The power of Pasteur's quadrant: cardiovascular disease at the turn of the century

Abstract

During the life span of The FASEB Journal, the decline in cardiovascular mortality was astonishing as the fundamental bases of the complex syndromes of cardiovascular disease were illuminated. In this Silver Anniversary Review, we highlight a few pivotal advances in the field and relate them to research in Pasteur's quadrant, the region of investigation driven by both a desire for fundamental understanding and the consideration of its use. In the second half of the 20th century, we advanced from little pathophysiologic understanding to a near-complete understanding and effective, evidence-based therapeutics for vascular disorders and a similar development of pharmacotherapy to address heart failure, primarily through agents that antagonize the excessive concentration of circulating neurohumoral agents. In the current era, we have witnessed “the rise of the machines,” from stents to cardiac resynchronization therapy. The next wave of treatments will build on an increasingly sophisticated understanding of the molecular determinants of cardiovascular disorders. We briefly consider the promise of regenerative medicine and are intrigued by the possibility for the direct reprogramming of resident cardiac fibroblasts into cardiomyocytes. As for the future, genomic profiling should help physicians recommend individualized risk factor modification targeted to prevent specific manifestations of cardiovascular disease. Transcriptional and biomarker analyses will almost surely be used individually to tailor therapy for those at risk of or experiencing cardiovascular disease. Given the ongoing exponential expansion of scientific knowledge, all of human ingenuity will be needed to fully utilize the power of Pasteur's quadrant and to unleash another quarter century in cardiology as scientifically fruitful and effective on human health as the last.—Levin, R. I., Fishman, G. I. The power of Pasteur's quadrant: cardiovascular disease at the turn of the century.

While medical specialization was well established in Egypt in the third millennium BCE, western medicine waited for Hippocrates of Kos to establish the order around 460 BCE. And incredibly—considering the pace of discovery in cardiovascular disease in the recent past—it then took 2000 yr and William Harvey's 1628 publication of De Motu Cordis to establish that blood, not air, circulated through the arteries. This makes the progress in cardiology since World War II all the more remarkable, including the impressive strides forward that took place in this journal's first quarter century (1). These advances have lowered morbidity and mortality from diseases of the heart and great vessels so dramatically because much of the research was done in Pasteur's quadrant (2), the area of investigation in the taxonomy of science characterized by desire for both a fundamental understanding and a consideration of use, spanning basic and applied research. Indeed, progress in cardiology may be considered the most successful application of research in Pasteur's quadrant.

In the United States, cardiovascular mortality declined astonishingly by 59% from 1950 through 1999 (3), and continues to decline despite the high overall prevalence of cardiovascular disease (CVD) risk factors and the new epidemics of obesity and diabetes (4). The decline in mortality reflects remarkable successes in fundamental research followed by a quarter century of translation into novel diagnostics and therapeutics. Building on the canonical Framingham Heart Study (5), researchers have equipped cardiologists with increasingly sophisticated and reliable predictive tools to assess risks for CVD (6). A vast and growing body of statistical evidence links the modifiable risk factors of hypertension, hypercholesterolemia, smoking, obesity, and diabetes to a higher incidence of CVD, and many have attributed the noted decline in cardiovascular mortality to a targeted reduction in prevalence of several of these risk factors (7).

Our contribution to the silver anniversary editorial celebrations of The FASEB Journal is an overview of medicine's highly successful and ongoing reinvention of cardiology, from epidemiology to genomic science. Rather than providing an exhaustive and inclusive review of this progress, of which there are many examples (8), we highlight a few pivotal advances in 3 areas of this vast field and relate them to Pasteur's quadrant to illustrate the means of their translation and invention of novel therapeutics. The first is atherosclerosis and its identification as an inflammatory disease; the second is heart failure and neurohumoral dysregulation; and the third is personalized (genomic) cardiovascular medicine.

ATHEROSCLEROSIS

While coronary atherosclerosis (CAD) was present in antiquity (9), its relation to Hebreden's angina was an 18th-century observation (10), and to myocardial infarction and sudden death, a 20th-century one (11, 12). It is a pathological manifestation of a chronic inflammatory process that results in the development of intimal arterial plaques, narrowing of the arterial lumen, and compensatory changes in the media and adventitia. The plaques are architecturally complex, with discontinuities that weaken vessels required to withstand the constant pounding of arterial pressure.

Atherosclerosis is a plague of modern times, threatening soon to become the leading cause of death worldwide. In the era of The FASEB Journal, it has been clearly identified as an inflammatory disease (13), caused by chronic endothelial exposure to oxidized lipids and other toxins, whose plaques rupture or erode and trigger thrombosis, causing acute coronary syndromes (ACS; refs. 14, 15) The decline in overall cardiovascular mortality in the United States reflects two developmental achievements: remarkable successes in fundamental research—a quarter century of paradigm-changing discoveries—and their translation into novel diagnostics and therapeutics in Pasteur's quadrant. From seminal epidemiology (6, 16), through the roles of chronic inflammation (13, 15) and thrombosis (11, 12), to the development of advanced imaging (17), enzymatic thrombolysis (18, 19), and angioplasty and catheter-based interventions (20), the treatment of heart attack in the late 20th century went from rudimentary pathophysiologic understanding and nostrums to a near-complete understanding and effective, evidence-based therapeutics.

The fundamental understanding and the definition of CVD risk factors that evolved over the quarter century of paradigm-changing discoveries and their translation into novel diagnostics and therapeutics in Pasteur's quadrant similarly allowed the development of strategies for prevention of atherosclerosis, avoiding the complications of plaque encroachment and disruption entirely. The evidence-based use of aspirin, statins, β blockers, and angiotensin-converting enzyme inhibitors demonstrably offer anti-inflammatory, antithrombotic, and plaque-stabilizing benefits (16). The cessation of smoking, the control of hypertension, the emphasis on exercise, and the amelioration of obesity and diabetes complete this part of the puzzle.

The future will solve the remaining uncertainties through the use of molecular prevention and genomic therapeutics. The chronic illness of CAD does not simply manifest itself as the tearing of older, plaque-ridden, degenerated tissue, akin to the collapse of an airplane wing from metal fatigue. There is a genetic component and predisposition to the development of myocardial infarction (21) that is not expressed through current understanding (22, 23) While the new epidemic of obesity threatens the progress that has been made in treating vascular disease, it is possible that the disease's burden will be lifted entirely with further inquiry and knowledge transfer to the public.

HEART FAILURE

Definitions of heart failure abound, but most are captured by Thomas Lewis' description, “a condition in which the heart fails to discharge its contents adequately” (24). While a multitude of primary causes, such as acute myocardial infarction, valvular disease, or infection, may all lead to myocardial remodeling and failure, the syndrome disproportionately affects older adults, where the prevalence approaches 10–14% in individuals >60 yr of age (25). Regardless of underlying etiology, heart failure is now recognized for the profound dysregulation of neurohumoural signaling cascades that contribute to its pathophysiology and disease progression. It is this recognition that has provided the opportunity for remarkable therapeutic advances.

The “modern” pharmacotherapeutic era may be traced to the contributions of the British physician William Withering, who in 1785 reported on 163 patients with “dropsy” that he had treated with foxglove, a plant rich in digitalis (26). Symptomatic treatment for “congestion” was greatly advanced by the introduction of diuretics (including organomercurials) in 1920, and the thiazides some 50 yr ago. However, therapies that potently change the natural history of heart failure and could therefore be placed in Pasteur's quadrant were ushered in by the 1975 introduction of β-adrenergic receptor blockers, though researchers recognized that the use of such agents in congestive cardiomyopathy “seems paradoxical since the heart might be dependent on raised sympathetic activity” (27). However, the insight that β-receptor antagonists might directly blunt the high sympathetic tone in humans with cardiomyopathy, and its associated hypertrophy, necrosis, and deterioration of heart function, proved prescient, and, indeed, the majority of subsequent pivotal pharmacotherapeutic trials for heart failure have built on this underlying concept of reducing excessive neurohormonal stimulation, whether the stimulus be catecholamines, angiotensin II, or aldosterone (28, 29).

Whereas the past few decades have seen the rise of pharmacotherapy, primarily through agents that antagonize the excessive concentration of circulating neurohumoral agents, the current era reflects “the rise of the machines.” Cardiac resynchronization therapy, i.e., dual or multisite electronic pacing of the ventricles to minimize dyssynchronous excitation and contraction, has led to significant improvement in contractile performance in a subset of patients with heart failure, although predictors of success and optimization of the therapy both remain somewhat elusive (30).

What does the future hold? Whereas primary prevention will undoubtedly diminish the burden of heart failure, for those afflicted by the syndrome, the next wave of treatment will build on an increasingly sophisticated understanding of molecular determinants of heart failure progression. Sequence variants in genes regulating neurohormonal activation will be used to individualize heart failure pharmacotherapy (31). Among the most promising avenues for translation into therapy are those related to therapeutic manipulation of microRNA expression. Discovered only a decade ago (32–34), these short noncoding RNAs inhibit mRNA translation or promote mRNA degradation, and their inhibitory effect can be abrogated by treatment with “antagomirs.” Targeted antagomirs may potently regulate the response of the heart to imposed load and pathological remodeling (35). Improved fundamental understanding of molecular pathophysiology will be married with advances in bioengineering. Indeed, one of the most exciting new areas of investigation focuses on modulation of cardiac autonomic tone by stimulation of the spinal cord. While still in its infancy, provocative new studies indicate that manipulation of autonomic tone by stimulation of the thoracic spinal cord with implanted devices can significantly improve contractile function following myocardial infarction (36). Much as the electronic pacemaker and implanted cardioverter-defibrillator have become routine approaches to regulate cardiac rhythm, one can envision implantation of spinal cord stimulators as a relatively straightforward technique to directly reset cardiac autonomic tone and improve contractile function in patients with even mildly symptomatic heart failure. And for those individuals resistant to pharmacotherapy and “autonomic reprogramming,” improvements in the design of another bioengineering marvel, the ventricular assist device, with improved safety, longevity and simplicity of implantation, will almost certainly lead to more widespread and earlier use of these devices in patients with refractory heart failure (37). It is uncertain whether an increase in organ availability for allotransplantation or breakthroughs in immunomodulation and xenotransplantation will affect heart failure morbidity and mortality (38).

Finally, no look to the future is complete without a word on regenerative medicine and stem cells. It has been almost 3 centuries since Spallanzani described the regenerative capacity of the newt (39), including its remarkable capacity to regenerate an injured heart (40). Alas, much of the regenerative capacity of the postnatal mammalian heart appears to have been lost. Nonetheless, several strategies based on fundamental principles of stem cell and developmental biology have provided a starting place for cardiac repair—either through transplanting exogenous cells or coaxing endogenous cells within the heart to proliferate and repopulate the damaged myocardium. Whereas much has been written about the potential for induced pluripotent stem cells (41), particularly intriguing is the possibility for direct reprogramming of resident cardiac fibroblasts into cardiomyocytes through transduction with a cocktail of transcription factors (42).

PERSONALIZED CARDIOVASCULAR MEDICINE

More than half a century ago, Ingram and Hunt identified a point mutation in human sickle hemoglobin, ushering in the era of the molecular basis of inherited diseases (43, 44). It took another two decades to create the technology to rapidly sequence DNA, enabling identification of the causative point mutation in the β-globin gene (45, 46). The past quarter century has seen the completion of the Human Genome Project (in 2003), the identification of some 340 genes responsible for Mendelian phenotypes (47), the International HapMap Project (in 2005), and an explosion of genome wide association studies (GWASs) to identify sequence variants associated with complex traits. The accomplishments are breathtaking, yet we find ourselves in a time of scientific and clinical mismatch: we are creating an abundance of “omic” data (genomic, proteomic, metabolomic, phenomic), but with relatively few exceptions, we have not yet translated this information to improve the human condition. Yet we optimistically assert that personalized medicine will almost certainly come of age during the next quarter century. For example, the GWAS approach has begun to identify loci tightly linked to disease phenotypes and surrogate endophenotypes. While the incremental risk associated with individual sequence variants or haplotypes is usually quite modest (typically on the order of <2-fold increased risk), it is reason to predict that combinatorial analyses of multiple loci will provide risk estimates of sufficient magnitude to broadly affect patient care. For example, based on genomic profiling, the healthcare provider of the future may recommend individualized risk factor modification targeted to prevent specific manifestations of cardiovascular disease, such as myocardial infarction, sudden cardiac death, or stroke. Similarly, genomic profiling, coupled with transcriptional and biomarker analyses, will almost surely be used to tailor individual therapies for those at risk of or suffering from cardiovascular disease. Already, dosing algorithms incorporating single-nucleotide polymorphisms (SNPs) in the CYP2C9 and VKORC1 genes provide some clinical utility, and it is likely that the field of pharmacogenomics will come of age during the next 25 yr, affecting drug selection and dosing.

CONCLUSIONS

In the summer of 1950, at a conference in Amsterdam, the famous sociologist of science, Derek Price, presented his theory on the expansion of scientific knowledge and calculated a doubling rate of 10.4 yr (48). Sixty years later, at the 2010 summer Techonomy conference held in Lake Tahoe, former Google CEO Eric Schmidt provided an update, stating that every 2 d, we create as much information as we did from the dawn of civilization up until 2003, or 5 EB of data (49). While Price references scientific papers and Schmidt includes everything that is published on the Web, the staggering speed of data synthesis is undeniable. The continuing challenge is to use the data to greatest advantage: in the health sciences, the advantage is to foster human potential.

The lifetime of The FASEB Journal has seen the field of cardiovascular disease move from symptomatic therapies without pathophysiologic understanding through the eras of cellular and molecular discovery that provided fundamental understandings of the complex disorders of the cardiovascular system. As research moved into Pasteur's quadrant, novel technologies were invented, challenging social convention. When David Sabiston performed one of the first coronary artery bypasses in 1962, there was still a taboo on touching the beating human heart. The genomic therapies of personalized medicine, the Blade Runner era of easily grown replacement parts, will challenge modern taboos. All of human ingenuity and our capacity for explication, as this journal demonstrates regularly, will be needed to fully utilize the power of Pasteur's quadrant.