of ethanol are known to pose risks for atrial fibrillation (AF) and arrythmias, supraventricular arrhythmias, angina, ischemic heart disease (IHD), hypertension, strokes and sudden cardiac death (SCD) [4-7]. Although numerous hypotheses have been advanced to explain alcohol-induced AF and SCD, such as genetic predisposition, underlying QT abnormalities, alterations in calcium homeostasis, underlying electrolyte abnormalities, baroreceptor disturbances, nutritional abnormalities and cardiac muscle structural changes, satisfactory explanations are still lacking [5- 9]. Exactly why female adults, prior to menopause, demonstrate onethird the rate of alcohol-induced hypertension, AF and SCD is also not known [10,11].
Alcohol abuse leads to primary malnutrition that is deficient utilization of nutrients. Alcoholic beverages provide what is termed “empty” calories because ethanol does not contain significant amounts of proteins, vitamins, or minerals. An individual who consumes 5 to 30 ounces of an 86-proof (43% v/v ethanol) beverage will ingest from 375 to 2,250 empty calories. In other terms, this represents from as little as 15% of the normal daily caloric requirements to 100%. The end result of such intake is a decreased intake of other foods and results in an imbalance of daily nutrient ingestion . Serum hypomagnesemia occurs in from 30 to 60% of the alcoholic population [13-16]. Nearly 90% of patients undergoing alcohol withdrawal are hypomagnesemic.
As early as the beginning of the nineteenth century, alcohol abuse was found to be detrimental to the heart. In 1902, MacKenzie coined the term “alcoholic heart disease” . Approximately 50 years later, William Evans reported on characteristic T-wave changes and the presence of AF, paroxysmal atrial tachycardia, and bundle blocks . Ettinger and co-workers, in 1978, coined the term “holiday heart” which is defined “as an acute cardiac rhythm and or conduction disturbance associated with heavy ethanol consumption in a person without any other clinical evidence of heart disease and disappearing without evident residual disturbances, with abstinence” . However, the most common arrhythmia found in this original study was AF. A Framingham study of more than 10,000 people reported, in 2004, that long-term consumption of alcohol (> 35 g alcohol/day) resulted in a high risk (e.q., more than 30%) for AF, and strokes, and SCD . Interestingly, a prospective cohort study in Denmark of nearly 50,000 men and women also found heavy consumption of alcohol resulted in a very high risk for AF, but with one difference women consuming daily alcoholic beverages demonstrated a very low risk for AF . Overall, looking at additional studies as well, there is a clear relationship between heavy alcohol ingestion (i.e., 3-5 drinks/day), AF and SCD [2- 7]. A similar relationship with “binge-drinking”, AF and SCD is also clear. In most of these subjects, the only findings at “post mortem” are fatty livers typical of heavy alcohol ingestion, often leading pathologists, inaccurately, to term the SCD to alcohol-induced liver toxicity, rather than “alcohol-associated arrhythmic death”. Less than 15% of these deaths have been associated with either a history of IHD or atheromas on the coronaries on autopsy [6,7]. This has led most pathologists to misdiagnose the actual cause of AF-induced SCD .
Over the past two decades, evidence has accumulated to indicate that daily dietary deficiency in magnesium (Mg) intake and/or errors in Mg metabolism poses serious risks for development of AF, hypertension, IHD, and SCD [22-37], whereas higher than normal Mg intake is found to be associated with decreased or ameliorated AF, myocardial infarctions, hypertension, strokes, and incidence of SCD [14,24-36]. It has been known for more than 40 years that chronic ingestion of alcoholic beverages results in body depletion of Mg [6,7].
Relationship of Mg to Cardiac Stability, Function, IHD and SCD: Importance of Ionized Mg
Mg is co-factor for more than 500 enzymes, and is the second most abundant intracellular cation after potassium. It is vital in numerous physiological, cellular and biochemical reactions including carbohydrate, lipid, protein, DNA, and RNA metabolism, among other pathways [24,38]. Several epidemiologic studies in North America and Europe have shown that people consuming Western-type diets are low in Mg content ( i.e., 30-65% of the RDA for Mg) [26,31-37,39]; most such diets in the USA show that 60-80% of Americans are consuming 185- 235 mg/day of Mg [35,40]. In 1900, in contrast, most Americans were consuming 450-550 mg/day of Mg . Low Mg content of drinking water, found in areas of soft-water and Mg-poor soil, is associated with high incidences of IHD, atherosclerosis, coronary vasospasm, hypertension, and SCD [23,26,31,34,41-47]. The myocardial level of Mg has consistently been observed to be lower in subjects dying from IHD and SCD in soft-water areas than those subjects living in hardwater areas [22-24,26,27,31,34,35]. More than 45 years ago, two of us demonstrated that Mg2+ behaves as a natural calcium channel blocker in both cardiac and vascular smooth muscle (VSM) cells [24,48-52]. We also showed in experimental animals that Mg behaves as a natural statin in that it can lower cholesterol and triglyceride levels as well as act as a powerful vasodilator in the microcirculation, on coronary arteries and as a cardiac muscle relaxant [24,31,35,47,51,53-57]. Hypermagnesemic diets have been shown to ameliorate hypertension and atherogenesis [24-28,31,33-36,47,58-61].
Using sensitive and newly-designed specific Mg2+-ion selective electrodes, our laboratories demonstrated that patients with alcohol -intoxication, hypertension, IHD, cardiac failure, ischemic and hemorrhagic strokes, alcohol-induced strokes, diabetes types 1 and 2, gestational diabetes, renal -induced vascular changes(associated with elevated cholesterol or chronic alcohol ingestion), preeclampsia, sickle cell anemia in children (and adults), and atherosclerosis exhibit significant reductions in serum/plasma/ whole blood levels of ionized, but not necessarily total, blood levels of Mg [31,35-37,62-83]. Our group has also shown that dietary deficiencies of Mg in rabbits and rats causes vascular remodeling (i.e., arteriolar wall hypertrophy and alterations in the matrices of the vascular walls) concomitant with atherogenesis , high blood pressure, and microvascular vessel vasospasm [25,53,84,85]. These exciting findings have been confirmed, essentially, by other investigators [59,86,87].
Low (Mg2+) Environments or The Presence of Alcohol Result in Concentration -dependent Coronary Arterial Vasoconstriction and Increased Vascular Reactivity: Potential Significance to Alcohol-induced AF
Approximately 40 years ago, our group found that declining levels of extracellular Mg2+ ([Mg2+]0]) resulted in concentration-dependent constriction and vasospasm of small (< 100 um in diameter), medium and large coronary arteries excised from dogs, sheep, baboons and rats [22-24,49,50,88-94]. These low (Mg2+)0-induced vasospasms could only be attenuated or inhibited with elevated concentrations of Mg2+ .In addition, we noted that low (Mg2+)0 levels enhanced vasoconstrictor responses to a variety of vasoactive and neurohumoral putative transmitters (i.e. , angiotensin II, serotonin, norepinephrine, etc.). We suggested, at that time, that low dietary levels of Mg could result in arrhythmias, IHD and SCD [22-24]. Ever since these early findings were published, a number of clinical studies have been published which support our hypothesis [95-99]. Using perfused, working rat hearts, and in-vivo studies, we found that low levels of Mg2+ result in reductions in coronary flows, reductions in cardiac output, reductions in stroke volume and peak systolic pressure development, reductions in myocardial intracellular Mg2+ levels, reduction in myocardial levels of ATP, increased levels of inorganic phosphate, acidification of atrial and ventricular myocytes, Ca2+ overload, and generation of powerful reactive oxygen and nitrogen species [100-104]. Taken together, such results, in themselves, could account in large measure for alcoholinduced AF since ethanol reduces blood and intracellular levels of Mg2+. But, added to this are the physiological, pharmacological and biochemical effects of ethanol on the various chambers of the heart.
Forty years ago, two of us reported that ethanol exerted powerful contractile actions on several types of isolated mammalian arteries [105-110]. Several years later, we found that ethanol could cause similar vasoconstrictor effects on the microscopic blood vessels of living animals using high, quantitative TV image -intensification [65,111- 120]. Moreover, two of us reported that ethanol causes concentration dependent constriction and vasospasm of a variety of small, medium, and large coronary arteries excised from dogs, rats, sheep piglets, and sub-human primates, similar to the actions of low [Mg2+]0 (vide supra) [111-120]. In addition, we found that these actions were associated with rapidly-induced reductions in intracellular levels of Mg2+ coupled to increased intracellular levels of calcium( [Ca2+]i) [105,110,112,115- 120]. Moreover, like low (Mg2+)0 perfusion of working rat hearts, we have reported that perfusion of isolated working rat hearts with increasing concentrations of ethanol caused decreased cardiac contractility, decreasing perfusion pressures, decreased coronary flows, decreased levels of myocardial ATP, rise of myocyte inorganic phosphate, acidification of the myocytes, and production of reactive oxygen and nitrogen species [65,102,117,119,120,121]. Such coronary arterial vascular and cardiac myocyte actions of alcohol (in the presence of low Mg2+ caused by imbibing ethanol) could certainly account for most of the observed AF, IHD, and SCD. However, these contentions must also be viewed in relation to other recent reports on sphingolipid metabolism (see below) and actions from release of platelet-activating factor (PAF) discussed below.
Low Mg2+ or Ingestion of Alcohol Induces Leukocyte Sticking , Increased Adhesivess to Venular Endothelial Walls, Increased Post capillary Permeability and Vasoconstriction in the Microcirculation: Relation to Inflammatory Reactions and Potential Role in Alcoholinduced AF
Approximately 40 years ago, Ross et al. advanced the hypothesis that atherosclerosis is an inflammatory disease brought about by injury to the endothelial surfaces of macro-and microcirculations , for summary of their hypothesis. The hypothesis stated that different forms of injury(e.g., ischemic events) will result in numerous dysfunctions in the homeostatic properties of the endothelium, e.g., increase in adhesiveness of leukocytes and/or platelets, alteration in the procoagulant properties, formation/release of cytokines/chemokines and growth factors. Usually, inflammation is defined as a response of microcirculatory blood vessels and the tissues they perfuse to infections and damaged tissues which bring cells and host-defense factors/molecules directly from the circulation to all the diverse sites where they are required, in order to eliminate/degrade the offending agents [123,124]. The mediators of the defense mechanisms include white blood cells, phagocytic leukocytes, antibodies, and chemokines and complement proteins [123,124]. The inflammatory process brings these cells and molecules to the damaged or necrotic tissues. During the normal inflammatory process, leukocytes, macrophages, and monocytes migrate across the venous capillary walls through the endothelium due to increases in permeability and move to the site(s) of injury via chemotaxis. The normal mediators for these processes to take place are: adhesion molecules; and cytokines and chemokines. Interestingly, we have found in diverse microcirculatory beds of rats and mice fed either low dietary Mg intake or doses of ethanol (consistent with what is found among heavy drinkers of alcoholic spirits and beer) increased adhesiveness of leukocytes, monocytes and platelets to the venular walls coupled with vasoconstriction and increased postcapillary venular permeability; obviously these phenomena are clear signs of inflammatory responses [14,25,31,35,53,65,115,125-132]. Toll-like receptor-mediated (TLRM) pathways appear to be activated in both the MgD and alcoholic animals. Interestingly, these TLRM pathways are activated through nuclear factor-kappa B (NF-kB) which we have found to be activated very early in MgD and feeding of ethanol [65,115,125-136]. In addition to these microcirculatory reactions, we have found that low dietary Mg intake or ingestion of heavy doses of ethanol result in elevated blood levels of cytokines and chemokines , hallmarks of inflammatory reactions. Clearly, such reactions in the atria would perforce, in themselves, result in AF.
Mg2+ Regulates Sphingolipid Pathways in Cardiac and Vascular Smooth Muscle Cells: Potential Impact on Alcohol-induced AF
Mg2+ depletion has long been known to result in calcium overload in cardiac and VSM cells , including all types of coronary arteries that have been investigated [24,31,34-36,47-52,65,72,85,88,92,93,104,131]. Moreover Mg2+ can act as a natural Ca2+ channel blocker. Recent studies indicate that Mg2+ can modulate sphingolipid pathways in both cardiac and VSM cells [32,35,132]. Ceramides are sphingolipids known to be released as a consequence of sphingomyelinses (SMases) acting on sphingomyelin (SM), a component of all cell membranes, or as a consequence of the activation of serine palmitoyl transferase 1 and 2 (SPT 1 and SPT 2) (a synthetic pathway) [132,137-146]. Ceramides are now thought to play important roles in fundamental processes such as inflammation, angiogenesis, membrane-receptor functions, cell proliferation, microcirculatory functions, cell adhesion, immunogenic responses, excitation-contraction coupling events in cardiac and VSM cells, and cell death ( i.e., apoptosis) [31,35,134,135,143,144,146-152]. SPT 1 and SPT 2 are the rate-limiting enzymes in the biosynthesis of sphingolipids . An upregulation of SPT 1 and 2 has been hypothesized to play an important role in apoptosis cell death events taking place in atherogenesis [136,153]. Such upregulation could be quite pivotal in producing plaques on the endothelium of coronary vessels leading to ischemia and AF. Working with perfused rat hearts, we have noted incremental rises in ceramides as the (Mg2+)0 was reduced concomitant with decreases in stroke volume, increased levels of lactic acid dehydrogenase and creatine phosphokinase, increased lipid peroxidation of cardiac muscle cells, reductions in myocardial intracellular pH, and generation of ROS [100-104,139,142,144,154]. We on the identical ceramide, physiological and biochemical parameters in perfused working rat hearts [102,115,117,121].
It is of considerable interest to note, here, that, experimentally, myocardial infarctions have been shown to be associated with rising levels of ceramides [155-157]. In human subjects, it has been reported that stable angina pectoris, unstable angina pectoris, and acute myocardial is also associated with rising levels of ceramides [158,159]. In some of these patients, a clear elevation in SMases was observed.
Binge-drinking, and alcohol withdrawal, which is very common among young adults, has been reported in murine animal experiments, to produce marked changes in ceramide regulatory genes along with metabolic products and reductions in SM in mouse brains [160-167]. In addition, apoptotic cell death of neuronal cells induced by ethanol is associated with rising levels of ceramide. As the heart’s chambers, including the atria, are normally under baroreceptor and sympathetic neural control mechanisms, generation of ceramides in heavy alcohol drinkers certainly could be expected to produce arrhythmias. We propose that the ethanol-induced reduction in blood, coronary and myocardial levels of Mg2+ would set into motion the generation and release of ceramides. This, taken together with the direct effects of low (Mg2+)0 and ethanol, would result in AF.
During the performance of our foregoing in-vitro and in-vivo studies, using proton -nuclear magnetic resonance spectroscopy, we noted rapid formation of platelet-activating factor (PAF) and PAF-like lipid molecules .
Mg2+- Deficient Environments or Rising Concentrations of Alcohol Lead to Formation of PAF : Potential Significance to Atrial Fibrillatory Events
PAF is now known to play major roles in inflammatory responses and atherogenesis [168-173]. In addition, PAF is known to affect the heart and cardiac muscle cells in numerous ways [170-172]. For example, PAF can produce coronary arterial vasoconstriction, lower arterial blood pressure, increase coronary vascular resistance, release several lipid-like molecules from the heart, reduce cardiac output, decrease cardiac contractility, alter atrial and papillary muscle chronotropicity and membrane action potentials, as well as alter potassium currents in isolated cardiomyocytes [133,171,172]. All of these attributes of PAF’s actions on the myocardium and coronary vascular tree would be more than enough to cause profound atrial fibrillation. Moreover, a variety of the circulating blood formed elements (e.g., polymorph nuclear leukocytes, platelets, basophils, and macrophages can elaborate PAF [133,171,172]. Recently, we have found that coronary, cerebral, and aortic VSM cells can also elaborate and release PAF . A number of investigators employing intravital microscopy techniques, similar to those used in our laboratories  have demonstrated that PAF increased the number of white blood cells in the microvessels concomitant with intense vasoconstriction-spasms with increasing concentrations of the putative lipid mediator (i.e., PAF), less leukocyte rolling, and increased adherence of the leukocytes to the endothelial surfaces with increased venular-postcapillary permeability . Interestingly, we have reported that ceramides can produce almost similar phenomena in a variety of microvascular beds when studied by high-resolution video microscopy [35,133,173]. We believe, rather firmly, that these older and newer experimental studies could be used to advance our hypothesis that generation and release of both PAF and ceramides due, in large measure, to ethanol’s effect on lowering Mg2+ resulting in MgD states are more than likely involved in generation of alcohol-induced AF.
Potential Reasons for Why Women are Much Less Susceptible to Alcohol-induced AF
As stated above, prior to menopause, women demonstrate onethird the rate of alcohol-induced AF, hypertension and SCD [10,11] We believe this may be due, mainly, to the ability of female cardiac VSM and endothelial cells , in the presence of estrogenic hormones, to be in a better position to retain more intracellular Mg2+ in these cell types. Several years ago, we showed, using diverse types of isolated VSM and endothelial cells in primary cultures that estrogenic hormones controlled the concentration of intracellular Mg2+ levels [160,161]. Studying women, prior to menopause, we found that the blood levels of ionized Mg are controlled by the ratio of estrogenic hormones to progestational hormones [162-167]. Obviously, having these pieces of cellular and blood level data, one could conclude that since women , prior to menopause, in the presence of estrogenic hormones, could be expected to retain critically-important levels of Mg2+, thus making it more difficult for consumption of alcoholic beverages to cause AF in these younger women. We believe this hypothesis can be easily tested in premenopausal vs. menopausal women.
Importance of Mg Supplemented Drinking Water and Beverages for Prevention and Amelioration of Alcoholinduced AF
Over the past 25 years, our laboratories have been investigating the utility of Mg-supplemented or naturally-occurring spring waters to avoid the pitfalls of dietary-and/or metabolically-induced MgD-states which affect heart health [31,35,65,104,132,136-139,141-144]. Our results, to date, bolster the idea that water intake (e.g., from tap waters, well waters, bottled waters, beverages using tap/well/spring waters, or desalinated waters) in humans should contain at least 25-40 mg/liter/ day of Mg2+ . A number of experiments done in our labs indicate that most , if not all of the cardiovascular manifestations (i.e., decreased cardiac output, decreased coronary flows, decreased myocardial contractility, lipid peroxidation of cardiac muscle membranes, synthesis/release of toxic ceramides, PAF, cytokines and chemokines, mitochondrial release of cytochrome C, increased Ca2+ entry and overload, myocardial acidification, loss of cardiac ATP levels, apoptosis, etc.) observed in hearts of experimental animals fed low dietary Mg, or given elevated ingestion of ethanol, can be prevented or ameliorated when imbibing drinking waters with appropriate amounts of Mg2+ [132,137-139,141-144 ]. We are convinced the latter inclusion in our diets should go a long-way towards the prevention and amelioration of atrial arrhythmias, supraventricular arrhythmias, and cardiac ischemic events in both “binge-drinkers” and people who ingest too much alcohol. Interestingly, on the basis of our work in animals , the World Health Organization has suggested people should consume drinking waters containing our recommended 25-40 mg/liter/day of Mg2+ . It is our hope that two large scale clinical trial studies , one on “bingedrinkers”, and one with people who consume heavy doses of ethanol, can be instituted to test our hypothesis.
Although the exact cause(s) of an increased incidence of alcoholinduced atrial fibrillation in heavy -drinkers and “binge-drinkers” is not known, Mg2+ depletion is clearly observed in all patients when looked-for. Experimentally, heavy ingestion of alcoholic beverages leads to AF, cardiac ischemia, decreases in cardiac output and contractility, losses in myocardial ATP, generation of reactive oxygen species, loss of myocardial intracellular Mg2+, myocardial Ca2+ overload, generation of ceramides and PAF, increased blood and myocardial cell cytokines and chemokine’s) coupled to inflammation-like events in the microcirculation. At least in experimental animals, elevated dietary levels of Mg2+ can overcome or ameliorate most of these effects of ethanol on the heart. We suggest that all human drinking waters contain at least 25-40 mg/liter/ day of Mg2+ as a preventive against alcohol-induced AF, supraventricular arrhythmias, and ischemic events.
Some of the original experimental and clinical studies mentioned in the above were supported, in part, by research grants from The N.I.H. (National Institute on Drug Abuse and The National Institute on Alcoholism and Alcohol Abuse to B.M.A. and B.T.A.). We also received unrestricted grant support from several pharmaceutical companies including CIBA-GEIGY, SANDOZ, and Bayer.
- Dai WS, La Porte RE, Hom DL, Kuller LH, D'Antonio JA, et al. (1985) Alcohol consumption and high- density lipoprotein cholesterol concentration among alcoholics. Am J Epidemiol 122: 620-627.
- KuppariMKM (2007) Alcohol and Cardiovascular Disease. John Wiley and SonsInc, New York.
- Kloner RA, Rezkalla SH (2007) To drink or not to drink? that is the question. Circulation 116: 1306-1317.
- Davidson DM (1989) Cardiovascular effects of alcohol. West J Med 151: 430-439.
- Koskinen P, Kupari M, Leinonen H , LuomanmuA AK (1987) Alcohol and new onset atrial fibrillation: a case -control study of a current series. Brit Heart J 57: 468-473.
- Templeton AH, Carter KLT, Sheron N, Gallagher PJ, Verrill C (2009) sudden unexpected death in alcohol misuse-- An unrecognized public health issue. Int J Environm Res Public Health 6: 3070-3081.
- George A, Figueredo VM (2010) Alcohol and arrhythmias: a comprehensive review. J Cardiovasc Med (Hagerstown)11: 221-228.
- Psaty BM, Manolio TA, Kuller LH, Kronmal RA, Cushman M, et al. (1997) Incidence of and risk factors for atrial fibrillation in older adults. Circulation 96: 2455-2461.
- Abdel-Rahman AR, Dar MS, Wooles WR (1985) Effect of chronic ethanol on arterial baroreceptor function and pressor and depressor responsiveness in rats. J PharmacolExpTher232: 194-201.
- Mukamal KJ, Tolstrup JS, Friberg J, Jensen G, Grønbæk M (2005) Alcohol consumption and risk of incident atrial fibrillation in women: the Copenhagen City Heart Study. Circulation 112: 1736-1742.
- Conen D, Tedrow UB, Cook NR, Moorthy MV, Buring JE, et al. (2008) Alcohol consumption and risk of incident atrial fibrillation in women. JAMA 300: 2489-2496.
- Lieber C (1992) Medical Aspects of Alcoholism. Plenum, New York.
- Flink EB, Omar M, Shane SR (1981) Alcoholism, liver disease and magnesium. Magnes Bull 3:209-216.
- Altura BM, Altura BT (1999) Association of alcohol in brain injury , headaches, and stroke with brain tissue and serum levels of ionized magnesium: a review of recent findings and mechanisms of action. Alcohol 19: 119-130.
- Abbott L, Nadler J, Rude RK (1994) Magnesium deficiency in alcoholism: Possible contribution to osteoporosis and cardiovascular disease in alcoholics. Alcoholism: ClinExp Res 18: 1076-1082.
- Lieber CS (1998) Hepatic and other medical disorders of alcoholism from pathogenesis to treatment. J Studies Alcohol 59: 9-25.
- Mackenzie J. (1902) The study of the Pulse, Arterial, Venous, and Hepatic, and of the Measurements of the Heart. Pulse 398.
- Evans W (1959) The electrocardiogram of alcoholic cardiomyopathy. Brit Heart J 21: 445-456.
- Ettinger PO, Wu CF, De La Cruz C Jr, Weisse AB, Ahmed SS, et al. (1978) Arrhythmias and the "Holiday Heart": alcohol -associated cardiac rhythm disorders. Am Heart J 95: 555-562.
- Djousse L, Levy D, Benjamin EJ, Blease SJ, Russ A, et al. (2004) Long-term alcohol consumption and the risk of atrial fibrillation in the Framingham Study. Am J Cardiol 93: 710-713.
- Frost L, Vestergaard P (2004) Alcohol and risk of atrial fibrillation or flutter: A cohort study. Arch Int Med 164: 1993-1998.
- Altura BM (1979) Sudden-death ischemic heart disease and dietary magnesium intake: Is the target site coronary vascular smooth muscle? Med Hypoth 5: 843-848.
- TurlapatyPDMV,Altura BM (1980) Magnesium deficiency produces spasms of coronary arteries: relationship to etiology of sudden death ischemic heart disease. Science 208: 198-200.
- Altura BM, Altura BT (1984) Magnesium , electrolyte transport, and coronary vascular tone. Drugs 28: 120-142.
- Altura BM, Altura BT, Gebrewold A, Ising H, Gunther T (1984) Magnesium deficiency and hypertension: correlation between magnesium deficiency diets and microcirculatory changes in situ. Science 223: 1315-1317.
- Altura BM, Altura BT (1985)New perspectives on the role of magnesium in pathophysiology of the cardiovascular system. I. Clinical aspects. Magnesium 4:226-244.
- Altura BM (1988) Ischemic heart disease and magnesium . Magnesium 7: 57-67.
- Seelig MS (1989) Cardiovascular consequences of Mg deficiency and loss: pathogenesis, prevalence and manifestations-MgCl loss in refractory potassium repletion. Am J Cardiol 63: 4G-21G.
- Rasmussen HS (1993) Justification for magnesium therapy in acute ischemic heart disease. Clinical and experimental studies. Danish Med Bull 40: 84-89.
- Orlov MW, Brodsky MA, Douban S (1994) A review of magnesium, acute myocardial infarction and arrhythmia. J Am CollNutr 13: 127-132.
- Altura BM, Altura BT (1995) Magnesium and cardiovascular biology: an important link between cardiovascular risk factors and atherogenesis. Cell MolBiol Res 41: 347-359.
- Satur CM (1997) Magnesium and cardiac surgery. Ann Roy CollSurgEngl 79: 349-354
- Saris NE, Mervaala E, Karppen H, Khawaja A, Lewenstam A (2000) Magnesium: an update on physiological, clinical and analytical aspects. ClinChimActa 294: 1-26.
- Seelig MS, Rosanoff A (2003) The Magnesium Factor. The Penguin Group, New York.
- Altura BM, Altura BT (2007) Magnesium: forgotten mineral in cardiovascular biology. New Perspectives in Magnesium Research. Springer 239-260.
- Dean C (2014) The Magnesium Miracle. 3rd EdtBallantine Books, New York.
- Altura BM, Altura BT (2016) Importance of ionized magnesium measurements in physiology and medicine and the need for ion-selective electrodes. J Clin Case Studies 1: 1-4.
- De Baaj JHE, Henderop JG, Bindels RJ (2015) Magnesium in man: Implicationa for health and disease. Physiol Rev 95: 1-46.
- Ford ES, Mokdad AH (2003) Dietary magnesium intake in a national sample of US adults. J Nutr 133: 2879-2882.
- Mosfegh A, Goldman J, Abuja J, Rhodes D, La Comb R (2009) What We Eat in America. NHANES 2005-2006: usual Nutrient Intakes from Food and Water Compared to 1997 Dietary Reference Intakes for Vitamin D, Calcium, Phosphorus, and Magnesium. U.S. Department of Agricultural Research.
- NHANES 2009-2012 (2016) Dietary Reference Intakes for Vitamin D, Calcium, Phosphorus, and Magnesium. U.S. department of Agricultural Research
- Marier JR, Neri LC (1985) Quantifying the role of magnesium in the interrelationship between human mortality/morbidity and water hardness. Magnesium 4: 53-59.
- Leary WP (1986) Content of magnesium in drinking water and deaths from ischaemic heart disease in white South Africans. Magnesium 5: 150-153.
- Chipperfield B, Chipperfield JR (1979) Relation of myocardial metal concentration to water hardness and death-rates from ischaemic heart disease. Lancet 2: 709-712.
- Marx A, Neutra RR (1997) Magnesium in drinking water and ischaemic heart disease. Epidemiol Rev 19: 258-272.
- Rubenowitz E, Molin I, Axelsson G, Rylander R (2000) Magnesium in drinking water in relation to mortality and morbidity from acute myocardial infarction. Epidemiology 11: 416-421.
- Altura BM, Altura BT (1990) Magnesium and the cardiovascular system: Experimental and clinical aspects updated. Metals in Biological Systems 26: 359-416.
- Altura BM,Altura BT (1971) Influence of magnesium on drug-induced contractions and ion content in rabbit aorta. Am J Physiol 220: 938-944.
- Altura BM, AlturaBT (1974) Magnesium and contraction of arterial smooth muscle. Microvascular Res 7: 145-155
- Altura BM, Altura BT (1981) Role of magnesium ions in contractility of blood vessels and skeletal muscles. Magnesium Bulletin 3: 102-114.
- Altura BM, AlturaBT (1981) General anesthetics and magnesium ions as calcium antagonists. In: New Perspectives on Calcium Antagonists. AmPhysiolSoc 131-145.
- Altura BM, Altura BT (1978) Magnesium and vascular tone and reactivity. Blood Vessels 15: 5-16.
- Altura BT, Brust M, Bloom S, Barbour RL, Stempak JG, et al. (1990) Magnesium dietary intake modulates blood lipid levels and atherogenesis. Proc Nat AcadSci USA 87(5): 1840-1844.
- Friedman HS, Nguyen TN, Mokraoui AM, Barbour RL, Murakawa T, et al. Effects of magnesium chloride on cardiovascular hemodynamics in the neurally intact dog. J PharmacolExpTher 24: 126-130.
- Nagai I, Gebrewold A, Altura BT, Altura BM (1988) Magnesium salts exert direct vasodilator effects on rat cremaster muscle micocirculation. Arch IntPharmacodynTher 294: 194-214.
- Nishio A, Gebrewold A, Altura BT, Altura BM (1988) Comparative effects of magnesium salts on reactivity of arterioles and venules to constritor agents. An in situ study on microcirculation. J PharmacolExpTher 246: 859-865.
- Nishio A, Gebrewold A, Altura BT, Altura BM (1989) comparative vasodilator effects of magnesium salts on rat mesenteric arterioles and venules. Arch IntPharmacodyn 298: 139-163.
- Altura BM, Altura BT (1984) Interactions of Mg and K on blood vessels-Aspects in view of hypertension: review of present staus and findings. MagnesExpClin Res 3: 175-195.
- Luthringer C, Rayssiguier Y, Gueux E, Berthelot A (1988) Effect of moderate magnesium deficiency on serum lipis , blood pressure and cardiovascular reactivity in normotensive rats. Br J Nutr 59: 243-250.
- Emila S, Swaminathan S (2013) Role of magnesium in health and disease. J ExpSci 4: 32-43.
- Long S, Romani AM (2014) Role cellular magnesium in human disease. Austin J Nutr Food Sci 18:1051
- Altura BT, Altura BM (1991) Measurement of ionized magnesium in whole blood, plasma and serum with a new ion-selective electrode in healthy and diseased human subjects. Magnes Trace Elem 10: 90-98
- Altura BT, Shirey TL, Young CC, Hiti J, Dell'Orfano K, et al. A new method for the rapid determination of ionized Mg2+ in whole blood, serum and plasma. Methods Find ExpClinPharmacol 14: 297-304.
- Handwerker SM, Altura BT, Royo B, Altura BM (1993) Ionized magnesium and calcium levels in umbilical cord serum of pregnant women with transient hypertension. Am J Hypertens 6: 542-545.
- Altura BM, Altura BT (1994) Role of magnesium in alcohol-induced hypertension and strokes as probed by in vivo television microscopy, digital image microscopy, optical spectroscopy, 31P-NMR spectroscopy and a unique magnesium ion-selective electrode. Alcohol ClinExp Res 18: 1057-1068.
- Markell MS, Altura BT, Barbour RL, Altura BM (1993) Ionized and total magnesium levels in cyclosporin-treated renal transplant recipients: relationship with cholesterol and cyclosporin levels. ClinSci 75: 315-318.
- Markell MS, Altura BT, Sarn Y, Delano BG, Hudo O et al. (1993) Deficiency of serum ionized magnesium receiving hemodialysis or peritoneal dialysis. ASAIO J 39: M801-M804.
- Resnick LM, Altura BT, Gupta RK, Alderman MH, Altura BM (1993) Intracellular and extracellular magnesium depletion in type 2 diabetes (non-insulin -dependent) diabetes mellitus. Diabetologia 36: 767-770.
- Altura BM, Lewenstam A (1994) Unique Magnesium-Sensitive Ion Selective Electrodes. Scand J Clin Lab Invest 54: 1-100.
- Altura BM, AlturaBT (1996) Role of magnesium in pathophysiological processes and the clinical utility of magnesium ion-selective electrodes. Scand J Clin Lab Invest 56: 211-234.
- Bardicef M, Bardicef O, Sorokin Y, Altura BM, Altura BT, et al. (1995) Extracellular and intracellular magnesium depletion in pregnancy and gestational diabetes. Am J ObstGynecol 172: 1009-1013.
- Altura BT, Memon ZI, Zhang A, Cracco RQ, Altura BM (1997) Low levels of serum ionized magnesium found in patients early after stroke which results in rapid elevation in cytosolic free calcium and spasm in cerebral vascular smooth muscle cells. NeurosciLett 230: 37-40.
- Resnick LM, Bardicef D, Altura BT, Alderman MH, Altura BM (1997) Serum ionized magnesium: Relation to blood pressure and racial factors. Am J Hypetens 10: 1420-1424.
- Seelig MS, Altura BM (1997) How best to determine magnesium requirement: Need to consider cardiotherapeutic drugs that affect its retention. J Am CollNutr 16:4-6
- Muneyyrici-Delale O, Nacharaju VI, Jalou S, Rahman M, Altura BM, et al. (2001) Divalent cations in women with PCOS: Implications for cardiovascular disease. GynecolEndocrinol 15: 198-201.
- Handwerker SM, Altura BT, Jones KY, Altura BM (1995) Maternal -fetal transfer of ionized serum magnesium during stress of labor and delivery: a human study. J Am CollNutr 14: 376-381.
- Scott VL, DeWolf AM, Kang Y, Altura BT, Virji MA, et al. (1996) Ionized hypomagnesemiainpatients undergoing orthotopic liver transplantation: a complication of citrate intoxication. Liver TransplSurg 2:343-347.
- Fogh-Andersen N, Altura BM, Altura BT, Sigaard-Andersen O (1996) Changes in plasma ionized calcium and magnesium in blood donors after donation of 450 ml blood. Effects of hemodilution and Donnan equilibrium. Scand J Clin Lab Invest 56: 245-250.
- Djurhuus S, Henriksen JE, Kligaard NA, Blaabjerg O, Thye-ron P, et al. (1999) Effect of moderate improvement in metabolic control on magnesium and lipid concentrations in type I diabetes. Diabetes Care 22: 546-554.
- Djurhuus S, Kligaard NA, Pedersen KK, Blaabjerg O, Altura BM, et al. (2001) Magnesium reduces insulin-stimulated glucose uptake and serum lipid concentrations in type I diabetes. Metabolism 50: 1409-417.
- Altura RA, Wang WC, Wynn L, Altura BM, Altura BT (2002) Hydroxyurea therapy associated with declining serum levels of magnesium in children with sickle cell anemia. J Pediatr 140: 565-569.
- Zehtabchi S, Sinert R, Rinnert S, Chang B, Hennis R, et al. (2004) Serum ionized magnesium levels and ionized calcium to magnesium ratios in adult patients with sickle cell anemia. Am J Hematol 77: 215-222.
- Apostol A, Apostol R, Ali E, Choi A, Ehsuni N, et al. (2009) Cerebral spinal fluid and calcium levels in preeclamptic women during administration of magnesium sulfate. FertilSteril 94: 276-282.
- Altura BM, Altura BT, Gebrewold A, Gunther T, Ising H (1992) Noise-induced hypertension and magnesium: relationship to microcirculation and calcium. J ApplPhysiol 72: 194-202.
- Altura BM, Altura BT (1996) Magnesium as an extracellular signal in cardiovascular pathobiology. J Jap SocMagnes Res 15: 17-32
- Ouchi Y, Tabata RE, Stegiopoulos K, Sano K, Hatori A, et al (1990) Effect of dietary magnesium on development of atherosclerosis in cholesterol-fed rabbits. Arteriosclerosis 10: 732-737.
- King JL, Miller RJ, Blue JP Jr, O'Brien WD Jr, Erdman JW Jr (2009) Inadequate dietary magnesium intake increases atherosclerotic plaque development in rabbits. Nutr Res 29: 343-349
- Altura BM, Altura BT (1977) Extracellular magnesium and contraction of vascular smooth muscle. In : Excitation-Contraction Coupling of Smooth Muscle, Casteels R, Godfraind T, Ruegg JC, eds. North-Holland Publ co, Amsterdam, 137-144.
- Altura BM (1978) Magnesium withdrawal and rhythmic contractility of arterial vs, venous smooth muscle. Differential effects of multivalent cations and EDTA. Artery 4: 512-527.
- Altura BT, Altura BM (1980) Withdrawal of magnesium causes vasospasm while elevated magnesium produces relaxation of tone in cerebral arteries. NeurosciLett 20: 323-327.
- Altura BM, Altura BT, Carella A, Turlapaty PDMV (1981) Hypomagnesemia and vasoconstriction: Possible relationship to etiology of sudden death ischemic heart disease and hypertensive vascular diseases. Artery 9: 212-231.
- Altura BM, Altura BT (1981) Magnesium modulates calcium entry and contractility in vascular smooth muscle. In: The Mechanism of Gated Calcium Transport across Biological Membranes. Ohinishi ST, Endo M, eds. Academic Press, New York, 137-144.
- Altura BM, Altura BT, Carella A, Turlapaty PDMV (1982) Ca2+ coupling in vascular smooth muscle: Mg2+ and buffer effects on contractility and membrane Ca2+ movements. Canad J PhysiolPharmacol 60: 459-482.
- Altura BM, Turlapaty PDMV (1982) Withdrawal of magnesium enhances coronary arterial spasms produced by vasoactive agents. Br J Pharmacol 77: 649-659
- Kimura T, Yasue H, Sakaino N, Rokutanda M, Jougasaki M, et al. (1989) Effect of magnesium on the tone of isolated human coronary arteries. Comparison with diltiazem and nitroglycerin. Circulation 79: 1118-1124.
- Goto K, Yasue H, Okumura K, Matsuyama K, Kugiyama K, et al. (1999) Magnesium deficiency detected by intravenous loading test in variant angina pectoris. Am J Cardiol 65: 709-712.
- Simko F (1994) Pathophysiological aspects of the protective effect of magnesium in myocardial infarction(review). Acta Med Hung 50: 55-64.
- Satake K, Lee JD, Shimizu H, Ueda T, Nakamura T (1996) Relation between severity of magnesium deficiency and frequency of angina attacks in men with variant angina. J Am CollCardiol 28: 897-902.
- Sueda S, Fukuda H, Watanabe K, Suzuki J, Saeki H, et al. (2001) Magnesium deficiency in patients with recent myocardial infarction and provoked coronary artery spasm. JpnCirc J 65: 643-648.
- Wu F, Altura BT, Gao J, Barbour RL, Altura BM (1994) Ferrylmyoglobin formation induced by acute magnesium deficiency in perfused rat heart causes cardiac failure. BiochimBiophysActa 1225: 158-164.
- Wu F, Zou LY, Altura BT, Barbour RL, Altura BM (1992) Low extracellular magnesium results in cardiac failure in isolated perfused hearts. Magnes Trace Elem 10: 364-373.
- Zou LY, Wu F, Altura BT, Barbour RL, Altura BM (1992) Beneficial effects of high magnesium on alcohol-induced cardiac failure. Magnes Trace Elem 10: 409-419.
- Altura BM, Barbour RL, Dowd TL, Wu F, Altura BT, Altura BM (1993) Low extracellular magnesium induces intracellular free Mg deficits , ischemia, depletion of high- energy phosphates and cardiac failure in intact working rat hearts: A 31P-NMR study. BiochimBiophysActa 1182: 328-332.
- Altura BM, Gebrewold A, Altura BT, Brautbar N (1996) Magnesium depletion impairs carbohydrate and lipid metabolism and cardiac bioenergetics and raises myocardial calcium content in vivo: relationship to etiology of cardiac diseases. BiochemMol Bio Int 40: 1183-1190.
- Altura, BM, Edgarian H, Altura BT (1976) Differential effects of ethanol and manitol on contraction of arterial smooth muscle. J PharmacolExpTher 197: 352-362.
- Edgarian H, Altura BM (1976) Differential effects of ethanol on prostaglandin responses of arterial and venous smooth muscle. Experientia 32: 618-619
- Altura BM, Edgarian H (1976) Ethanol-prostaglandin interactions in contraction of vascular smooth muscle. ProcSocExpBiol Med 152: 334-346.
- Altura BM, Carella A, Altura BT (1978) Acetaldehyde on vascular smooth muscle: Possible role in vasodilator actions of ethanol. Eur J Pharmacol 52: 73-83.
- Altura BM, Ogunkoya A, Gebrewold A, Altura BT (1979) Effects of ethanol on terminal arterioles and muscular venules: Direct observations on the microcirculation. CardiovascPharmacol 1: 97-113.
- Altura BM, Altura BT, Carella A, Turlapaty PDMV, Weinberg J (1980) Vascular smooth muscle and anesthetics. Federation Proc 39: 1584-1591.
- Altura BM, Altura BT (1982) Microvascular and vascular smooth muscle actions of ethanol, aceraldehyde and acetate. Federation Proc 41: 2447-2451.
- Altura BM, Altura BT, Carella A (1983) Ethanol produces coronary vasospasm. Evidence for a direct action of ethanol on vascular muscle. Br J Pharmacol 78: 260-262.
- Altura BM, Altura BT (1983) Peripheral vascular actions of ethanol and its interaction with neurohumoral substances. NeurobehavToxicolTeratol 5: 211-220.
- Altura BM (1984) Alcohol, stroke, hypertension and the heart. Alcohol 1: 321-323.
- Altura BM, Altura BT (1989) Cardiovascular functions in alcoholism and after acute administration of alcohol: heart and blood vessels. In: Alcoholism: Biochemical and Genetic Aspects. Goedde HW, Agarwal DP, eds. Pergamon Press, Elmsford, 167-227.
- Altura BT, Zhang A, Altura BM (1996) Differential actions of alcohol on peripheral, umbilical-placental and cerebral blood vessels: Implications for hypertension, fetal alcohol syndrome, stroke and alcohol tolerance. In: Alcohol and The Cardiovascular System. Zakhari S, Wassef M, eds. NIAAA Research Monograph No. 31. US Government Printing Office, Bethesda, 615-645.
- Altura BM, Zou LY, Altura BT, Jelicks LA, Wittenberg BA, et al, (1996) Beneficial versus detrimental actions of alcohol on heart and coronary vascular muscle: Roles of Mg2+ and Ca2+. Alcohol 13:499-513.
- Altura BM, Zhang A, Cheng TP-O, Altura BT (1996) Exposure of piglet coronary arterial smooth muscle cells to low alcohol results in elevation of intracellular free Ca2+: Relevance to fetal alcohol syndrome. Eur J Pharmacol 314: R9-R11.
- Zou LY, Altura BT, Wu F, Jellicks LA, Wittenberg BA, et al, (1997) Roles of Mg2+ and Ca2+in beneficial vs. detrimental actions of alcohol on heart. Advances in Magnesium Res. Smetana, ed. John Libbey, London, 211-214.
- Altura BM, Gebrewold A, Zhang A, Wu F, Zou LY, et al, (1999) Alcohol-induced vascular injury: Role of oxygen-derived radicals, antioxidants, cellular bioenergetics, divalent cations, transcription factors and protein kinase C. Int J Cardiovasc Med Sci 2: 7-24.
- Ross R (1999) Atherosclerosis- An inflammatory disease. N Engl J Med 340(2): 115-126.
- Majno G, Jorris I (1996) Cells, Tissues, and Disease. (2ndedn), Oxford University Press.
- Kumar V, Abbas K, Fasuto N, Aster JC (2010) Robbins and Cotran Pathologic Basis of Disease. (8th edn), Elsevier, New York, USA.
- Altura BM, Gebrewold A (1996) Alpha-tocopherol attenuates alcohol-induced cerebral vascular damage: possible role of oxidants in alcohol brain injury and strokes. NeurosciLett 220: 207-210.
- Ema M, Gebrewold A, Altura BT, Zhang A, Altura BM (1998) Alcohol-induced vascular damage of brain is ameliorated by administration of magnesium. Alcohol 15: 95-103.
- Altura BM, Gebrewold A (1998) Pyrrolidinedithiocarbamate attenuates alcohol-induced leukocyte-endothelial cell interaction and cerebral vascular damage in rats: possible role of activation of transcription factor NF=kappa B in alcohol brain. Alcohol 16: 25-28.
- Altura BM, Gebrewold A, Zhang A, Altura BT (2002) Role of leukocytes in the rat brain in situ: potential role in alcohol brain pathology and strokes. Eur J Pharmacol 448:89-94.
- Altura BM, Gebrewold A, Zhang A, Altura BT (2002) Ethanol induces rapid lipid peroxidation and activation of nuclear factor-kappa B in cerebral vascular smooth muscle: relation to alcohol-induced brain damage. NeurosciLett 325.
- Altura BM, Gebrewold A (2002) Inhibitor of nuclear factor-kappa B activation attenuates venularconstriction, leukocyte adhesion and microvessel rupture in intact rat brain microcirculation: relation to ethanol-induced brain injury. NeurosciLett 334: 21-24.
- Altura BM, Kostellow AB, Zhang A, Li W, Morrill GA, et al (2003) Expression of the nuclear factor-kB and proto-oncogenes c-fos and c-jun are induced by low extracellular Mg2+ in aortic and cerebral vascular smooth muscle cells: possible links to hypertension, atherogenesis, and stroke. Am J Hypertens 16: 347-359.
- Altura BM, Shah NC, Shah GJ, Zhang A, Li W, et al. (2012) Short-term magnesium deficiency upregulatesceramide synthase in cardiovascular tissues and cells: cross-talk among cytokines, Mg2+, NF-kB and de novo ceramide. Am J Physiol Heart CircPhysiol 302: H319-H332.
- Altura BM, Li W, Zhang A, Shah NC, Shah GJ, et al (2016) The expression of platelet-activating factor is induced by low extracellular Mg2+ in aortic, cerebral and neonatal coronary vascular smooth muscle; cross-talk with ceramide production, NF-kB and proto-oncogenes: possible links to atherogenesis and sudden cardiac death in children and infants, and aging: Hypothesis, review and viewpoint. Int J Cardiol Res 3: 47-67
- Morrill GA, Gupta RK, Kostellow AB, Ma GY, Zhang A, et al. (1997) Mg2+ modulates membrane lipids in vascular smooth muscle cells: a link to atherogenesis. FEBS Lett 408: 191-194.
- Morrill GA, Gupta RK, Kostellow AB, Ma GY, Zhang A, et al. (1998) Mg2+ modulates membrane sphingolipids and lipid messengers in vascular smooth muscle cells. FEBS Lett 440: 167-171.
- Altura BM, Shah NC, Jiang XC, Perez-Albela JL, Sica AC, et al. (2009) Short-term magnesium deficiency results in decreased levels of serum sphingomyelin, lipid peroxidation, and apoptosis in cardiovascular tissues. Am J Physiol Heart CircPhysiol 297: H86-H92.
- Altura BM, Shah NC, Li Z, Jiang XC, Perez-Albela JL, et al. (2010) Magnesium deficiency upregulates serine palmitoyltransferase(SPT 1 and SPT 2) in cardiovascular tissues: relationship to serum ionized Mg2+ and cytochrome C. Am J Physiol Heart CircPhysiol 299: H932-H938.
- Shah NC, Liu JP, Iqbal J, Hussain M, Jiang XC, et al. (2011) Mg deficiency results in modulation of serum lipids, glutathione, and NO synthase isozyme activation in cardiovascular tissues : relevance to de novo synthesis of ceramide, serum Mg and atherogenesis. Int J ClinExp Med 4: 103-118.
- Zheng T, Li W, Altura BT, Shah NC, Altura BM (2011) Sphingolipids regulate [ Mg2+]0 uptake and [Mg2+]i content in vascular smooth muscle cells: potential mechanisms and importance to membrane transport of Mg2+. Am J Physiol Heart CircPhysiol 300(2): H486-H492.
- Altura BM, Shah NC, Shah GJ, Li W, Zhang A, et al. (2013) Magnesium deficiency upregulatessphingomyelinases in cardiovascular tissues and cells: cross-talk among proto-oncogenes, Mg2+, NF-kB, and ceramide and their potential relationships to resistant hypertension, atherogenesis and cardiac failure. Int J ClinExp Med 6: 861-879.
- Shah NC, Shah GJ, Li Z, Jiang XC, Altura BT, et al. (2014) Short-term magnesium deficiency downregulates telomerase, upregulates neutral sphingomyelinase and induces oxidative DNA damage in cardiovascular tissues: relevance to atherogenesis, cardiovascular diseases and aging. Int J ClinExp Med 7: 497-514.
- Altura BM, Shah NC, Shah GJ, Perez-Albela JL, Altura BT (2016) Magnesium deficiency results in oxidation and fragmentation of DNA, down regulation of telomerase activity, and ceramide release in cardiovascular tissues and cells:Potential relationship to atherogenesis, cardiovascular diseases and aging. Int J DiabetolVasc Dis Res 4: 1-5.
- Altura BM, Shah NC, Shah GJ, Altura BT (2016) Genotoxic effects of magnesium deficiency in the cardiovascular system and their relationships to cardiovascular diseases and atherogenesis. J Cardiovasc Dis Diagnosis S1:009.
- Merrill AH Jr, Jones DD (1990) An update of the enzymology and regulation of sphingolipid metabolism. BiochimBiophysActa 1044: 1-12.
- Zheng T, Wang J, Altura BT, Altura BM (2000) Sphingomyelinase and ceramideanalogs induce contraction and rises in [ Ca2+]i in canine cerebral vascular muscle. Am J Physiol Heart CircPhysiol 278: H1421-H1428.
- Altura BM, Gebrewold A, Zheng T, Altura BT (2002) Sphingomyelinase and ceramide induce vasoconstriction and leukocyte-endothelial interactions in cerebral venules in the intact rat brain: insight into mechanisms and possible relation to brain injury and stroke. Brain Res Bull 58: 271-278.
- Halmovitz -Friedman A, Kolesnick RN, Fuchs Z (1997) Ceramidesignaling in apoptosis. Br Med Bull 53: 539-553.
- Hannun YA, Obeid LM (2002) Theceramide -centric universe of lipid -mediated cell regulation: stress encounters of the lipid kind. J BiolChem 277: 25847-25850.
- Andrieu-Abadie N, Gouaze V, Salvayre R, Levade T (2001) ceramide in apoptosis signaling: relationship with oxidative stress. Free Rad Biol Med 31: 717-728.
- Auge N, Negre-Salvayre R, LevadeT (2000) Sphingomyelin and metabolites in vascular signaling and atherosclerosis. Prog Lipid Res 39: 207-239.
- Pandey S, Murphy RE (2007) Recent advances in the immunobiology of ceramide. ExpMolPathol 82: 298-309.
- Williams RD, Sgoutas DS, ZastariGS (1986) Enzymology of long-chain base synthesis by aorta: induction of serine pamioyltransferase activity in rabbit aorta during atherogenesis. J Lipid Res 27: 763-770.
- Altura BM, Barbour RL, Dowd TL, Wu F, Altura BT, Gupta RK (1993) Low extracellular magnesium induces intracellular free Mg deficits, ischemia, depletion of high-energy phosphates and cardiac failure in intact working rat hearts: A 31P-NMR study. BiochimBiophysActa 1182: 329-332.
- Bielawska AE, Shapiro JP, Jiang L, Melkonyan HS, Piot C, Wolfe CL, et al. (1997) Ceramide is involved in triggering of cardiomyocyte apoptosis induced by ischemia and reperfusion. Am J Pathol 151: 1257-1263.
- Park T-S, Hu Y, Hoh H-L, Drosatos K, Okajima K, Buchanan J, Tuinei J, et al. (2008) J Lipid Res 49:2101-2112.
- Getz GS (2008) The two Cs: ceramide and cardiomyopathy. J Lipid Res 49: 2077-2078.
- Empinado HM, Deevska GM, Nokolova-Karakashian M, Yoo, J-K, Christou DD, Ferreira LF (2014) Diaphragm dysfunction in heart failure is accompanied by increases in neutral sphingomyelinas activity and ceramide. Europ J Heart Failure 16: 519-525.
- Yu J, Pan W, Shi R, Yang T, Li Y, Yu G, Bai Y, et al (2015) Ceramide is upregulated and associated with mortality in patients with chronic heart failure. Canad J Cardiol 31: 357-363.
- Zhang A, Altura BT, Altura BM (1992) Endothelial -dependent sexual dimorphism in vascular smooth muscle. Brit J Pharmacol 105: 305-310.
- Li W, Zheng T, Altura BM, Altura BT (2001) Sex steroid hormones exert biphasic effects on cytosolic magnesium ions in cerebral vascular smooth muscle cells: possible relationship to migraine frequency in premenstrual syndromes and stroke incidence. Brain Res Bull 54: 83-89.
- Muneyyrici-Delale O, Nacharaju VL, Altura BM, Altura BT (1998) Ionized magnesium and calcium levels throughout the menstrual cycle in women .FertilSteril 69: 958-962.
- Munneyrici-Delale O, Nacharaju VL, Dalloul M, Altura BM, Altura BT (1999) Serum ionized magnesium and calcium in women after menopause: inverse relationship of estrogen with ionized magnesium. FertilSteril 71: 869-873.
- Muneyyrici-Delale O, Nacharaju VL, Altura BM, Altura BT (1999) Serum ionized magnesium and calcium and sex hormones in healthy young men: importance of serum progesterone level. FertilSteril 72: 817-822.
- O'Shaughnessy A, Muneyyyrici O, Nacharaju VL, Dalloul M, Altura BM, Altura BT (2001) Circulating divalent cations in asymptomatic ovarian hyperstimulation and in vitro fertilization patients. GynecolObstet Invest 52: 237-242.
- Muneyyrici-Delale O, Nacharaju VL, Jalou S, Rahman M, Altura BM, Altura BT (2001) Divalent cations in women with PCOS. GynecolEndocrinol 15: 198-201.
- Seelig MS, Altura BM, Altura BT (2004) Benefits and risks of sex hormone replacement in postmenopausal women. J Am CollNutr 23: 482S-496S.
- Pascual M, Valles SL, Renau-Piqueras J, Guerri C (2003) ceramide pathways modulate ethanol-induced cell death. J Neurochem 87: 1535-1545.
- Bac M, Bandaru VVR, Patel N, Haughey NJ (2014) Ceramide metabolism analysis in a model of binge drinking reveals both neuroprotective and toxic effects of ethanol J Neurochem 131: 645-654.
- Fruwirth GO, Loidl A, Hermetter A (2007) Oxidized phospholipids: from molecular properties to disease. BiochimBiophysActa 1772: 718-736.
- Prescott SM, Zimmerman GA, Stafforini DM, McIntyre TM (2000) Platelet-activating factor and related lipid mediators. Annu Rev Biochem 69: 419-445.
- Montrucchio G, Alloattti G, Camussi G (2000) Role of platelet-activating factor in cardiovascular pathophysiology. Physiol Rev 80: 1669-1699.
- Altura BM, Gebrewold A, Zheng T, Altura BT (2002) Sphingomyelinase and ceramideanalogs induce vasoconstriction and leukocyte-endothelial interactions in cerebral venules in the intact brain: insights into mechanisms and possible relation to brain injury and stroke. Brain Res Bull 58: 271-278.
- Altura, B. M., &Altura, B. T. (2009). Atherosclerosis and magnesium, in calcium and magnesium in drinking water: public health significance. World Health Organization, Geneva, 77-83.
- Calcium and Magnesium in Drinking-Water (2009) Public Health Significance. WHO, Geneva,
Citation: Altura BM, NC Shah, Shah GJ, Altura BT (2016) Why is Alcohol- Induced Atrial Arrhythmias and Sudden Cardiac Death Difficult to Prevent and Treat: Potential Roles of Unrecognized Ionized Hypomagnesemia and Release of Ceramides and Platelet-Activating Factor. Cardiovasc Ther 1: 112.
Copyright: © 2016 Altura BM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.