Cardiomyopathies Induced by Drugs or Toxins

History

Ancient Egyptians were one of the first civilizations to manufacture beer for both pleasure and religious rituals. In ancient China, rice wine was a tradition and consumed in moderation. In the 16th century, distilled liquor was prepared and termed alcohol . The potential beneficial effects that alcohol could have on the heart were first described in medieval times. In the United States, the 21st amendment was added to the Constitution, which ended prohibition; since then, alcohol has become a widely available product.

For several decades, the deleterious effects of excessive alcohol intake on organ systems, including the cardiovascular system, have become widely recognized, and alcohol abuse is now considered a major cause of morbidity, mortality, and burden to the economics of society. The following section discusses the types of damage that excess alcohol causes to the heart and blood vessels.

Epidemiology

Alcohol is the most commonly used and abused substance across the globe. Approximately 40% of adults use alcohol worldwide. In the United States, approximately 70% of adults use alcohol. Eastern Europe and the former Soviet Union report the highest rates of alcohol consumption, at 10 L of pure alcohol per person per year, while the lowest areas of consumption are southeast Asia and the Middle East, at less than 2.5 L per person per year of pure alcohol. Because of the heavy economic burden of alcohol abuse, the World Health Organization had a goal of decreasing alcohol consumption by 10%. Unfortunately, that goal was not achieved, and in fact, alcohol consumption is on the rise.

Although men consume significantly more alcohol compared with women, the latter are more sensitive to the drug, and the prevalence of alcoholic cardiomyopathy is equal between men and women. Moderate drinking is considered up to one drink per day in women and up to two drinks per day in men. Binge drinking (four drinks for women and five drinks for men in approximately 2 hours, resulting in blood alcohol concentration to 0.08 g/dL or greater) is becoming an increasing problem. Binge drinking in the elderly is on the rise, and it is estimated to occur in approximately 10% of adults older than 65 years of age. Definitions of heavy drinking (Centers for Disease Control and Prevention [CDC]) include 15 drinks or more per week for men and 8 drinks or more per week for women. Both binge drinking and heavy drinking are associated with alcohol use disorder or alcoholism, the inability to control drinking related to both physical and emotional dependence upon alcohol consumption. There have been recent concerns that isolation during the COVID-19 pandemic crisis of 2020 may be associated with an increase in alcohol abuse.

Pharmacology and Pathophysiology

When ingested, ethanol is oxidized by the enzyme alcohol dehydrogenase into acetaldehyde. Acetaldehyde is then oxidized into acetic acid and acetate by the enzyme aldehyde dehydrogenase. These metabolites have an impact on cardiac myocytes, impairing mitochondrial function, enhancing oxidative stress, and increasing myocyte apoptosis, ultimately leading to both systolic and diastolic cardiac dysfunction. The deleterious effects of alcohol drinking depend on the amount consumed and the duration of consumption. The degree of alcohol-induced cardiac effects varies by individual based on many genotypic and phenotypic variants. Although various manifestations of alcoholic heart disease are mainly associated with chronic heavy alcohol abuse, acute binge drinking may also cause myocardial injury, enhance inflammation, and result in cardiac arrhythmias. Other factors that contribute to the cardiac effects of alcohol include associated nutritional deficiencies as well as many additives that may be found in different alcoholic drinks.

Alcoholic Cardiomyopathy

Heavy alcohol drinking for prolonged periods of time affects systolic and diastolic heart function and may lead to overt heart failure (see Chapter 52 ). The amount of alcohol drinking to be considered an alcoholic is generally more than 90 g/day of alcohol for 5 years or more. William MacKenzie first described the cardiac effects of alcohol in 1902, calling it alcoholic heart disease. As many as 30% of chronic alcoholics have evidence of left ventricular (LV) dysfunction by two-dimensional echocardiography. Alcoholic cardiomyopathy represents approximately 20% to 30% of cases of nonischemic dilated cardiomyopathy. The incidence is affected by both phenotypic and genotypic factors. Increased amounts of alcohol consumed per day and a long duration of alcohol use are associated with higher incidence of cardiomyopathy. Women are more susceptible to the development of the disease. The clinical picture of this disease ranges from asymptomatic cardiac abnormalities to clinically advanced congestive heart failure with symptoms of dyspnea, fatigue, and exercise intolerance; the clinical findings on physical examination include jugular venous congestion, rales in the lungs, and peripheral edema (see also Chapter 48 ). In history taking, the term social drinking does not capture the extent of alcohol use. The type, number of drinks per day, and the duration of drinking is essential in evaluating such patients. A 12-lead electrocardiogram (ECG) may show sinus tachycardia (particularly during acute intoxication), nonspecific ST and T wave abnormality, right and left bundle branch block, and various atrial and ventricular arrhythmias. Chest radiography shows cardiomegaly and pulmonary congestion when patients are in decompensated heart failure. Echocardiography is an important noninvasive diagnostic modality. The earliest echocardiographic abnormality in heavy alcohol drinkers is diastolic dysfunction, present in at least one-third of asymptomatic patients. With progression of the disease, global systolic dysfunction ensues, and the echocardiogram may be indistinguishable from advanced idiopathic nonischemic cardiomyopathy. Atrial and ventricular thrombi may be detected in advanced cases, resulting in systemic embolization. Longitudinal, circumferential, and radial strain echocardiography can detect very early cases of alcoholic cardiomyopathy, which will aid in early detection and management of the disease.

The histopathology of alcoholic cardiomyopathy is similar to dilated cardiomyopathy, except there is lower myocyte count in histologic sections in the former compared to the latter. Guzzo-Merello et al. followed 94 consecutive patients with alcoholic cardiomyopathy for a median follow-up of approximately 5 years. In that study, 5% of patients died from heart failure, 8.5% had sudden death, and 15% ended up with cardiac transplant. The remaining patients either remained clinically stable or improved after reducing alcohol intake. Atrial fibrillation, absence of beta blocker therapy, and QRS duration longer than 120 milliseconds were associated with poor prognosis.

Management of alcoholic cardiomyopathy parallels the treatment for heart failure with a reduced ejection fraction (see Chapter 50 ). Abstinence of alcohol drinking should be the first major component of treatment. Patients who stopped drinking or even decreased drinking to mild or moderate levels demonstrated improvement in LV ejection fraction upon follow-up. Patients who completely stop drinking alcohol may normalize their ejection fraction in 1 year. Factors that were associated with the best recovery of ejection fraction included narrow QRS, beta blocker therapy, and lack of use or need for diuretic therapy.

Cardiac Arrhythmias

Frequent atrial and ventricular arrhythmias reported with alcohol drinking are secondary to the effect of alcohol on atrial muscle and ventricular myocytes as well as electrolyte abnormalities. The most common abnormality, and the one that needs more attention in the clinical setting, is atrial fibrillation. Low levels of alcohol intake, with only one standard drink per day, is not associated with increased incidence of atrial fibrillation. Moderate drinking increases the incidence of atrial fibrillation in males only, whereas heavy drinking is associated with atrial arrhythmias in both sexes. The Framingham study showed an increase in the incidence of atrial fibrillation in 34% of patients who consumed more than three standard drinks per day. In a randomized study, 140 patients who consumed at least 10 drinks per week and had atrial fibrillation were randomized to either continuing drinking or no drinking. Those who stopped drinking had significantly lower incidence of atrial fibrillation.

Several decades ago, “holiday heart” syndrome was described as cardiac arrhythmias that were mainly atrial flutter and atrial fibrillation. This syndrome describes patients who consume excessive alcohol on weekends and holidays, who then develop these arrhythmias a day or two later. It is more common in men than in women, occurs in patients with an apparently normal heart, and has a relatively benign prognosis.

Ventricular arrhythmias occur with heavy alcohol drinking and may be fatal. A V-shaped or J-shaped curve that characterizes the relationship between alcohol drinking and mortality has been described. Mild to moderate drinking is associated with lower cardiovascular mortality, whereas heavy drinking leads to increased mortality. Alcohol drinking was followed in 33,593 healthy volunteers who drank alcohol for 26 years. Significant alcohol drinking was associated with higher mortality ( Fig. 84.1 ). Alcohol drinking in the presence of left bundle branch block and decreased ventricular function are determinants of malignant ventricular arrhythmias.

Alcohol and Lipid Metabolism

Alcohol increases high-density lipoprotein (HDL) and may reduce low-density lipoprotein (LDL). It may even have some favorable effect on lipoprotein(a) ( Fig. 84.2 ). In addition, moderate intake of beer enhances the antioxidative properties of HDL; thus it prevents lipid deposition in blood vessel walls. Severe alcohol consumption may increase triglyceride levels, blunting the beneficial effect of moderate alcohol drinking. ^,

Alcohol and Coronary Artery Disease

In addition to a potential benefit on HDL levels, alcohol may have other protective effects that limit coronary atherosclerosis. Systemic inflammation is shown to promote atherosclerosis. Alcohol has antioxidant and antiinflammatory effects. It is associated with a decrease in C-reactive protein as well as interleukin-6. The beneficial effect is limited to low to moderate drinking, and it appears to be more pronounced in men compared with women. In heavy drinkers, the opposite occurs. Heavy drinking and binge drinking are associated with an increase in inflammatory markers. After mild to moderate alcohol drinking, there is a decrease in platelet aggregation. However, binge drinking may have the opposite effect, which may account for the increase in cardiac events following binge drinking. Some alcoholic beverages, specifically wine, contain resveratrol, which has an antioxidant effect that stimulates mitochondria biogenesis. It is quite clear that low to moderate alcohol consumption is associated with a decreased risk of atherosclerotic burden. Mild alcohol drinking, particularly wine, is associated with a decrease in cardiovascular risk. There is a favorable effect on mortality when mild alcohol drinking is combined with other healthy lifestyle factors such as no smoking, a healthy diet, and moderate physical activity. The American Heart Association (AHA) suggests that if a person already drinks, their intake be limited, with one or two drinks per day for men and only one drink for women. A “drink” is considered to be 12 ounces of beer, 5 ounces of wine, or a mixed drink containing 1.5 ounces of hard liquor. However, the AHA does not recommend that people start drinking to lower their cardiovascular risk.

Alcohol and Hypertension

Mild alcohol drinking does not affect blood pressure. However, heavy alcohol drinking, which initially may cause vasodilation, may later result in an increase in blood pressure. It is expected that controlling excessive alcohol drinking in people 40 to 60 years of age will result in a decrease in hypertension, and that is expected in both men and women. In a randomized study, 25 normotensive volunteers received either 375 mL of red wine or a nonalcoholic beverage. Blood pressure fell 4 hours after drinking alcohol but was significantly higher 24 hours later as compared with the control subjects. When drinking is combined with weight gain and smoking, the effect on blood pressure is accentuated. The deleterious and protective effects of alcohol on the cardiovascular system are summarized in Figure 84.3 .

The Effect of Electronic Cigarettes/Vaping on the Cardiovascular System

It is well known that smoking tobacco cigarettes leads to a number of health problems including ischemic heart disease, lung cancer, other forms of cancer, chronic obstructive lung disease, and peripheral vascular disease. Tobacco smoking accelerates atherosclerosis and leads to myocardial infarction (MI), stroke, and peripheral arterial disease. Carbon monoxide in tobacco smoke reduces oxygen availability. The nicotine in tobacco smoke is known to stimulate the sympathetic nervous system, which results in an increase in heart rate, blood pressure, heart contractility, and coronary vasoconstriction. Nicotine lowers HDL cholesterol, increases triglyceride levels, and induces endothelial dysfunction. Tobacco smoke results in oxidant chemicals, particulates, and combustion products that cause inflammation, endothelial dysfunction, and activates clotting mechanisms.

There is a common perception that electronic (e-)cigarettes may be safer than tobacco cigarettes because they lack the tars that cause cancer and do not contain as many of the over 4000 chemical compounds that are created by a burning tobacco cigarette. It is also thought that they might help smokers quit tobacco smoking. E-cigarettes consist of a liquid cartridge that typically contains propylene glycol and vegetable glycerin and may contain nicotine at various doses (including very high doses). The e-liquid may also contain flavorings, some of which are fruit flavored and sweet and appeal to young people. The e-cigarette devices also include a sensor, a microprocessor, and a battery. The electronic cigarette is activated with inhalation by the sensor or by pushing a button; this triggers the heating of coils, which then vaporizes the e-liquid within the cartridge. E-cigarette vapors reach the mouth or the air and condense into particles that form an aerosol. Some of the devices have a light that simulates the glow of a lit cigarette, which is turned on by the microprocessor. Although e-cigarettes do not contain tar or generate carbon monoxide as do tobacco cigarettes, when the e-liquid is heated the results may include formation of formaldehyde, acetaldehyde, and acrolein, which result in reactive oxygen species and inflammation that can contribute to an acceleration of atherosclerosis and clotting. Electronic cigarettes are commonly used as a nicotine delivery device. Nicotine can result in the cardiovascular effects described earlier and is addictive. In addition, the high temperatures of e- cigarettes can result in the generation of very small particulate matter that can enter the lungs and possibly the vasculature to a greater extent than tobacco cigarettes and contribute to vascular damage. Metals and flavoring contained in e-cigarette vapor can contribute to adverse cardiovascular effects including inflammation.

Electronic cigarettes have been around since approximately 2003, and they have become increasingly popular, even as overall tobacco smoking has declined. It is estimated that approximately 9 million adults in the United States vape on a regular basis. In 2019, approximately 28% of high school students reported using e-cigarettes, while only 5.8% reported smoking tobacco cigarettes. Approximately 10.5% of middle school students reported using e-cigarettes. E-cigarette use increased from 12% to 21% among high school students from 2017 to 2018.

E-Cigarette or Vaping Product Use Associated Lung Injury (see Chapter 28 )

Beginning in July 2019, a new form of lung injury was described in people who vape and has now exploded into a true epidemic. The condition is now known as E-cigarette or vaping product use associated lung injury (EVALI). As of January 14, 2020, there have now been over 2660 clinical cases of EVALI reported, with 60 deaths in the United States. Over 90% of victims have been hospitalized, and over 30% required respirators. Cases have been reported in nearly all states in the United States. The typical victim is a young male who has been using e-cigarettes (vaping) within days to weeks of the illness. The patients present with respiratory distress including shortness of breath, cough, chest pain, fever, fatigue, and gastrointestinal symptoms including nausea, vomiting, and diarrhea. The patients are often hypoxic. Chest radiography typically shows ground glass–appearing bilateral pulmonary infiltrates. Histology has shown pneumonitis, bronchiolitis, and diffuse alveolar damage. Some reports have described lipid-laden macrophages. The phenomenon has been observed in people using a wide variety of e-cigarette liquid brands, substances, and devices. The exact cause of EVALI remains to be determined. Of note, over 80% of cases included use of tetrahydrocannabinol (THC). One leading theory suggested by the CDC is that contaminants such as vitamin E acetate oil, which is often used to dilute THC, may be responsible for EVALI. However, although studies have shown that there is an association between the presence of vitamin E acetate in the lungs of victims and the presence of EVALI, these studies have not clearly demonstrated that vitamin E is responsible for the pulmonary problems that develop. Over 60% of the victims of EVALI also used e-liquid that contained nicotine. Although vitamin E acetate and nicotine may contribute to EVALI, additional studies will be necessary to determine the role of these agents. Other than stopping vaping, there is no specific treatment, as yet, for EVALI other than supportive measures and hospitalization if needed. Influenza testing should be considered, and other causes of pneumonia and respiratory distress (including COVID-19) should be ruled out and treated. Some patients have responded to corticosteroids.