In western countries, more than half the population drink alcohol, and approximately 10 to 18% of this drinking population will have an alcohol abuse problem. Given the frequency of alcohol consumption in our society, identifying those at risk of alcoholism and its adverse health consequences poses a great challenge to health care professionals. Alcohol abuse causes a wide range of medical complications. Its effect on the cardiovascular system is however two-fold. Evidence suggests that long-term consumption of low levels of alcohol may provide a degree of protection to the myocardium and vasculature. On the other hand, alcohol in excess exerts a direct toxic effect on the myocardium. As a consequence of this effect, alcohol abuse is a major cause of dilated cardiomyopathy in the west today.
Alcohol consumption has been linked with cardiovascular complications for over 100 years. Towards the end of the 19th Century, heart failure symptoms were detected in alcoholics and Bollinger described an enlargement of the heart associated with chronic beer drinking as early as 1884. However, at first it was believed that the cardiovascular complications of alcoholism were caused either by nutrient malabsorption that resulted from heavy drinking (e.g. thymine deficiency), or by the consumption of contaminated alcoholic beverages, such as the beer contaminated with arsenic in the early 1900’s. Although such factors may have contributed in the individual case, in the 1950’s alcohol’s toxic effect on the myocardium was confirmed.
Fortunately, not all alcoholics develop a dilated cardiomyopathy. However, one third of asymptomatic alcoholics have been shown to have some degree of cardiac dysfunction. The prevalence of alcoholic cardiomyopathy (ACM) makes up between 23 and 40% of dilated cardiomyopathy [1,2,3] and accounts for at least 2% of new heart failure in the UK [4]. Four year mortality without abstinence approaches a staggering 50% [5].
ACM occurs in two stages: the asymptomatic stage and the symptomatic stage, where the latter is characterized by the presence of symptoms of heart failure [6]. Asymptomatic patients are patients with a history of alcohol abuse who are found to have abnormalities on echocardiography indicating a dilated cardiomyopathy, without symptoms of heart failure. The condition is characterized by the following findings: dilatation of the ventricles, an increased left ventricular mass, wall thinning and ventricular dysfunction, in the absence of coronary artery disease and nutritional deficiencies [7]. As the disease progresses the remaining normal myocytes hypertrophy in response to their increasing workload. It is not yet clear in exactly what order these changes occur, but Lazarevic et al8 found that left ventricular dilatation, diastolic dysfunction and increased left ventricular mass are early findings of asymptomatic ACM, which would suggest that research should be aimed at finding treatments that can prevent the above mentioned abnormalities from occurring.
In general, individuals consuming over 90 grams of alcohol per day (roughly six standard drinks per day) over 5 years are at risk of developing asymptomatic ACM [1,8]. Consumption of over 80 grams per day for over 10 years puts one at risk of developing symptomatic ACM [9]. These cut-off points are far from clear-cut, and it remains unclear at exactly what level and duration of alcohol consumption the asymptomatic and symptomatic stages are caused. Although Urbano-Márquez et al [10] found a correlation in 1989 between the total lifetime consumption of alcohol and the increase in left ventricular mass and decrease in ejection fraction, the vast majority of subsequent studies report no linear relationship between alcohol consumption and myocardial damage [11]. Unfortunately, recent data is very limited in terms of what level and duration of alcohol consumption is required to cause the changes seen in ACM. The most conclusive studies were done in the 1980’s and suggested that the duration of alcohol consumption was significantly longer (four to eight years longer) in symptomatic patients than asymptomatic patients, whereas the level of daily consumption seemed less significant [10,12].
Unfortunately, most cases of ACM become apparent after patients present with symptoms of heart failure, when the disease has often progressed to its end-stage where significant myocardial fibrosis occurs. The most common symptoms include breathlessness, fatigue, exercise intolerance and fluid retention [13]. Other less common symptoms are orthopnoea, paroxysmal nocturnal dyspnoea, nocturnal cough and nocturia. Patients are classified according to the New York Heart Association’s (NYHA) classification:
Dilated cardiomyopathy also predisposes to a number of arrhythmias, most commonly atrial fibrillation, but also ventricular arrhythmias sometimes causing sudden cardiac death. Arrhythmia due to alcohol consumption has been well documented. Ettinger et al [14] showed that cardiac arrhythmias were induced by heavy drinking or binge drinking as early as 1978. Since then a number of studies have confirmed that binge drinking increases risk of AF. However, there is conflicting evidence regarding long term alcohol consumption and risk of AF. The Cardiovascular Health Study [15] reported that alcohol consumption reduced risk of atrial fibrillation in a dose-response related manner. However, evidence from more recent studies suggests the contrary. In their prospective study, Djousse et al [16] demonstrated that consumption of more than 36 grams of alcohol per day (roughly 3 drinks per day) was associated with a 34% increase in risk of AF, though consumption of less than 36 grams seemed insignificant. Frost and Vestergaard [17] found a steadily increasing risk of AF and atrial flutter with increasing consumption of alcohol in men, but no correlation in women. It is not yet clear what the precise relationship between long-term alcohol consumption and risk of AF is, and there is a need for further research to either confirm or refute the recent findings that suggest that long-term alcohol consumption may increase risk of AF. ACM also predisposes to thrombo-embolic events, as a result of the dilated cardiac chambers and haemostasis that follows.
An elevated jugular venous pressure is a very sensitive sign of heart failure whereas other signs such as resting tachycardia, displaced apex, third heart sound have little predictive value if found in isolation [18]. Additionally, systolic murmurs may be heard suggestive of mitral regurgitation secondary to left ventricular dilatation. However, even when multiple symptoms and signs are present, diagnosis can only be verified through further investigation.
Essentially there are three elements to diagnosing ACM. The first part is to demonstrate an enlargement of the ventricular chambers and a reduced ejection fraction, indicating a dilated cardiomyopathy. This is accurately assessed using an echocardiogram. Table 2 shows the criteria for diagnosis of a dilated cardiomyopathy. Cardiac biopsy is rarely performed in clinical practice, as the findings of myocyte hypertrophy, myocytolysis and interstitial fibrosis are non-specific [19], though it can be useful in isolated cases where cardiac haemochromatosis or other forms of infiltrative or malignant disease is suspected. Once a dilated cardiomyopathy is found on echocardiography, the next step is to find a cause. It is important to point out that ACM is pathologically indistinguishable from idiopathic dilated cardiomyopathy, and it is therefore imperative to make every effort to rule out any other cause of dilated cardiomyopathy such as coronary artery disease, valvular heart disease, nutritional deficiencies etc. Once other causes have been ruled out, the diagnosis depends on a history of excessive alcohol consumption. Findings that may suggest alcohol abuse in addition to the history include an elevated red cell mean corpuscular volume (MCV), elevated aspartate aminotransferase (AST), elevated ?-glutamyl transferase (?-GT), elevated serum uric acid, elevated high-density lipoprotein, and mild thrombocytopenia.
No formal diagnostic criteria exist for ACM. Since it is generally agreed that idiopathic dilated cardiomyopathy is pathologically and clinically identical to ACM, this author puts forward the idea of using the above diagnostic criteria as a template for diagnosis of symptomatic ACM with some subtle changes. ‘Chronic alcohol excess’ would be part of the inclusion criteria and ‘absence of family history of familial dilated cardiomyopathy’ part of the exclusion criteria:
Most alcoholics are only diagnosed with ACM when they present with features of heart failure. The current NICE guidelines recommend that an ECG is recorded and the BNP is measured in any patient where heart failure is suspected. ECG changes in dilated cardiomyopathy include isolated T-wave changes, septal Q-waves, prolonged AV conduction, bundle branch blocks and ventricular tachyarrhythmias [22]. Both tests are highly sensitive to heart failure: the sensitivity of ECG may be as high as 94% [23], and the sensitivity of BNP is thought to be between 90-97%24. If both investigations are negative, heart failure is highly unlikely. If any or both investigations are abnormal, then an echocardiogram is indicated to confirm heart failure. If the echocardiogram is normal, heart failure is again highly unlikely and efforts should be made to find an alternative diagnosis. Other tests that should be performed include a routine chest X-ray (signs of heart failure include alveolar oedema, Kerley B lines, cardiomegaly, dilated prominent upper lobe vessels and pleural effusion), a full blood count (alcohol causes macrocytosis) and urea and electrolytes. Figure 1 summarizes the NICE guidelines for investigation of suspected heart failure.
One of the most important factors affecting prognosis of patients with ACM is abstinence from alcohol. In 2000, Fauchier et al [1] and Gavazzi et al [3] conducted prospective studies, with mean follow-ups of 59 ± 35 months and 47 ± 40 months respectively. Both groups followed up patients with ACM and idiopathic cardiomyopathy receiving standard heart failure treatment only. Patients were divided into three groups: patients with ACM with abstinence, patients with ACM without abstinence, and patients with idiopathic cardiomyopathy. Both studies found that mortality was significantly higher in patients without abstinence compared to abstinent patients and patients with idiopathic dilated cardiomyopathy (See Figure 2). These findings proved beyond any doubt that abstinence from alcohol is a major prognostic factor in ACM. Interestingly, Nicolás et al [25] demonstrated that patients who limit their alcohol intake to 20 to 60 grams per day, without binging, had similar outcomes after one year as patients who abstained completely. As a result, their findings gave rise to a threshold of 60 grams per day (about four standard drinks) below which no significant damage seems to be inflicted on the myocardium. This may help doctors identify patients who are lying about their alcohol consumption, when their condition deteriorates despite claiming to be abstinent or near-abstinent.
The first step to promoting abstinence is always assessing alcohol use. It is the duty of the General Practitioner to acquire an adequate alcohol history from his patients. Unfortunately, GP’s these days rarely have sufficient time to perform a thorough assessment of alcohol consumption, and therefore alcohol abuse may not always be recognized by the GP. Nonetheless, when alcohol abuse is strongly suspected, from the history or if a patient presents with physical complications of alcohol abuse (such as symptoms of heart failure), the patient should be referred to a specialist, often a psychiatrist, that can conduct an in depth assessment.
Recent evidence suggests that brief alcohol interventions are useful methods of bringing about reduction in drinking. Brief alcohol interventions usually involve raising the patient’s awareness of his or her drinking, giving feedback on risk status and advice on safe limits. These sessions are short, reassuring and aimed at enhancing the patient’s optimism. Numerous reviews have confirmed that these sessions bring reductions in drinking of between 20% to 40% [26,27]. In patients with a lack of desire to change drinking habits, the clinician can use motivational interviewing as the therapeutic style. Motivational interviewing is a non-confrontational, client-centered method of producing or enhancing intrinsic motivation to change. Instead of telling the patient what to do, motivational interviewing aims to direct the conversation toward behaviour change through empathic listening and questioning.
Once abstinence is achieved, it is essential that relapse is prevented. Relapse often follows situations related to anxiety, interpersonal conflict, depression, loneliness, loss or social isolation. By helping patients to monitor these high-risk situations, to identify strategies that have been successful in promoting abstinence in the past, and to become engaged in treatment, relapse may be avoided and abstinence maintained28. Treatments such as cognitive-behavioural therapy, group and family therapies and self-help groups are shown to be effective across all age groups. Medicinal adjuncts, like naltrexone and acamprosate, have been shown to significantly reduce craving and risk of relapse [29,30]. Additionally, clinicians should perform regular blood tests in order to monitor variables that are affected by alcohol use (see 3.2 Investigation and Diagnosis).
In addition to alcohol abstinence, there are numerous other general lifestyle strategies aimed at patients with cardiomyopathy or heart failure. Overweight or obese patients are advised to lose weight, and to monitor their weight daily being watchful of any sudden weight gain indicative of acute fluid retention (the European Society of Cardiology recommends patients to alert their health care provider in case of a weight gain in excess of 2 kg in 3 days [31]). Dietary and fluid restriction is commonly advised by physicians, though the NICE says that further research is required in the area. There is limited research on the effects of stopping smoking in patients with cardiomyopathy and heart failure. Nonetheless, as smoking has a number of adverse effects on the cardiovascular system, smokers should always be strongly advised to stop smoking and referred to smoking cessation services. Although patients in acute heart failure are advised bed rest, patients with chronic heart failure should be encouraged to exercise to a limit that does not induce symptoms. Both aerobic exercise, such as brisk walking, and resistive exercise, such as weight training, have been shown to improve symptoms [32,33].
Pharmacological treatment is aimed at symptom management, prevention of disease progression and prevention of further complications such as congestive heart failure, sudden cardiac death and thrombo-embolic events. Due to lack of appropriate clinical trials, there exists no proven therapy for ACM. Treatment is therefore a result of the recommended treatment for heart failure and that for dilated cardiomyopathy.
ACE-inhibitors make up the mainstay of treatment of heart failure of any given cause [31] and high-dose lisinopril has specifically been shown to reduce risk of death and hospitalization in dilated cardiomyopathy [34] (see Figure 3 for the complete algorithm of heart failure treatment). Interestingly, the Fauchier [1] and Gavazzi [3] trials showed that heart failure treatment improved ventricular ejection fraction in all subjects (patients with idiopathic dilated cardiomyopathy, patients with ACM with abstinence, and patients with ACM without abstinence), but for unknown reasons the treatment did not reduce cardiac deaths in the drinking group. This once again highlights the importance of abstinence over all other treatment.
Treating arrhythmias in dilated cardiomyopathy has proven difficult. Elliott [20] suggests that class I anti-arrhythmics should not be used, citing evidence that has showed an increased mortality with their use. Class III agents are thought to be safe, but it is unclear whether or not they affect mortality and are therefore not yet recommended for sudden cardiac death prophylaxis [35]. Amiodarone, which is used by many clinicians, is shown to be effective against AF and supraventricular arrhythmias, but does not seem to affect mortality in ventricular arrhythmias [21]. There is a clearly need for more clinical trials investigating the prophylactic use of various anti-arrhythmics in dilated cardiomyopathy. Additionally, warfarin therapy should be discussed with patients with AF, severe systolic dysfunction, severe ventricular dilatation or a history of thrombo-embolic events [20].
Patients with ACM have been known to have marked neuro-hormonal imbalances. Jing et al [36] demonstrated in rats that angiotensin I, angiotensin II and renin levels progressively increased at two, four and six months of alcohol intake, and that mRNA expression of renin, angiotensinogen, angiotensin-converting enzyme and angiotensin was increased at 6 months. They also found that the activation RAS accompanied the development and progression of ACM in the rats. Furthermore, they found that irbesartan prevented this increase (see Figure 4). Other studies have produced similar results. Cheng et al [37] showed that chronic alcohol consumption is followed by progressive cardiac dysfunction and that blockade of the angiotensin II type I receptor by irbesartan prevented the cardiac dysfunction and development of ACM in the dogs. These findings have two implications: firstly, that activation of the angiotensin II type I receptor plays a key role in the development of ACM; and secondly (more significantly) that this provides a potential therapeutic target for clinicians to prevent the development of the disease in alcoholics. Naturally, more research is required, in experimental animal models to start with, and in randomized clinical trials at a later stage to confirm the same effect in human ACM.
There is also a proposed link between zinc homeostasis and cardiac fibrosis. Zinc depletion has been demonstrated to be a common finding in patients with dilated cardiomyopathy [38]. Wang et al [39] developed a mouse model (metallothionein-null mice) in which cardiac hypertrophy and fibrosis were produced by chronic alcohol consumption. Using this model they showed that alcohol with zinc supplementation kept total collagen accumulation close to control values, whereas alcohol feeding alone induced collagen deposits in the myocardium, indicating that zinc supplementation prevents cardiac fibrosis. This effect however was specific for fibrosis, and there was no notable change in alcohol-induced myocardial hypertrophy. Given the numerous limitations of using mice models (shorter life span of mice does not allow for sufficient alcohol exposure as that seen in humans), it is difficult to say whether or not these findings are limited to the mouse model. Nonetheless, the mouse model used by Wang et al offers great promise, as it reproduces both the hypertrophy and fibrosis seen in the human disease, whereas previous models reproduced the hypertrophy but not fibrosis.
Although, there are clear clinical benefits to all treatments mentioned above, it must be added that none of them do anything to repair the heart. Traditionally the heart has been thought to be a terminally differentiated organ unable to undergo repair or regeneration. Thanks mainly to the work of Beltrami et al [40] it is now known that this belief was flawed, as they established that human cardiac myocytes are capable of mitosis after myocardial infarction. Since this discovery, much research has been aimed at making use of the ability of cardiac muscle cells to divide after myocardial infarctions to find means of regenerating heart tissue. Much of this research has been focused on a procedure called cardiomyoplasty, which involves transplanting progenitor cells into the heart. Among potential cellular sources used in cardiomyoplasty, mesenchymal stem cells (MSCs) derived from bone marrow are emerging as a leading candidate41. Kraitchman et al used MSCs and transplanted them by intramyocardial injection in a swine model [42]. The results certainly gave cause for optimism as the stem cells differentiated into a myocyte-like phenotype. The study also demonstrated that cardiomyoplasty improved left-ventricular function and produced neovascularization within two weeks of the myocardial infarction. Nagaya et al [43] demonstrated similar results in their rat model with dilated cardiomyopathy, and showed that MSC transplantation induced myogenesis and angiogenesis, and also inhibited further myocardial fibrosis. These discoveries have brought forth much optimism regarding the role of cardiac progenitor cells as a viable treatment strategy for cardiomyopathies in addition to their potential role post myocardial infarction.
At present, heart transplantation remains the only definitive cure to end-stage heart failure of any cause. This is far from ideal though, given the scarcity of hearts available for transplantation. Left ventricular assist devices (LVADs) can be used as a bridge between end-stage heart failure and heart transplantation, and also for long term support in patients ineligible for heart transplants [44]. Ventricular assist devices are mechanical pumps that assist the function of the weakened ventricle in order to restore normal blood flow. They have been shown to normalize haemodynamics, improve progressive dysfunction of the heart, improve exercise tolerance, and allow patients to become outpatients [45]. However, NICE guidelines do not yet recommend their use as a bridge to transplantation, nor as a chronic therapy, citing “insufficient data on the mechanisms of response and the identification of patients in whom the devices can be safely removed” [24].
Partial left ventriculectomy (the ‘Batista’ procedure) has been proposed as an alternative treatment for end-stage heart failure secondary to dilated or hypertrophic cardiomyopathy [46]. The procedure seeks to restore left ventricular function by reducing cardiac volume and left ventricular tension through the resection of the posterolateral (or lateral, or anterior) wall of the left ventricle. The procedure is performed with the aid of cardiopulmonary bypass and is not without complications. Often, valvuloplasty may be needed to prevent post-operative mitral regurgitation. Studies have shown good results considering the complexity of the procedure. However, there are several drawbacks. Some patients survive only with the aid of a left ventricular assist device, or still require a transplant at a later stage. Similarly, the occurrence of peri-operative failures and return to heart failure after surgery, has limited its use, as appropriate patient selection has proved challenging. As a result, most experts have concluded that the procedure is not yet a reliable alternative to heart transplantation, but may be used as a bridge to transplantation [46,47]. As there are clear beneficial effects, despite the many and unpredictable drawbacks, there is a case for further clinical trials, especially in patients not yet requiring heart transplant.
Implantable cardioverter-defibrillators (ICDs) are shown to prolong life in patients with impaired left ventricular function and a history of sustained ventricular arrhythmia [48]. Guidelines for the indication of ICDs do not specifically include dilated cardiomyopathy (Table 4). However, trials where ICDs have been used prophylactically to prevent sudden cardiac death have shown promising results. Kadish et al [49] enrolled 458 patients with idiopathic dilated cardiomyopathy into a randomized controlled trial. Their study provided evidence that the implantation of cardioverter-defibrillators significantly reduced the risk of death due to arrhythmias, and non-significantly reduced the risk of any death. Grimm et al [50] drew similar conclusions from their study, suggesting that ICDs have a role in both primary and secondary prevention of sudden death in dilated cardiomyopathy. However, it is unclear whether prophylactic implantation of cardioverter-defibrillators is superior to prophylactic medical treatment. Strickberger et al [51] found no statistical difference between amiodarone and ICD, but suggested that amiodarone therapy be more cost-effective. On the other hand Bardy et al [52] found that in patients in NYHA class II or III heart failure with an ejection fraction of less than 35%, ICD therapy reduced mortality by 23%, whereas amiodarone therapy was ineffective. Due to the contrasting results ICDs are not yet recommended for primary prevention in dilated cardiomyopathy.
The aim of cardiac resynchronization therapy (CRT), also known as Dual Chamber Pacing, is to improve the efficiency of the heart by simultaneously pacing both the left and right ventricles, thus improving mechanical contractility. Strickberger et al [53] analyzed numerous clinical trials and recommended that optimal patients for CRT “have a dilated cardiomyopathy on an ischemic or nonischemic basis, an LVF ?0.35, a QRS complex >120ms, and sinus rhythm, and are NYHA fuctional class III or IV despite maximal medical therapy”. Furthermore, when CRT is combined with ICD therapy total mortality is significantly reduced [54].
Excessive alcohol consumption is significant problem worldwide with immense health consequences. A proportion of individuals with heavy chronic alcohol consumption will develop ACM and ACM is a leading cause of dilated cardiomyopathy in the West. It is important to identify patients who are at risk of developing ACM, in order to diagnose the condition at an early stage. In general, individuals consuming over 90 grams of alcohol per day for over 5 years are at risk of developing asymptomatic ACM. Unfortunately, the vast majority of patients are only diagnosed once they present with symptoms of heart failure or other complications such as cardiac arrhythmia or thrombo-embolic events. At present no formal diagnostic criteria for alcoholic cardiomyopathy exist. Common practice is to use the criteria for dilated cardiomyopathy in addition to history of alcohol abuse.
The current treatment regime of ACM includes alcohol abstinence and treatment of heart failure. There is strong evidence to suggest that alcohol abstinence is vital in the treatment of ACM, with studies indicating that although heart failure treatment improves left ventricular function, it does not affect mortality without abstinence. How to best treat ventricular arrhythmia due to ACM remains unclear. There are conflicting results of what pharmacotherapy is best, and whether or not ICD’s should be used prophylactically to prevent sudden cardiac death.
Studies implicating the role of RAS activation in the development of ACM have indicated a role of angiotensin type I receptor blocker in disease prevention. Additionally, with research showing that cardiomyoplasty can induce regeneration of myocardial tissue post-MI, this procedure may serve as a viable treatment strategy for cardiomyopathies as well. In terms of surgical treatment, heart transplantation remains the only definitive cure for ACM, with partial left ventriculectomy not yet deemed a suitable alternative.
Although research has provided some potential treatment alternatives for the future, there are still many blurry areas surrounding ACM. In terms of diagnosis, the fact remains that a majority of patients are diagnosed at the symptomatic stage once the disease has nearly progressed to its end-stage. In terms of treatment, most alternatives aim to prevent further damage, instead of actually repairing the heart. It is the opinion of this author that research therefore needs to be aimed at finding ways of diagnosing ACM earlier, at the asymptomatic stage, and finding treatment alternatives that can repair the heart both structurally and functionally.
Published: Saturday, July 18th, 2009
Category: Volume 1 Issue 2
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