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Advances In The Prevention And Treatment Of Cardiovascular Disease
Over the past thirty-five years, U.S. age-adjusted mortality from cardiovascular disease declined 50 percent. This marked reduction reflects advances in the prevention, diagnosis, and treatment of common cardiovascular conditions. Pharmaceutical agents play a major role in prevention of atherosclerosis and its consequences: heart attack, stroke, and heart failure. Additionally, novel device-based therapies contribute to the decline in cardiac morbidity and mortality. Whereas innovative strategies based on accurate imaging of the heart and blood vessels are implemented widely now, hope exists that lifestyle changes, early risk-factor screening, and more efficacious drugs will strikingly reduce cardiovascular disease in the future.
INCREASING LIFE EXPECTANCY IN WESTERN SOCIETY is the result of two major success stories in the prevention and treatment of human disease. The first milestone was eliminating the scourge of common infectious diseases through public health measures, vaccines, and antibiotic drug development. The second was the decline in cardiovascular mortality and morbidity, which began in the 1970s (Exhibit 1  ).1 This marked reduction in cardiovascular disease and its consequences was largely driven by the development and implementation of drugs for long-term use and by complicated and costly procedures and operations for acute disease management. In addition to physician judgment and skill, such lifesaving and -preserving procedures require a detailed knowledge of the anatomy, an evaluation of severity of disease, and an assessment of the potential dire consequence of disease in terms of heart or brain damage. This critical need for information led to the advent of extensive imaging of the heart, brain, and blood vessels.
Atherosclerosis. Most cardiovascular morbidity and mortality occurs as a result of atherosclerosis (lipid accumulation) in various arteries of the body. This lipid deposition is often earliest and most aggressive in the coronary arteries, which supply blood to the heart. The most dramatic consequence of atherosclerosis in the coronaries is acute myocardial infarction (AMI—death of heart muscle tissue with scarring of the heart). For centuries it was speculated that the sudden occlusion of a diseased coronary vessel by a blood clot resulted in infarction, but this was not proved until the early 1980s.2 At that time, approximately 400,000 major infarctions were occurring in the United States each year. Moreover, 20 percent of these patients died during the initial hospital stay, and 40 percent died within the first year. Now, one-year mortality is 4–8 percent. The number of major AMIs per year is similar today, but the number of infarctions of all sizes has risen to 1.2 million per year. In addition to acute coronary blockage, chronic nonocclusive obstruction of the coronary arteries from atherosclerosis also leads to disabling chest pain (angina).3 Heart failure. Atherosclerotic disease, causing large or multiple small MIs, may lead to enlargement or remodeling of the heart, which decreases its pumping ability. This clinical condition is referred to as "heart failure." Symptoms of heart failure include shortness of breath with exertion and fluid accumulation in the legs or lungs, or both. Although atherosclerosis is the most frequent cause of heart failure, alternative mechanisms include high blood pressure with consequent enlargement or hypertrophy of the heart and other inherited or acquired problems that decrease the functioning of heart muscle. Currently, 550,000 patients are diagnosed with heart failure per year in the United States.4 Many older patients with heart failure do not have problems with cardiac muscle contraction, but their heart walls are stiff, which limits filling of the pumping chambers between beats. Specific therapies are not yet available for this type of heart failure. Stroke. Another major consequence of atherosclerosis is stroke. Similar to the death of heart muscle in an AMI, stroke is the death of brain tissue with scarring caused by an interruption in blood supply. In addition to atherosclerotic blockage of brain vessels, stroke may be caused by hemorrhage into brain tissue or by occlusion of brain arteries from clots originating in the heart or the central arterial vessels. It is estimated that 500,000 new strokes occur in the United States each year.5 Hypertension. Increased blood pressure is the most common form of cardiovascular disease in the United States. The etiology of hypertension is multifactorial and includes changes in volume-regulating hormones, genetic predisposition, atherosclerosis, as well as the natural stiffening process of the arteries as they age. Hypertension increases the risk for stroke, atherosclerosis, atrial fibrillation, MI, heart and kidney failure, and overall mortality. The incidence and prevalence of hypertension increases with age, such that approximately 60 percent of those over age sixty carry the diagnosis.6 Unlike other forms of cardiovascular disease, hypertension is often asymptomatic. Atrial fibrillation. This is an irregular and chaotic heart rhythm that does not permit the filling chambers of the heart, the "atria," to contract properly. It increases in frequency with age and is increasingly recognized as a frequent cause of debilitating strokes from clots formed in the fibrillating left atria. It is also a major contributing factor to heart failure and cardiac disability. Current estimates are that 2.2 million Americans have atrial fibrillation, most over age sixty-five.7 Sudden cardiac death. Cardiovascular disease is by far the most common cause of death occurring within minutes of "appearing normal or near normal." Failure of the pacemaker tissue of the heart leads to death from absent or slow heartbeats. This can be prevented with electronic pacemakers. Sudden death is more often due to lethal rapid or nonuniform chaotic electrical activity and is preventable with internal or external shocks or "defibrillation." Atherosclerotic coronary disease and a variety of acquired or inherited heart conditions predispose to sudden death. Despite public health measures to prevent death with public-access defibrillators and emergency medical systems, 350,000 Americans die from cardiac-related sudden death each year.8 Obesity and aging. Although not necessarily "cardiovascular conditions," these two rapidly growing demographic characteristics are driving the escalating incidence and prevalence of U.S. cardiovascular disease. The rising tide of obesity and the associated increase in diabetes produce a population with a rising predisposition to vascular disease. Cardiovascular disease in the setting of diabetes is more premature, relentless, and recurrent, despite aggressive therapies and interventions. Obesity and diabetes are also commonly associated with hypertension ("metabolic syndrome"). Chronic kidney disease is also accelerated by diabetes, which, in turn, hastens the pace of hypertension, atherosclerosis, and heart failure.
The second major driver toward increasing cardiovascular patients is the relative aging of the population. Age is the most significant risk factor for cardiovascular disease. The decreasing overall age-adjusted mortality (Exhibit 1
Protein enzymes, receptors, or channels identified by the pharmaceutical industry as "drugable targets" have led to striking, remarkable, and repeated achievement. However, unlike therapies used in infectious diseases, these agents offer no rapid "cure." Rather, they prevent or reduce the progression of disease when ingested continuously. The efficacy of these treatments to reduce cardiovascular morbidity and mortality in stroke, heart attack, and heart failure was established principally through large-scale clinical trials. Examples of targeted drugs. Statins. By blocking an enzyme in the formation of low-density lipoproteins (LDL), this class of drugs reduces levels of LDL in the blood and diminishes the accumulation of lipids in arteries. Statins may exert a beneficial effect by decreasing inflammation and oxidative stress, both of which contribute to AMI. Accordingly, these agents reduce acute infarction, recurrent minor infarction, heart failure, stroke, and even atherosclerotic disease of the leg and other arteries. First, large groups of patients with elevated LDL levels, with and without overt cardiovascular disease, were shown to benefit from the drug.10 Next, patients with atherosclerotic disease but with previously considered normal levels of LDL were shown to benefit by a reduction in recurrent cardiac events.11 This has led to a lowering and reclassification of "normal" and "ideal" values for LDL. Thus, more and more adults now have an "indication" for the long-term use of this medication class. Antihypertensive agents. Similar to the high cholesterol epidemic, large segments of the population have hypertension, a risk factor for AMI, stroke, heart and kidney failure, and likely sudden death. Safe agents that modify specific "drugable targets," and thereby lower blood pressure, have emerged. Over time, newer agents have evolved that reduce morbidity and mortality similar to older antihypertensives, but with reduced or different side effects. Antihypertensive drugs include blockers of enzymes, receptors, or hormones and vascular channels such as angiotensin-converting enzyme (ACE) inhibitors, blockers of the adrenergic nervous system (beta and alpha adrenergic blockers), calcium-channel blockers, and angiotensin-receptor blockers (ARBs). When compared for relative efficacy in a recent clinical trial sponsored by the National Institutes of Health (NIH), these various agents were effective, but none more so than very inexpensive diuretic agents, which are now strongly recommended for routine initial use in hypertension.12 Unfortunately, most patients with hypertension require multiple antihypertensive drugs for optimal blood pressure control. As with the reduction in LDL targets over time, the "normal" and "ideal" values for blood pressure have been progressively lowered as data support the finding that such blood pressure reduction lowers the incidence of heart attack, stroke, heart and kidney failure, and sudden death. At least 30 percent of adults do not know that they have hypertension; of those who do, only 60 percent have blood pressures in these ideal zones.13 Therapeutic treatment of hypertension is one area where specific drugs are proving more or less efficacious in certain ethnic or demographic groups. This may explain why not all members of the population benefit similarly from the use of specific agents in a particular drug class. This observation has spawned the advent of ethnic and gene-specific therapy (pharmacogenetics). Thrombolytic agents. A major breakthrough that proved life-saving in the management of AMI was the advent of thrombolytic drugs and the use of aspirin. Thrombolytics dissolve clots in arteries, while aspirin prevents platelets from forming new clots. Several European studies initially identified an inexpensive, nonselective thrombolytic agent, streptokinase, as effective and generally safe for clot dissolution.14 A more directed drug, tissue-plasminogen activator (t-PA), which activates a specific protein target in the blood-clotting cascade, was tested in hopes that targeting a specific target would improve efficacy and safety over streptokinase. Such proved to be the case, but only by a relatively modest amount.15 Agents for use in heart failure. Until the 1990s, heart failure management emphasized reducing activities that caused shortness of breath. Salt restriction and diuretic drugs were the mainstay to decrease fluid accumulation in the legs, lungs, and abdomen. Digitalis glycosides were prescribed, as they were known to increase heart muscle functioning experimentally in animals and had a positive effect on diuresis. A recent, properly designed and executed effectiveness study of digitalis in humans with heart failure showed that like most drugs that increase heart muscle function, digitalis lessened shortness of breath and symptoms and reduced recurrent hospitalizations, but not overall mortality.
Over the past fifteen years (Exhibit 2
In addition to these effective pharmaceutical strategies, some forms of heart failure are amenable to surgery, particularly when the cause is related to an obstruction or incompetence of the heart valves. Surgical resection of an expanded scar tissue in areas of previous injury due to MI is also a feasible option. On other innovative fronts, heart failure is also a major target for stem cell therapy in attempts to heal or improve the functioning of injured or scarred heart muscle. Antiplatelet and anticoagulation therapies. Because the most dire consequences of atherosclerotic disease, heart attack and stroke, result from the ultimate occlusion of an artery by a blood clot, therapies that prevent, reduce, or dissolve blood clots have been instrumental in reducing cardiovascular morbidity and mortality. For twenty to thirty years it has been clear that "low dose" aspirin administration has long-term benefit in preventing and managing chronic and acute coronary artery, cerebrovascular, and peripheral vascular disease. Moreover, aspirin has been effective in the primary prevention of heart attack and stroke in high-risk patients. With time, more specific drug targets to inhibit platelet adhesion have been discovered. Some of these agents are limited in use to acute coronary states (heparin and glycoprotein IIb/IIIa inhibitors), and some are used for both acute and chronic administration (clopidogrel). Similarly, the benefit of short- and long-term anticoagulation with warfarin for prevention of stroke, pulmonary embolism, and peripheral venous complications of a wide variety of surgical procedures was established in clinical trials. Chronic warfarin therapy reduces the most feared complication of stroke in patients with chronic atrial fibrillation. Warfarin treatment requires frequent (weekly to monthly) blood tests for dose regulation. Newer anticoagulant agents are being developed for specific indications that could provide greater safety and ease of use.
With the rise of modern genetics and genomics and the identification of specific blood biomarkers that aid in the differentiation of patients with common disorders such as heart failure or atherosclerosis, more targeted use of drugs is likely to emerge in the next decade or so. The use of such information to better tailor drugs for specific groups of patients will greatly improve therapeutic efficacy. Another horizon in drug development is the inclusion of multiple drugs in a single tablet, the "polypill." Combining several generic drugs in previously proven safe and effective dosages would be particularly useful in underserved populations with limited resources. This simplified strategy also might improve medication compliance, which often involves the lifelong use of upward of five different medications. To be visionary, we would emphasize the potential importance of developing definitive preventive or curative treatments for common diseases through vaccine, gene modification, or use of modified stem cells. Technological or medical advances might allow hypertension or atherosclerosis to be treated at one point in time with a lifelong benefit. Such dramatic alterations in the care and prevention pattern for human disease would have immense impact on the ongoing disparities in health care, access, and outcomes for the underserved.
Imaging and the rise of cardiac surgery and interventional cardiology.
In the early 1960s (Exhibit 2 Coronary angiography was pivotal in the development of invasive treatment.18 Placing a catheter in the heart as a diagnostic technique to measure pressures and the severity of congenital and acquired valvular heart disease began during the 1950s. Initially, professionals feared placing a catheter in an organ so prone to arrhythmia and sudden failure. The possibility of a clot forming on the catheter, breaking off, and causing a stroke or AMI also created anxiety. However, experienced cardiologists soon made catheter-based diagnostic procedures routine.
Coronary angiography involves imaging of the coronary arteries by placing a catheter through the leg artery, advancing it into the opening of each coronary artery, and injecting contrast material that is seen radiographically in a movie format. These images shed light on the nature of chronic coronary artery disease. In most patients, coronary lesions were relatively short in length. Obstructions were found in the large coronary arteries, while the smaller coronary arteries penetrating into the heart muscle were relatively free of disease. These striking anatomic findings led surgeons to the idea of bypassing these coronary blockages with veins taken from the leg.19 Veins continue to be used in coronary bypass graft surgery, but preference is now given to internal mammary arteries (Exhibit 2 Frank disbelief accompanied Andreas Gruntzig’s remarkable observation that blowing up a balloon across one of these severe anatomic obstructions in the coronary arteries could obliterate or diminish the blockage.21 Throughout the late 1980s and 1990s, employment of this procedure, coronary angioplasty, grew remarkably. Over the past ten to twelve years, industry developed intracoronary stents—fine metal scaffolding to keep the artery open after angioplasty—and ultimately drug-coated stents.22 Angioplasty was not initially preferred over coronary artery bypass grafting (CABG) for treatment of coronary artery disease because at least one-third of the lesions treated with angioplasty recurred within the first several months or year after the procedure. In contrast, CABG surgery was 90–95 percent effective at eliminating obstruction in the coronary arteries over five to ten years. As with angioplasty, coronary lesions treated with bare metal stents often reoccluded over time. To combat this problem, specialized stents were developed with an antibiotic or chemotherapeutic coating. Recurring obstruction during the first six months after the deployment of a drug-coated stent is about the same as with CABG surgery. As stents and cotherapies improve, fewer bypass operations are being performed. Recently, however, surgery has also become less invasive, with many operations being done with small incisions and without stopping the heart. It is estimated that over a million angioplasty-stent procedures are performed each year in the United States.23 In addition to its use in chronic angina and to prevent MI, angioplasty-stent is the preferred treatment of AMI if adequate facilities are available to conduct it within one to two hours.24 The evaluation, prevention, and management of stroke have shadowed those for coronary artery disease. Angiograms are used to evaluate blockages in carotid arteries. Thrombolytic therapy is now an option to dissolve acute clots in brain arteries to abort strokes, but success is somewhat dependent on presentation to the hospital within one to two hours after the onset of symptoms. Surgery and angioplasty (stents) to prevent strokes focus on severely obstructed accessible carotid arteries in the neck. The operation, endarterectomy, involves removing the atherosclerotic material after opening the artery. Unlike for coronary blockages, bypass procedures are not generally used on carotid arteries. Noninvasive imaging. Given the high value of viewing the heart and coronary arteries and measuring intracardiac pressures through cardiac catheterization established, cardiology embraced imaging. One of the goals was to develop techniques whereby similar visual and functional information could be obtained without the risk associated with placing a catheter in the heart or the coronary arteries. Two imaging techniques that have proved invaluable to assess cardiac functioning and structure noninvasively are echocardiography and studies using nuclear tracers. Echocardiography uses ultrasonic waves, which are delivered to the heart by a probe placed over the chest; the reverberations are recorded as images. The resultant information allows not only real-time pictures of the beating heart and valvular function but also information on blood flow and intracardiac pressures. Although neither echocardiography nor nuclear imaging is capable of visualizing the coronary arteries, nuclear testing allows relative estimations of the blood flow to the heart muscle, particularly segments served by specific coronary arteries. Both echocardiography and nuclear imaging are used for provocative "stress" testing of the heart. When combined with exercise or other forms of stress such as administering inotropic or vasodilating drugs, both are able to identify the presence of coronary artery–obstructing lesions that decrease the cross-sectional area of the coronary artery 40 percent or more. Stress testing has become valuable to screen for significant anatomic coronary artery disease. This allows the clinician to "sort out" chest pain or other symptoms such as shortness of breath and to assess the success or failure of bypass surgery or angioplasty/stent placement. Sudden death prevention. As noted above, approximately 350,000 sudden cardiac deaths occur in the U.S. population each year, despite current approaches to prevention. Cardiopulmonary resuscitation (CPR) with defibrillation of appropriate patients by emergency medical systems (EMS), or now lay volunteers, using automatic external defibrillators can result in excellent survival if the victim is reached within three to five minutes.25 Realistically, this rarely occurs. Thus, overall survival from cardiac arrest is no better than 5–10 percent, even in optimal systems. Therefore, the efforts have shifted from treatment to prevention. Accordingly, the incidence of sudden cardiac death has decreased somewhat by the prevention and treatment of the major causes of lethal rhythms: AMI, chronic coronary disease, and heart failure. Without other preventive approaches, though, sudden death—including that caused by congenital rhythm disturbances—remains a significant problem. The hope into the 1980s and 1990s was that "antiarrhythmic drugs" would prevent sudden death. However, an NIH-sponsored clinical trial showed that specific types of drugs actually increased the risk of sudden death. Beta-sympathetic blocking drugs and amiodarone, a long-acting antiarrhythmic agent with considerable toxicity, do have a modest preventive effect. A device-based approach has been broadly adopted for prevention of sudden cardiac death. This strategy involves implantation of an arrhythmia-detecting device that automatically administers a corrective shock: the implantable automatic intracardiac defibrillator (ICD).26 About 250,000 Americans per year have the device implanted, at a cost of about $100,000 each. In the United States, the ICD is mainly placed in patients whose heart-pumping capacity is severely impaired. It is estimated that almost 400,000 new patients per year would meet the criteria for an ICD.27 Data from clinical trials comparing ICDs versus antiarrhythmic drugs demonstrate that the device reduces sudden cardiac death occurrence 5–10 percent per year for two to three years.28 We cannot appropriately select which specific patients would benefit from ICD implantation; almost 40 percent will never have a potentially lethal rhythm.29 Thus, cardiologists are seeking more specific criteria to better choose patients who would optimally benefit from this device. Evolution of management of atrial fibrillation. As described above, atrial fibrillation is a common irregular and chaotic heart rhythm, which increases the risk of stroke, AMI, and heart failure and may limit patients’ functional status. The routine management of this condition is to leave the arrhythmia itself alone and to use anticoagulation to prevent clots and drugs to slow the ventricular rate. A more aggressive approach is to electrically convert the arrhythmia back to normal rhythm. Unfortunately, this strategy does not often offer long-term success. Another option is to leave the patient in atrial fibrillation, create a scar that blocks conduction from the atria to the ventricles, and then place a pacemaker to make the ventricles contract slowly and regularly. Unfortunately, this approach does not result in better long-term outcomes than drug treatment, but it is occasionally used in patients who are refractory, or intolerant of drug therapy. Recently, an innovative and very intensive approach to "cure" atrial fibrillation has been developed and become increasingly popular. That approach, atrial fibrillation ablation, involves putting a catheter in the heart and destroying electrical conduction tissue in or near the atria. In selected patients, atrial fibrillation does not recur in up to 80 percent of patients following the ablation. This is a three-to-five-hour procedure only performed by an ultra-specialized cardiologist. Atrial fibrillation ablation is performed in about 8,000 patients per year, but the rate is increasing rapidly as more physicians are trained in this procedure. The CT revolution. A major change in the identification and management of chronic coronary artery disease is unfolding. High-resolution computed tomography (CT) scanning now allows more precise imaging of the heart and the coronary arteries with dazzling three-dimensional computer reconstructions.30 Such detailed images allows early detection of atherosclerotic lesions and thus can be used as a screening tool as well as a method to assess the location and degree of blockages in patients with symptoms. Similarly, this low-risk technique is very helpful in confirming the absence of coronary disease in patients with atypical symptoms. In contrast to the risks of invasive coronary angiography, this test requires only the injection of contrast material into the arm vein. Thus, the major risk of this procedure is radiation exposure (which is similar to that of a cardiac catheterization). The frequency of use of cardiac and coronary CT scanning is rising as manufacturers have increased image resolution. This improvement is likely to continue and is valuable for the correctness of anatomical and pathological detail. As CT scanning resolution sharpens, it is highly likely that this technique will identify characteristics of the atherosclerotic plaque itself that could predict whether a lesion is likely to become "unstable" or suddenly occlusive, leading to AMI. It is possible that we might be able to prevent many heart attacks by stenting only specific types of high-risk lesions that are not occlusive. Cardiac CT scanning could well replace many commonly used imaging techniques, including diagnostic catheterization. Ideally, the only patients brought to the catheterization lab would be those in need of coronary intervention. Initially, the availability of this technique, and its ability to detect clinically covert disease, will raise the number of patients undergoing interventional procedures because it is simple, fast, and low-risk. Since the technique may require only one or a few heartbeats to images and measurements, CT scanning is very efficient. The cost could be as little as several hundred dollars. There are a number of theoretical and practical approaches to reducing patients’ radiation exposure. Should the radiation burden fall to 10 percent or less of a cardiac catheterization, as expected, this technique will have a major impact on the diagnosis and evaluation of coronary artery disease. End-stage treatment. Strides have been made in the therapeutic options for patients with "end-stage" heart disease, defined as the time when disease reversal is unlikely and other therapeutic strategies are exhausted. Cardiac transplantation and use of artificial cardiac pumps to sustain life are expensive but can offer major improvement in quality of life for some patients. Cardiac transplant is greatly limited by donor heart availability. Artificial heart pumps, including left ventricular assist devices and recently more portable units, mainly serve as a bridge to transplant and are also limited by management needs and expense. Work continues toward development of better pumps and fully artificial hearts.
This is both an exciting and challenging time for cardiology. On the basis of the aging of the population and the association of aging with increased cardiac disease and the rise in obesity and diabetes, the incidence and prevalence of cardiovascular disease are rapidly expanding. Accordingly, we are pushing toward the training of greater numbers of cardiologists. This drive should be weighed against the advent of new technologies, such as CT scanning, that simplify the diagnosis and assessment of cardiac disease and reduce the time and effort necessary to create and interpret multiple tests. The growing availability of generic drugs and tailored multicomponent agents, such as the polypill, will continue to focus on prevention and management of common cardiac diseases. The relative success or failure of efforts to limit or eliminate tobacco use, obesity, sedentary lifestyle, and poor nutrition will certainly be influential for the future of cardiovascular disease. Human genetics will aid not only in prediction of disease but also in the identification of patients for whom a specific pharmacologic or device-related treatment is optimal. In this setting, more-specialized drugs for subpopulations will be developed. As imaging techniques become more definitive and criteria are developed for intervention, it will be easier to review diagnostic information in a straightforward manner, allowing clear monitoring and assessment of the needs for intervention and use of procedures. We hope for a paradigm shift in the focus of research initiatives, from complex prevention and chronic treatment strategies to long-term, effective risk-factor reduction; shorter treatment duration; and even single time-point curative measures. The success of such a shift would undoubtedly parallel the triumphs we have made over many infectious diseases.
Myron Weisfeldt (mlw5{at}jhmi.edu) is the William Osler Professor of Medicine and chairman of the Department of the Medicine, Johns Hopkins Medicine, in Baltimore, Maryland. Susan Zieman is an assistant professor of medicine in the Division of Cardiology, Johns Hopkins University School of Medicine. The authors acknowledge superb administrative help from Claire O’Neill. Susan Zieman is supported by funding from National Heart, Lung, and Blood Institute Grant no. 1K23HL073059. The authors have no conflicts of interest with regard to the content of this paper.
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