doi: 10.1161/01.CIR.0000129765.04512.A9
(Circulation. 2004;109:2256-2262.)
© 2004 American Heart Association, Inc.
Special Report |
Clinical Research
Whose Agenda Is It?
From the Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minn.
Correspondence to Jay N. Cohn, MD, Cardiovascular Division, Mayo Mail Code 508, University of Minnesota Medical School, 420 Delaware St SE, Minneapolis, MN 55455. E-mail cohnx001{at}umn.edu
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Introduction |
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 Top Introduction The Patient’s AgendaThe Investigator’s AgendaThe Industry’s AgendaThe Hospital’s and...The Public’s AgendaReferences |
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I would like to begin by expressing my deep appreciation to the Clinical Council for honoring me this year with the annual James B. Herrick Award. As a longstanding maverick cardiovascular investigator, I recognize the unfortunate fate of many mavericks who more often face sanction than accolades, and I am therefore particularly grateful that the Council has seen fit to honor me for a lifetime of effort that has often challenged traditional thinking.
My maverick attitudes surfaced early in my training, when I began a cardiovascular research fellowship at Georgetown University after completing a tour of duty in the public health service. Having initiated my research career in clinical and animal hemodynamic studies under the tutelage of Dr Edward Freis, I became focused on physiological mechanisms. During clinical rounds with Dr Proctor Harvey, a group of us young fellows surrounded the bed of a man with heart failure and watched as Dr Harvey carefully palpated the radial pulse and announced the presence of pulsus alternans. Each fellow in turn took the patient’s wrist and nodded agreement with the finding. I frankly was unable to detect an alteration in the strength of the pulsation, and my protestation was met by the comment that I needed to educate my fingers. Unwilling to accept this simple explanation for my perceived deficiency, I went to my laboratory, brought a transducer and recorder to the bedside, and proceeded to puncture the radial artery to record the arterial pressure. The long recording revealed no alteration in systolic or pulse pressure but only the usual respiratory pressure variation. I excitedly brought the tracing to Dr Harvey, who calmly announced to me that his fingers were more sensitive than my transducer.
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The Patient’s Agenda |
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TopIntroductionThe Patient’s AgendaThe Investigator’s AgendaThe Industry’s AgendaThe Hospital’s and...The Public’s AgendaReferences |
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That early experience convinced me that there was much to learn about clinical pathophysiology that might be missed by traditional clinical evaluation. The individual patient drove my research agenda. An area of clinical frustration was the patient with shock. On every medical ward in the early 1960s, critically ill patients were being treated with infusions of Levophed (l-norepinephrine) for hypotension and shock. Their prognosis was exceedingly poor, and maintaining their blood pressure seemed to require increasing doses of Levophed until a terminal event supervened. Troubled by the lack of insight into the mechanism of this perceived hypotension, I developed a mobile cart that could be wheeled to the bedside for hemodynamic observations. This included a small 2-channel recorder, transducers for both central venous and arterial pressure monitoring, a densitometer for recording indocyanine green dye curves, a Harvard pump for constant arterial blood withdrawal, and the necessary needles, syringes, and catheters. Institutional review boards did not exist at that time, so my decision to investigate hemodynamics in these acutely ill patients did not require intensive peer review. In fact, many of my colleagues were distressed that I was molesting such critically ill patients with what they perceived to be a research study.
Very soon, however, we discovered that rather than doing research, we were providing critically valuable patient care. The first patient we examined had a palpable brachial artery pressure recorded by the nurse of 90 mm Hg, was comatose and anuric, and was receiving a high-dose Levophed infusion. The brachial artery pressure recorded directly was 190/130 mm Hg, and the central venous pressure recorded from a catheter passed into the superior vena cava was 20 mm Hg. We turned off the Levophed, and central venous pressure fell to 0 mm Hg while the pulse pressure narrowed strikingly and the blood pressure fell to 90/70 mm Hg. An indocyanine green dye curve displayed the very slow and long curve typical of a very low cardiac output. An infusion of dextran was begun, and after infusing 300 to 400 mL, the central venous pressure had risen to 10 mm Hg, the cardiac output had more than doubled, the blood pressure rose to 110/70 mm Hg, the patient woke up, and urine flow began. Thus was born the concept that bedside hemodynamic measurements by documenting pathophysiology could lead to effective therapy that could reverse circulatory shock.1
The fascinating discrepancy of auscultatory blood pressure in monitoring true intraarterial pressure excited my curiosity. I theorized that intense vasoconstriction of the arm vasculature obliterated the Korotkoff sounds and the palpatory pulsations of the radial artery. We therefore undertook studies in healthy volunteers who agreed to have vasoconstrictor drugs infused into the axillary artery. A tiny catheter was advanced retrograde from the brachial artery into the axilla where infusions of norepinephrine were initiated while forearm blood flow was monitored by strain gauge plethysmography, pressure in the brachial artery was monitored with a transducer, and radial pulsations were recorded with a tonometer. As the infusion rate of the drug was increased, blood pressure was essentially unchanged because of the small systemic infusion rate, forearm blood flow fell progressively, the auscultatory blood pressure recorded with a cuff on the upper arm and a microphone over the brachial artery declined and disappeared, and the pulsations in the radial artery disappeared despite the fact that the intraarterial pressure was unchanged.2 These data confirmed to me that intense vasoconstriction, probably augmented by the infusions of Levophed that many of these patients were receiving, accounted for the inaccuracy of auscultatory blood pressure and the gross mismanagement of such patients because of the false assumption that their intraarterial pressure was low. Thus was born the need for intraarterial blood pressure monitoring in acutely ill patients and eventually the need for the development of intensive care units for more effective diagnosis and management of such patients. Most of these patients suffered from low cardiac output, not low blood pressure, and the treatment of choice usually was volume expansion.3
Acute myocardial infarction was at that time a catastrophic illness that led to long stays in the hospital, a high in-hospital mortality rate, and little therapy other than pain relievers and type I antiarrhythmic drugs. Shock as a complication of acute myocardial infarction was a common occurrence and in the absence of coronary care units management was limited to drugs such as catecholamines and narcotics. I felt that we needed to understand the disturbed physiology that characterized this postinfarction shock and began studying such patients at the bedside with our mobile unit. The agenda again was the individual sick patient. Unfortunately, however, in this setting of acute left ventricular damage, I was concerned that the central venous pressure would not be an accurate reflection of the dysfunction of the left ventricle. Therefore it became necessary to devise a technique to catheterize the left ventricle at the bedside to obtain pressures directly. I fashioned a Kifa catheter with a teardrop shape at the tip that I thought would allow the catheter to plop into the left ventricle without molesting the aortic valve. I initially performed the procedure in a few patients who were undergoing diagnostic cardiac catheterization and found that the catheter would slip easily into the left ventricle, its arrival there usually heralded by a short burst of premature ventricular beats or nonsustained ventricular tachycardia.4 Reassured that the blind procedure was possible and apparently safe, we went to the bedside of patients in shock after acute myocardial infarction. Again I was chastised by more senior physicians who felt we were exposing these ill patients to dangerous procedures only to obtain research data.
In our initial series of patients, our concern about central venous pressure was validated. The left ventricular end diastolic pressure (LVEDP) was much higher than the pressure in the right atrium, consistent with acute isolated left ventricular failure as a cause of the low output and shock state. In contrast, patients with septic shock exhibited a normal ratio of LVEDP to right atrial pressure. We also studied several patients whose acute shock was thought to be attributable to pulmonary embolism. In these patients, the hemodynamic confirmation was that the right atrial pressure was higher than the LVEDP, which was in fact quite low.5 These data confirmed the site of the problem as being in the pulmonary vascular bed. We encountered another patient, however, whose ECG suggested acute inferior wall myocardial infarction but whose hemodynamic pattern was consistent with that of pulmonary embolism. The patient was in profound shock, and we felt obligated to perform pulmonary angiography to identify the site of the vascular occlusion. The pulmonary vasculature was, surprisingly, clear, and the patient responded favorably to aggressive volume expansion with dextran. Some months later, another patient with similar hemodynamics died despite our aggressive management. An autopsy revealed extensive infarction involving the right ventricle. Thus was born the concept of right ventricular infarction as a cause of predominant right ventricular failure.6 The syndrome of inferior myocardial infarction, clear lung fields, hypotension, and often heart block is now recognized as highly suggestive of right ventricular infarction, a premortem diagnosis that had not previously been possible.7
But what about the patient with an uncomplicated myocardial infarction? Are these patients also suffering from undiagnosed left ventricular failure that might be contributing to high in-hospital mortality? We decided to perform bedside hemodynamic studies on these patients long before the Myocardial Infarction Research Units were funded by the National Institutes of Health and before Jeremy Swan and Willy Ganz had developed their balloon flotation catheter. By that time, we felt the need for institutional approval of our bedside diagnostic approach, and our institution sought and obtained support from several senior cardiologists from across the country. The observation of elevated LVEDPs in nearly all of these patients8 was a confirmation of almost universal left ventricular pump dysfunction that has fueled aggressive management strategies of acute myocardial infarction in recent years. The American Society for Clinical Investigation selected our abstract for plenary presentation in Atlantic City, but given the widespread concern about our studies, they demanded assurance that we had institutional approval before allowing the presentation.
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The Investigator’s Agenda |
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TopIntroductionThe Patient’s AgendaThe Investigator’s AgendaThe Industry’s AgendaThe Hospital’s and...The Public’s AgendaReferences |
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Armed with our bedside left ventricular catheter, we sought other worlds to conquer, the agenda now being driven not only by patient need but also by investigator curiosity. We wondered how the left ventricle tolerated the very high pressures in patients with severe hypertension. Uncontrolled hypertension was a common diagnosis in the Veterans Administration (VA) hospitals in the 1960s. If we were going to study the acute effects of blood pressure reduction on the left ventricle, I needed to find a drug that had no action on the heart. I selected sodium nitroprusside, a potent vasodilator that was available only in powder form and not prepared for clinical use. In canine experiments, I demonstrated that infusing the drug directly into the coronary artery produced no changed in myocardial contractility as measured with a force transducer. We therefore made sterile supplies of sodium nitroprusside by using a micropore filter and colored bottles to protect it from light. We found 2 dramatically different patterns of hemodynamic response in our first series of hypertensive patients. In one group of patients with severe hypertension, the LVEDP was within normal limits, and in response to sodium nitroprusside, the fall in blood pressure was accompanied by a slight fall in filling pressure and a modest decline in cardiac output. In the other group of patients with hypertension, none of whom had clinically apparent heart failure, the LVEDP was elevated, and in response to nitroprusside, the LVEDP fell dramatically and the cardiac output rose.9 Indeed, we found that the fall of LVEDP in this latter group occurred before the reduction in arterial pressure. Thus was developed the concept of an impedance load on the left ventricle.10 The normal ventricle could tolerate a striking increase of impedance imposed by a high arterial pressure and remain on the ascending limb of its Starling curve, so that nitroprusside infusion by reducing filling pressure led to a slight decline in cardiac output. In the failing ventricle, however, even one not associated with symptoms, the impedance became the determinant of cardiac output and the nitroprusside infusion by lowering impedance led to an increase in cardiac output even though the preload was reduced, and this rise in cardiac output maintained blood pressure despite the reduction in vascular resistance.
This concept of impedance load as a determinant of cardiac performance led us back to the patients with acute myocardial infarction. Was it possible that the low output in those patients was in part dependent on heightened impedance imposed either by inappropriate drug therapy or more importantly by endogenous neurohormonal activation? Our first experience was a proof of concept. A 47-year-old black man was in severe pump failure after an acute anterior wall myocardial infarction. His hemodynamic pattern, as predicted, showed a very low cardiac output and an LVEDP of 40 mm Hg. Despite an arterial blood pressure of 105/90 mm Hg, we cautiously introduced an infusion of nitroprusside. His LVEDP fell progressively, his cardiac output increased, his profound diaphoresis abated, his urine output picked up, and he woke up and reported to us that he was feeling much better. The experience was repeated in other patients.11 Thus the heretical concept of vasodilator therapy to treat acute pump failure was born. The initial report of our observations of the efficacy of sodium nitroprusside in acute myocardial infarction was submitted to the New England Journal of Medicine, where it resided for 6 months while the editors debated the appropriateness of the publication. It was eventually rejected in a long, painful letter from the editor, Dr Franz Ingelfinger, who reported that the editorial board felt our approach to management of acute myocardial infarction was so dangerous that the New England Journal of Medicine should not publish it. The paper was subsequently submitted to Lancet, who accepted it by return mail without peer review and published it shortly thereafter.11 I have subsequently embraced the concept that rejection of a revolutionary paper by a peer-reviewed journal might be a clue to its importance.
The dramatic hemodynamic response to nitroprusside in these patients with acute myocardial infarction shifted our focus from the bedside of an individual patient to a larger arena. In fact, the agenda became the investigator’s need to know in order to foster a change in medical practice. The research strategy was to do a large-scale trial involving multiple investigators around the country. I approached my colleagues at Veteran Administration hospitals to participate in a double-blind trial of nitroprusside infusion in patients with acute myocardial infarction with elevated pulmonary capillary wedge pressures, as documented by the now-available balloon flotation catheters. This remarkable invasive hemodynamic and outcome study in more than 800 patients12 was the initial collaborative effort of a group that was destined to remain together through the subsequent V-HeFT studies in chronic heart failure.
I was so impressed by the favorable hemodynamic effect of vasodilator drugs in the setting of pump failure13 that I thought impedance increase could in fact be the major factor contributing to progressive chronic heart failure. This hypothesis was supported by an experience in a 57-year-old man who remained in severe pump failure after an acute myocardial infarction. With infusion of sodium nitroprusside, his pulmonary edema and hypoperfusion were dramatically improved, but every time we tried to wean him from the nitroprusside, his pump function deteriorated and he developed recurrent pulmonary edema. After 3 weeks of continuous nitroprusside infusion, which he maintained himself while walking the corridors of the hospital dragging his IV pole, we felt that a better solution must be found. I wondered whether an oral nitrate might in some way replace the intravenous nitroprusside by exerting a similar action in the vasculature. Isosorbide dinitrate administered in increasing doses at 3-hour intervals seemed to restore his hemodynamics and allow the discontinuation of the nitroprusside infusion. With great trepidation after several additional weeks of monitoring him in the hospital, we sent him home on his oral nitrate therapy, which he was to take around the clock to maintain adequate left ventricular function.14 This strategy seemed to work, and he continued on this management for several months. In July of that year, a new fellow joined my service and was skeptical of the role of the oral nitrate in maintaining clinical stability. At his urging, I embarked on a single-blind trial of a matching placebo, a procedure that required at the time no patient consent and no institutional review board review. The patient’s wife called me 2 days later to report that her husband had developed recurrent pump failure and pulmonary edema. He was rushed to the hospital, where nitroprusside was again infused and oral nitrate therapy was reinstituted. I received Christmas cards from this patient for several years thereafter.
If oral nitrate therapy could keep this patient in circulatory stability for several months, we decided that an oral regimen for the management of heart failure was appropriate. Various drugs were studied, including various forms of oral and topical nitrates and other vasodilators such as hydralazine.15–17 Because nitrates are predominantly venodilators and large artery dilators whereas hydralazine is predominantly an arteriolar dilator, we theorized that the combination might provide a hemodynamic effect similar to that of sodium nitroprusside, which clearly exerts its action on both the small and large arteries as well as the venous system. Our early hemodynamic studies confirmed that the combination of isosorbide dinitrate and hydralazine exerted a sustained hemodynamic effect that was quite similar to that achieved by infusion of sodium nitroprusside.18 We therefore embarked on the first long-term controlled mortality trial in heart failure, a VA cooperative study named Vasodilator-Heart Failure Trial (V-HeFT). By standards at that time, the trial was quite large, but the total of 642 patients entered into the study in 13 VA medical centers is miniscule by current standards. Because digitalis and diuretic were the only standard therapies for heart failure at that time, it was possible to design a trial in which placebo would be added to standard background therapy. Although we were enthused about our nitrate-hydralazine combination therapy, early data had been published that the 
-blocker prazosin demonstrated a similar hemodynamic effect. We therefore embarked on a 3-arm study in this modest population with the assumption that we would merge the 2 vasodilator arms to compare with the placebo arm if the experience in the 2 arms was comparable. Consequently, we randomized 43% of the population to the placebo and 28% to each of the vasodilator arms to maximize statistical power. The Data Safety and Monitoring Board appointed to oversee the trial noted early on that the nitrate-hydralazine therapy group was exhibiting a reduced mortality whereas the prazosin arm was not. Thus, the final analysis was to compare nitrate and hydralazine versus placebo, and this analysis demonstrated a favorable effect of the vasodilator drug combination on mortality.19
If vasoconstriction were contributing so importantly to the left ventricular dysfunction in heart failure, was there a way to deal more directly with the mechanism of the vasoconstriction? We theorized that it may represent the consequence of reflex neurohormonal activation. The 2 most well-known hormonal mechanisms, the renin-angiotensin system and the sympathetic nervous system, became our focus. We began measuring plasma norepinephrine and plasma renin activity in patients with heart failure and found a relationship between hormone levels and hemodynamics.20 A relationship between plasma norepinephrine and mortality was first observed in our own laboratory21 and was subsequently confirmed in large-scale trials.22,23 These observations served as the basis for efforts over the past 20 years to inhibit neurohormonal-induced vasoconstriction.24
In V-HeFT-I, the vasodilator effect of prazosin persisted, as evidenced by a chronic reduction in blood pressure but mortality in this group tracked with placebo. This observation questioned the concept that vasorelaxation was the major determinant of the long-term outcome benefit in heart failure and suggested that some other effect of the nitrate-hydralazine combination was probably responsible. We were not aware at that time of the long-term interaction of isosorbide dinitrate and hydralazine, which is now known to involve the antioxidant properties of hydralazine to preserve the efficacy of generated nitric oxide.
In the 1970s, left ventricular function was described traditionally by use of Frank Starling curves. Heart failure was defined by a function curve depressed downward and to the right with an elevated filling pressure and a reduced stroke volume. Vasodilator therapy reduced filling pressure to normal and raised stroke volume and cardiac output to normal, thus correcting the depressed Frank Starling curve, but it did not reverse the patient’s chronic symptoms or dramatically reduce the risk. Thus it was clear that the Frank Starling curve was not an adequate depiction of the dysfunction of the left ventricle that characterized the syndrome. The missing link, of course, was ventricular volume. Restoration of filling pressure to normal did not normalize the dilated left ventricular chamber dimension. Indeed, our early studies of nitroprusside infusion revealed a paradoxical effect on left ventricular chamber dimension. As the filling pressure fell in response to the drug, the chamber did not get smaller but, in fact, appeared to get slightly larger.9 There was, therefore, a marked increase in compliance of the left ventricle in response to nitroprusside but not a correction of the chamber dilation, which clearly was related to sarcomere growth and myocyte hypertrophy rather than stretch. The clue to the illness, we therefore hypothesized, was a structural remodeling process of the left ventricle that eventuated in chamber dilatation on which the functional disorder characterized by the Frank Starling curve could be superimposed.25
To study the structural remodeling process of the left ventricle, we developed a technique for producing localized damage to the left ventricle without opening the chest or obstructing the coronary vasculature. Repetitive DC shock had been reported in humans to result in myocardial necrosis, and we built on this observation by developing a repetitive shock model by inducing current between the chest wall and a catheter placed retrograde into the left ventricle of dogs. The resulting necrosis involved approximately 20% of the left ventricular myocardium and exhibited a sharp demarcation between the necrotic zone and the adjacent healthy zone.26 By using MRI to quantify the structural changes in the left ventricle, we found that over a period of several months, the left ventricle remodeled with hypertrophy of myocytes and enlargement of the chamber dimension.27 This progressive enlargement of the left ventricle resulted in a progressive decline of ejection fraction over several months despite the fact that all of the injury had been induced on the first day. Thus, localized myocardial injury is followed by a structural remodeling process that results in the decline of ejection fraction characteristic of heart failure. The function of the left ventricle, therefore, as defined by the Frank Starling curve disregards the structural change that seems to be the mechanism of progressive heart failure. Furthermore, when animals were treated with ACE inhibitors or nitrates, the structural remodeling process was aborted.28,29 Therefore, the structural remodeling is not necessarily an obligatory or compensatory response of the left ventricle but is rather a process mediated by mechanisms that can be inhibited pharmacologically.
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The Industry’s Agenda |
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The growing importance of heart failure as a disease that consumes a large fraction of our health care expenditures and occupies a large fraction of our hospital beds now stimulated another prominent contributor to the research enterprise. Industry saw an opportunity for new therapy that could generate significant revenues. The agenda began to shift from research serving the patient or the investigator to research serving the pharmaceutical industry and, subsequently, the device industry. Industry’s interest was in the development of inotropic drugs, because their presumed efficacy in treating the failing heart was more rational and because the vasodilator drugs were largely generic. The new inotropic drugs aimed at shifting the Frank Starling curve upward and to the left spawned multiple hemodynamic studies in our laboratory30–35 and eventually long-term trials.36–38 These efforts were doomed from the beginning,39 because they failed to adequately recognize that although a favorable functional effect might relieve symptoms acutely, it does not address the chronic remodeling process that mediates long-term deterioration and shortened life expectancy.40
More promising were the strategies to develop neurohormonal inhibitors that might slow the structural remodeling process. When the Squibb corporation began developing ACE inhibitors to treat severe hypertension, I proposed to them the possibility that the inhibitors would be useful to treat heart failure. Squibb and their consultants considered the idea bizarre, but they nonetheless provided me a small supply of their first ACE inhibitor product, an intravenous snake venom.41 The rest is history. Neurohormonal inhibitors have now become standard therapy for heart failure, and the idea that drugs that lower blood pressure are safe and effective is no longer considered outlandish.42 Although the agenda may have been industry’s profit motive, the research funding for studies of neurohormonal inhibitors has led to profound new insights about mechanism and management of disease.43
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The Hospital’s and Subspecialist’s Agenda |
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But there were other intererests that began to drive the research agenda. Hospitals, clinics, and subspecialists all earn their income by providing highly skilled and expensive care for patients with advanced disease. Attracting these patients and intervening aggressively is not only a life-prolonging service to those with advanced disease but also a growing source of revenue to specialized health care providers. More and more cardiac facilities were built to provide state-of-the-art care that was unquestionably reimbursed by third-party payers.44 The research agenda shifted from asking fundamental questions about mechanisms of disease and therapeutic principles to studies aimed at determining whether one proprietary drug or procedure was better than another. Industry drove the research agenda by funding studies of their therapeutic modalities that were happily embraced by the hospitals, clinics, and physicians, who were rewarded for studying and using them.
As I increasingly recognized the evolving natural history of structural cardiovascular disease and the effectiveness of therapy to slow its progression, I became disillusioned with our focus on end-stage disease. Prolonging life in those with advanced disease imposes a growing financial burden on our health care system and leaves us with an enlarging population of partially disabled people. Could we identify disease earlier, long before symptoms impair quality of life and consume health care costs? Why not intervene with therapy that by slowing disease progression can prevent or profoundly delay the morbid events that are so costly? The drugs that had proved so effective in slowing progression of advanced disease, including statins and various neurohormonal inhibitors, seemed remarkably suited to accomplish that goal.
But this exciting potential to prevent cardiovascular disease was not received enthusiastically by hospitals, clinics, industry, or subspecialty physicians. This core of our health care system profits from disease. Just as Dwight Eisenhower warned in the early 1950s of the danger of the military-industrial complex that thrives on war, the health care–industrial complex is equally dangerous in the 21st Century. Subspecialty cardiovascular physicians have trained for procedures to deal with advanced disease, and clinics and hospitals have geared their services toward state-of-the-art care of these diseases, including interventional procedures, devices, surgery, and transplants. The health care industry is booming because of the incredible advances that have been made in the past generation in keeping people with advanced disease alive with expensive techniques that nurture the physicians, hospital, and industry. Managed care and insurance companies should appreciate efforts to prevent disease, but their focus is too short-term to appreciate the benefit of spending modest preventive dollars to avoid major expenses 5, 10, and 20 years in the future. The subspecialists not only are focused on patients with advanced disease but they have no access to individuals without overt disease, whose care is in the hands of primary care physicians who have neither the time nor incentive to undertake extensive investigations to identify early disease. Furthermore, Medicare has essentially eschewed cardiovascular preventive services. Even in their hyped attention to "Preventive Services to Help You Stay Healthy" in the 2004 brochure, cardiovascular screening tests are notable for their absence. Bone scans, Pap smears, mammograms, and colonoscopy all are covered services, whereas electrocardiograms, echocardiograms, and studies of vascular structure or function are notably absent, despite the fact that cardiovascular disease will be the mode of death in well over 50% of Medicare beneficiaries.
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The Public’s Agenda |
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We have therefore in recent years shifted our focus from patients with end-stage disease to identifying individuals at risk for disease so that therapy can be instituted before they become ill. It is time for the clinical research agenda to shift to the public’s benefit. We have established a screening clinic, the Rasmussen Center for Cardiovascular Disease Prevention, aimed not primarily at identifying risk factors but at using the newest physiological and imaging modalities to identify the earliest stages of vascular and cardiac disease likely to progress.45 We know enough about progressive cardiovascular disease today to focus our attention on keeping people healthy rather than waiting until they become disabled in order to prolong their lives. The British Medical Journal recently brought attention to a polypill designed to be given to the entire population to prevent more than 80% of heart attacks and strokes.46 This provocative but impractical approach disregards the likelihood that we can now distinguish those with early disease from those who are healthy and not in need of intervention. The combination of genes and environment produces in each of us an individualized trajectory of aging and atherosclerotic disease (Figure 1). Identifying where one resides on that trajectory can be a stimulus to effective management strategies that we now know can slow the trajectory. This must be the agenda for the 21st Century, so that we can take advantage of all that we have learned mechanistically and pharmacologically to alter the health of the nation and reduce the burden of cardiovascular disease on our population and our economy.
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My devotion to cardiovascular disease over the past 40 years has brought me from the beds of terminally ill patients to the sides of healthy individuals at risk for future morbid events, all with the underlying concept that understanding the mechanisms of disease can lead to rational management. None of these insights would have been possible without the dedication and intellectual stimulation of the scores of trainees, colleagues, and coinvestigators who have been critical to the concepts and publications cited. They have shared in the joy of discovery that has traditionally fueled clinical research.47 That atmosphere of excitement about challenging what we think we know is threatened in the current academic health care system. Future advances in our understanding and management of cardiovascular disease are dependent on preserving and nurturing that environment and on maintaining an agenda for clinical research that serves the patient and the public.
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Footnotes |
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Presented as the Herrick Award Lecture, Clinical Cardiology Council, American Heart Association, Orlando, Fla, November 11, 2003.
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References |
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1. Cohn JN, Luria MH. Studies in clinical shock and hypotension: the value of bedside hemodynamic observations. JAMA. 1964; 190: 891–896.
2. Cohn JN. Blood pressure measurement in shock: mechanism of inaccuracy in auscultatory and palpatory methods. JAMA. 1967; 199: 972–976.
3. Cohn JN, Luria MH. Studies in clinical shock and hypotension, III: comparative effects of vasopressor drugs and dextran. Arch Intern Med. 1965; 116: 562–566.
4. Cohn JN, Khatri IM, Hamosh P. Bedside catheterization of the left ventricle. Am J Cardiol. 1970; 25: 66–69.[CrossRef][Medline] [Order article via Infotrieve]
5. Cohn JN, Tristani FE. Studies in clinical shock and hypotension, VI: relationship between left and right ventricular function. J Clin Invest. 1969; 48: 2008–2018.[CrossRef][Medline] [Order article via Infotrieve]
6. Cohn JN, Guiha NH, Broder MI, et al. Right ventricular infarction: clinical and hemodynamic features. Am J Cardiol. 1974; 33: 209–214.[CrossRef][Medline] [Order article via Infotrieve]
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8. Hamosh P, Cohn JN. Left ventricular function in acute myocardial infarction. J Clin Invest. 1971; 50: 523–533.[Medline] [Order article via Infotrieve]
9. Cohn JN. Blood pressure and cardiac performance. Am J Med. 1973; 55: 351–361.[CrossRef][Medline] [Order article via Infotrieve]
10. Cohn JN. Vasodilator therapy for heart failure: the influence of impedance on left ventricular performance. Circulation. 1973; 48: 5–8.
11. Franciosa JA, Guiha NH, Limas CJ, et al. Improved left ventricular function during nitroprusside infusion in acute myocardial infarction. Lancet. 1972; 1: 650–654.[Medline] [Order article via Infotrieve]
12. Cohn JN, Franciosa JA, Francis GS, et al. Effect of short-term infusion of sodium nitroprusside on mortality rate in acute myocardial infarction complicated by left ventricular failure. N Engl J Med. 1982; 306: 1129–1135.[Abstract]
13. Guiha NH, Cohn JN, Mikulic E, et al. Treatment of refractory heart failure with infusion of nitroprusside. N Engl J Med. 1974; 291: 587–592.[Medline] [Order article via Infotrieve]
14. Cohn JN, Mathew KJ, Franciosa JA, et al. Chronic vasodilator therapy in the management of cardiogenic shock and intractable left ventricular failure. Ann Intern Med. 1974; 81: 777–780.
15. Franciosa JA, Mikulic E, Cohn JN, et al. Hemodynamic effects of orally administered isosorbide dinitrate in patients with congestive heart failure. Circulation. 1974; 50: 1020–1024.
16. Mikulic E, Franciosa JA, Cohn JN. Comparative hemodynamic effects of chewable isosorbide dinitrate and nitroglycerin in patients with congestive heart failure. Circulation. 1975; 52: 477–482.
17. Franciosa JA, Pierpont G, Cohn JN. Hemodynamic improvement after oral hydralazine in left ventricular failure: a comparison with nitroprusside infusion in 16 patients. Ann Intern Med. 1977; 86: 388–393.
18. Pierpont GL, Cohn JN, Franciosa JA. Combined oral hydralazine-nitrate therapy in left ventricular failure: hemodynamic equivalency to sodium nitroprusside. Chest. 1978; 73: 8–13.
19. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study (V-HeFT). N Engl J Med. 1986; 314: 1547–1552.[Abstract]
20. Levine TB, Francis GS, Goldsmith SR, et al. Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relationship to hemodynamic abnormalities in congestive heart failure. Am J Cardiol. 1982; 49: 1659–1666.[CrossRef][Medline] [Order article via Infotrieve]
21. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984; 311: 819–823.[Abstract]
22. Francis GS, Cohn JN, Johnson G, et al, for the V-HeFT VA Cooperative Studies Group. Plasma norepinephrine, plasma renin activity, and congestive heart failure: relations to survival and the effects of therapy in V-HeFT II. Circulation. 1993; 87 (suppl VI): VI-40–VI-48.[Medline] [Order article via Infotrieve]
23. Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation. 2003; 107: 1278–1283.
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25. Francis GS, Cohn JN. Heart failure: mechanisms of cardiac and vascular dysfunction and the rationale for pharmacologic intervention. FASEB J. 1990; 4: 3068–3075.[Abstract]
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27. McDonald KM, Francis GS, Carlyle PF, et al. Hemodynamic, left ventricular structural and hormonal changes after discrete myocardial damage in the dog. J Am Coll Cardiol. 1992; 19: 469–467.
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29. McDonald KM, Francis GS, Matthews JH, et al. Long-term oral nitrate therapy prevents chronic ventricular remodeling in the dog. J Am Coll Cardiol. 1993; 21: 514–522.[Abstract]
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32. Franciosa JA, Cohn JN. Hemodynamic effects of oral ephedrine given alone or combined with nitroprusside infusion in patients with severe left ventricular failure. Am J Cardiol. 1979; 43: 79–83.[CrossRef][Medline] [Order article via Infotrieve]
33. Sharma B, Hoback J, Francis G, et al. Pirbuterol: a new oral sympathomimetic amine for the treatment of congestive heart failure. Am Heart J. 1981; 12: 533–541.[CrossRef]
34. Petein M, Levine TB, Cohn JN. Hemodynamic effects of new inotropic agent, MDL 19205, in patients with chronic heart failure. J Am Coll Cardiol. 1984; 2: 364–371.
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36. Petein M, Levine TB, Cohn JN. Persistent hemodynamic effects without long-term clinical benefits in response to oral piroximone (MDL 19,205) in patients with congestive heart failure. Circulation. 1986; 73: 230–236.
37. Kubo SH, Gollub S, Bourge R, et al, for the Pimobendan Multicenter Research Group. Beneficial effects of pimobendan on exercise tolerance and quality of life in patients with heart failure: results of a multicenter trial. Circulation. 1992; 83: 942–949.
38. Cohn JN, Goldstein S, Greenberg BH, et al, for the Vesnarinone Trial Investigators. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. N Engl J Med. 1998; 339: 1810–1816.
39. Cohn JN. Inotropic therapy for heart failure: paradise postponed. N Engl J Med. 1989; 11: 729–731.
40. Cohn JN, Ferrari R, Sharpe N, on behalf of an International Forum on Cardiac Remodeling. Cardiac remodeling: concepts and clinical implications. A consensus paper from an international forum on cardiac remodeling. J Am Coll Cardiol. 2000; 35: 569–582.
41. Curtiss C, Cohn JN, Vrobel T, et al. Role of the renin-angiotensin system in the systemic vasoconstriction of chronic congestive heart failure. Circulation. 1978; 58: 763–770.
42. Cohn JN. Is there a common mechanism of benefit for effective treatment of heart failure? [editorial]. Eur J Heart Fail. 1999; 1: 31–34.
43. Cohn JN. Lessons learned from the Valsartan-Heart Failure Trial (Val-HeFT): angiotensin receptor blockers in heart failure. Am J Cardiol. 2002; 90: 992–993.[CrossRef][Medline] [Order article via Infotrieve]
44. Abelson R. Generous Medicare payments spur specialty hospital boom. New York Times, October 26, 2003:1.
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46. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. Br Med J. 2003; 326: 1419–1424.
47. Cohn JN. The joy of discovery [editorial]. J Card Fail. 1997; 3: 1–2.[CrossRef][Medline] [Order article via Infotrieve]
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