CARDIAC DISEASE

The human heart receives about 1/20th of cardiac output under basal conditions, and when this blood flow delivery is reduced or compromised, cardiac damage or death can occur.

Several intriguing studies have examined the effects of DMSO on experi-mental myocardial infarction and cardiac hemodynamics. One early study reported that DMSO provided significant protection of rat heart exposed to reoxygenation-induced cell injury.⁶⁷ This model of anoxic injury to cardiac cells involves perfusing the heart with an anoxic perfusate followed by reoxygenation with an oxygen perfusate, a technique that induces a rapid release of oxygen–

creatine kinase (CK), causing reduced coronary flow and severe cardiac con-traction with the formation of concon-traction bands. Prior to reoxygenation, 10%

DMSO was given by mixing it with the anoxic perfusate, an action that resulted in increased coronary flow rate, a marked reduction of the oxygen–CK release, and a significant decrease in the number of contraction bands from 43% in con-trol hearts to 23% using DMSO.⁶⁷ This study indicated that DMSO has the poten-tial to protect cardiac tissue from a hypoxic insult, an ability that could be useful in cardiac ischemia or heart failure.

One of the actions of DMSO in the ischemic myocardium is to aid in the diffusion of oxygen into the thick myocardial tissue, thus aiding the myocyte protection from anoxia or ischemia.⁶⁸

The effects of DMSO infusion on a canine model of myocardial ischemia and systemic hemodynamics were reported by Levett et al.⁶⁹ Hourly measurements of cardiac output, pulmonary wedge pressure, pulmonary artery pressure, heart rate, mean arterial pressure, cerebral blood flow, intracranial pressure, and blood gases were monitored before and after the ligation of the left descending coronary artery.

After 15  min of coronary artery ligation, control saline or 500 mg/kg of a 50%

DMSO solution was injected as an intravenous (IV) bolus.⁶⁹ By the third hour after ligation, cardiac output increased significantly, and both systemic and cerebrovas-cular resistances decreased in the DMSO-treated animals as compared to controls.

CBF also increased after DMSO but not in controls, and there were no significant differences in heart rate, mean arterial pressure, pulmonary artery wedge pres-sure, or cerebral or pulmonary resistances in the control as compared to the DMSO group.⁶⁹ This study concluded that DMSO infusion in a canine model of myocardial

ischemia has protective activity and merits further evaluation by extending the time course after infarction to a more realistic clinical setting.⁶⁹

The study by Levett et al.⁶⁹ recently received confirmation using a rat model of acute myocardial infarction caused by left anterior descending coronary artery liga-tion.⁷⁰ Before myocardial infarction was induced, 500 µL/kg of DMSO was given intraperitoneally daily for 3 days with the last dose given 15 min before ligation.⁷⁰ After 90 min of occlusion, postmortem examination showed markedly less cardiac damage reflected by a reduction of mean necrotic volume in the infarcted left ven-tricular wall area and by significantly lowered levels of the cardiac injury markers troponin I and myoglobin, as compared to controls. The mechanism by DMSO in protecting cardiac tissue from ischemic injury remains unsettled but appears to be similar to its protection of focal ischemic brain tissue following occlusion of the middle cerebral artery in rats.⁷¹

A review of the experimental cardiac effects of DMSO may provide some clues.⁷² For example, DMSO can produce either positive or negative inotropic effects on car-diac tissue depending on the dose used and animal species and specific carcar-diac tissue studied.⁷³ Myocardial tissue preparations using 70 mM DMSO concentration or less will increase positive inotropic contractile response, while using more than 70 mM concentration, the inotropic effect will be species dependent.⁷⁴ Moreover, none of the contractile effects of DMSO is antagonized by blocking beta-adrenergic receptors or by blocking other classical myocardial receptors at doses that do not intrinsi-cally alter cardiac contractility.⁷⁵ In isolated atrial preparations, DMSO decreases contractile rate without appreciably altering cardiac rhythm. However, when the DMSO concentration is above 140 mM, a concentration not likely to be used in vivo, both rate and rhythm are decreased possibly by DMSO’s effect on acetylcholinergic response to slow down conduction via the atrioventricular node.⁷⁴ However, these effects on the myocardium are reversible when DMSO exposure stops.

A reduction of systemic vascular resistance and an increase in cardiac output were found after slow DMSO infusion at a dose of 2 g/kg 50% solution in canine myocardium.⁷⁶ These values were temporary and returned to normal 10 min after DMSO infusion had been completed although cardiac output remained high for sev-eral hours when compared to saline control infusions.⁷⁶ These findings were consid-ered to result from a possible transient expansion of plasma volume that increased cardiac preload and cardiac output and could be relevant in treating hypovolemic patients with clinical brain injury or cardiac ischemia.⁷⁶

The case for using DMSO as a primary agent in the clinical treatment of myo-cardial infarction and coronary artery ischemia or hypoxia can be argued by not-ing some of the specific properties reported for this drug. These cardiac conditions diminish blood flow to the heart either by coronary vessel narrowing due to platelet aggregation on vessel walls or by atherosclerotic epicardial plaque-related stenosis.

Present treatments for these conditions include coronary vasodilators such as rano-lazine and nitrate preparations, platelet deaggregators such as aspirin or clopidogrel bisulfate, coronary artery balloon angioplasty or stenting, and coronary artery bypass surgery. Other pharmacological treatments such as calcium channel blockers, beta blockers, angiotensin-converting enzyme inhibitors, cholesterol-lowering drugs, and angiotensin receptor blockers may be useful in long-term therapy, but they do not

reverse coronary artery ischemia or myocardial infarction acutely. DMSO addresses an important aspect related to the pathology seen in coronary artery ischemia.

First, DMSO, as we have reviewed earlier, is a powerful platelet deaggregator.

A report by Pace et al.⁷⁷ showed that when DMSO was used as a solubilizing agent to test the potential of cardiac anti-aggregatory drugs in experimental coronary artery stenosis, it was discovered that the active agent was DMSO, not the drugs that were tested. When used alone, DMSO was observed to reverse the reduction of coronary blood flow induced by a critical stenosis on the canine circumflex coronary artery without changing other hemodynamic measures in the animals tested.⁷⁷ These findings suggested that DMSO acted a platelet deaggregator in reversing the coronary artery stenosis that allowed platelet aggregation and low-ered coronary blood flow. The findings by Pace et al.⁷⁷ were confirmed by Dujovny et  al.,⁷⁸ who reported scanning electron microscopic examination of rat carotid artery–induced occlusion induced by arteriotomy and suture closure where the formation of heavy platelet deposits, fibrin, and red blood cell clumps at the arteri-otomy site collected. The administration of DMSO 2 g/kg slowly infused intrave-nously resulted in minimal signs of fibrin clumping and platelet deposition at the carotid artery suture line.⁷⁸ The platelets appeared spherical with no pseudopod formation, while the adjacent endothelium appeared intact in contrast to control non-DMSO-treated animals who showed heavy platelet deposits and fibrin and erythrocyte clumping.⁷⁸

We have discussed the antiplatelet action of DMSO from the studies of Panganamala et al.,⁴⁸ who showed that DMSO inhibited arachidonic-acid-induced platelet aggregation possibly by inhibiting prostaglandin biosynthesis, particularly PGE₂. Holtz and Davis⁷⁹ and Harrison et al.⁸⁰ have suggested that DMSO is a sulf-hydryl inhibitor and that this action prevents platelet-to-platelet bonding, whereas Wieser et al.⁸¹ showed that DMSO could increase cyclic AMP by inhibiting phos-phodiesterase in a non platelet system (Figure 2.2). DMSO was found to inhibit the cardiac hypertrophy, anemia, and depression in a model of copper deficiency of the heart. This finding suggests that the hydroxyl radical–scavenging ability by DMSO may contribute to the protection of cardiovascular defects caused by dietary copper deficiency.⁸²

The second property DMSO possesses that may be useful in coronary artery pathology is its hydroxyl radical–scavenging action and its ability to function as an antioxidant and inhibitor of superoxide anion formation.^83–86

Oxygen-derived free radicals, such as the superoxide anion, hydrogen perox-ide, and the hydroxyl radical, are implicated as mediators in myocardial injury and ischemia during reoxygenation of ischemic tissue.^87–89 The naturally occurring anti-oxidant enzymes, superoxide dismutase and catalase, are reported to prevent the formation of the cytotoxic hydroxyl radical during physiological conditions but may not be able to cope with the free radical generation that follows ischemia and reperfusion.⁹⁰

The third property by DMSO that may be useful in cardiac ischemia serves as a sodium channel blocker. Heart muscle homeostasis depends on the optimal flux of Na⁺ and Ca⁺ for its proper rhythmic contractions, and when an equilibrium of myocyte influx and efflux of these two ion species fails, it results in rhythm and

contractile dysfunction (Figure 2.3). Drugs that prevent abnormal sodium influx into heart tissue provide an effective protection against Na⁺ and Ca⁺ overload. It has been reported that DMSO has an effect on blocking Na⁺ and Ca⁺ entry into cells.^48,91 Since substantial Na⁺ and Ca⁺ entry into myocytes typically occurs after cardiac arrhyth-mias and myocardial infarction, DMSO administration may prevent this inward cellular ion flux while preserving K⁺ outflux from cardiac tissue. The mechanisms exerted by DMSO on Na⁺ and Ca⁺ channels need to be further investigated in mam-malian models since the results of such studies could produce an extremely use-ful and relatively safe agent for a variety of cardiac disorders affected by changes involving these cations.

The fourth property shown by DMSO as a potential cardiac agent is its protective activity against tissue factor (TF) expression in human endothelial cells in response to tumor necrosis factor-α (TNF-α) or thrombin exposure⁹¹ (Figure 2.3). There is general agreement that TF is a key protein in the activation of coagulation and thrombus formation.⁹² This activation of thrombus formation and coagulation is a cause of acute coronary syndromes and myocardial infarction.⁹³

High levels of TNF-α may result in acute coronary disease where it can induce increasing levels of TF in coronary vessels.⁹²

DMSO was found to suppress, in a concentration-dependent manner, TF expression and activity in response to TNF-α or thrombin exposure in human endothelial cells, monocytes, and vascular smooth muscle cells (VSM) in vitro.⁹¹ Moreover, it was additionally observed that DMSO prevented proliferation and migration of VSM from human aorta, an outcome that could have important clinical application in treating coronary thrombosis and myocardial infarction.⁹¹

DMSO cardiac actions

Prevents VSM migration and proliferation

Inhibits platelet aggregation after LAD occlusion Blocks abnormal Na⁺ and Ca⁺ cell entry Blocks tissue factor expression

Restores cardiac output and cerebral blood flow after LAD occlusion

FIGURE 2.3 Cardiac actions reported following administration of DMSO. DMSO prevents the migration and proliferation of vascular smooth muscle cells (VSM) following cardiac ischemia, a common occurrence seen after heart attacks and stroke. Restoration of cardiac output is reported following occlusion of the lateral anterior descending (LAD) coronary artery, which mimics a heart attack. Tissue factor, a powerful cardiac thrombogen, is sup-pressed by DMSO. DMSO may have salutary effects on injured cardiac tissue by blocking abnormal Na⁺ and Ca⁺ influx into cardiac myocytes, preventing myocardial ischemia. See text for details.

In vivo, DMSO treatment significantly suppressed TF activity and prevented thrombotic occlusion in the mouse carotid artery model subjected to a photochemi-cal injury⁹¹ (Figure 2.3).

In summary, DMSO combines four important properties that could be beneficial in cardiac disease: platelet deaggregation, sodium channel blocker, TF antagonist, and free radical scavenger and antioxidant.

There is no drug therapy at the present time that combines these four properties shown by DMSO, thus giving this agent a novel therapeutic advantage as a potential treatment of coronary syndromes. As an antiplatelet agent, DMSO could have ben-eficial effects in coronary artery disease by inhibiting blood clot formation and thus prevent vascular ischemic events involving atherosclerosis in the periphery as well as in the heart and brain vasculature. As a sodium channel blocker, DMSO may show usefulness in the treatment of cardiac arrhythmias.^94,95

DMSO’s antagonism of TF could prevent or treat clot formation in coronary syndromes as well as other disorders associated with TF elevation, such as hyper-tension, diabetes, and dyslipidemia.⁹³ Since these cardiac conditions involve tissue injury to cardiac cells, the formation of oxygen and hydroxyl radical formation is to be expected. DMSO, as a powerful free radical scavenger, may be pivotal as a primary or adjuvant therapeutic agent in controlling cytotoxic damage from radical formation.