There are more things in heaven and earth, Horatio,
Than are dreamt of in your philosophy.
William Shakespeare, Hamlet (1.5.166–7), Hamlet to Horatio.
Shakespeare uses the term “philosophy” to encompass all knowledge, and the past few decades have certainly taught us that prediction in science and medicine is perilous. Hamlet's words also suggest that the current emphasis on identifying the future impact of proposed experiments is fraught with error. The best defense against such folly is the prepared mind. The review articles in this series, which focus on selected aspects of cellular responses in heart failure, illustrate the emergence of concepts during the past few decades with possible practical application for human disease. As originally conceived, these concepts might have been categorized as science fiction, but over time they have morphed into science “fact.” But facts and dogma are malleable, and no doubt many of the concepts summarized in this series of articles will be discarded in the future. The problem is that we cannot predict which ones will survive. Nevertheless, it behooves us to keep an open mind and to hope that the proper seeds have been planted and will grow into a thick forest of knowledge that, after pruning, can be used to treat both common and emerging cardiovascular disorders in human patients.
In the first of these articles, Ye and Yeghiazarians review the current state of knowledge of cardiac progenitor cells that have been used for cardiac cell therapy both experimentally and therapeutically. The characteristics of these cells are detailed in tables, which provide the reader, both novice and expert, with an overview of the breadth and complexity of this young field of research. Their review summarizes both older and recent clinical trials and the prospects for success as well as future directions, including the potential roles of biomaterials and microRNA technology. The results of the studies cited in this review also emphasize the importance of collaboration between basic scientists and clinicians and the need, in some instances, for investigators to curb their enthusiasm before a solid base of knowledge is established. This conclusion shows that Hamlet had it right!
Nowhere is the gap between promise and delivery greater than in the field of gene therapy. In the second review article, Hajjar et al summarize the progress that has been made in developing an approach to the gene therapy of congestive heart failure by targeting SERCA2a using an adeno-associated virus. This concept makes use of information gained in basic studies of cardiac pathophysiology in both humans and animal models and illustrates the need for such studies before clinical progress can be made using new technologies. In this review, other targets for gene therapy in heart failure are identified, as are gene therapy vectors and delivery systems and their pitfalls. Finally, the review summarizes the current results of clinical trials. It should be noted that gene therapy is likely to be in long-term competition with small implantable ventricular assist devices for the treatment of heart failure. Which technology will emerge as preferable is impossible to predict, as noted above.
Although both stem cell therapy and gene therapy have garnered most of the headlines in the scientific and the popular press, much progress has been made in understanding the immune system. However, there has been relatively little collaboration between cardiologists and immunologists in elucidating the role of the immune system in response to acute myocardial infarction and postinfarction remodeling of the heart, a process that is critical in the pathogenesis of congestive heart failure. This gap is narrowed if not closed in the review by Frangogiannis, who has summarized the roles of innate and acquired immunity under these pathophysiologic conditions. This review considers the heart's short- and long-term responses to myocardial infarction from the perspective of an inflammatory reaction and describes various signals that are activated either to augment or reduce this reaction. A whole host of regulatory molecules is considered. Most of these are well known to immunologists, but many may be unfamiliar to cardiologists. Thus, cross-fertilization in the knowledge of these signal transduction mechanisms is key, and Hamlet's admonition to Horatio is again borne out.
It is well known that mitochondria are dynamic structures, which are a major source of the heart's energy, and also of reactive oxygen species under conditions of oxygen deprivation via NAPDH oxidase. As emphasized in the review by Knowlton, it is now recognized that mitochondria are organized in a network, which undergoes regulated fission and fusion and is disturbed in heart failure leading to mitochondrial dysfunction. The author discusses various factors that influence mitochondrial responses, including the regulatory proteins involved in fission and fusion. Whether abnormalities in this aspect of mitochondrial function are a cause or a consequence of heart failure has not yet been determined. Included is a summary of the effects on mitochondria of drugs commonly used in the treatment of heart failure. Future therapeutic targets relative to mitochondrial biology are also discussed. In addition to providing a comprehensive overview of the current state of research in this field, this review charts new directions that may further mechanistic understanding and lead to more effective therapies.
Another aspect of heart failure of which the medical Horatios of the world were unaware turns out to be the incidence of diastolic heart failure, which is now thought to be one of the predominant clinical manifestations of this syndrome, especially in the elderly. As a result, new nomenclature has been added to the lexicon, such as heart failure with reduced or preserved ejection fraction, the latter designated by the awkward term “HFpEF.” One of the sarcomeric proteins implicated in the regulation of myocardial passive stiffness and stress sensitive signaling is a giant among molecules, aptly named titin. Lewinter reviews the biology of titin, emphasizing many modifications that influence its role in the heart, including isoform variations, mutations, phosphorylation variations, and mutations of genes that code for proteins that interact with titin. All of these may result in symptoms of cardiac dysfunction, the origin of which may not be readily apparent, and may account for a substantial proportion of heretofore unexplained cases of heart failure. As pointed out by the author, targeting of titin is in its infancy but heed Hamlet's admonition!
The recognition that catecholamine excess could lead to heart failure prompted emphasis on the study of beta-adrenergic receptor biology and the development of drugs that inhibit beta-agonist effects. This fundamental work eventually earned 2 of the pioneering investigators in this field, Dr. Robert Lefkowitz and his former student Dr. Brian Kobilka, the Nobel Prize in chemistry. Initially, beta-adrenergic receptor blockers were thought to be contraindicated in cardiac dysfunction, but in a striking reversal of pharmacologic fortune, beta-blockers were found to be effective in the treatment of systolic heart failure and have been a mainstay of therapy for many years. Relatively ignored, however, have been other G-protein-coupled adrenergic receptors in the heart, such as alpha-1-adrenergic receptors. These subtypes are the subject of a review by Simpson in this series. He recounts the adaptive functions of alpha-1-adrenergic receptors including physiologic hypertrophy, positive inotropy, and cardioprotective properties. He provides evidence both in animals and in humans that alpha-1-adrenergic blockade may be detrimental in heart failure, and conversely proposes the novel idea (listen up Horatio) that alpha-1-adrenergic agonism could be a useful approach for the treatment of heart failure.
In the final review of this series, Hill et al examine metabolic control in heart failure. They point out that cardiac metabolic flexibility—the ability of the heart to move among diverse energy substrates—is impaired in ischemic heart failure. This impairment leads to alterations in myocardial energetics and subsequently to worsening cardiac dysfunction. Abnormalities of triglyceride, glucose, free fatty acid, amino acid, and nucleotide metabolism are summarized and extensively referenced. The role of lipotoxicity, glucolipotoxicity, metabolic hypertrophy, and mitochondrial dysfunction in relation to metabolism in nonischemic cardiomyopathy is examined. Therapeutic considerations such as promoting glucose utilization and drugs that affect metabolism are also reviewed.
Despite all we have learned, there remain substantial gaps in information which provide opportunities for future therapeutic approaches. The following serves as a fitting coda to Hamlet's pronouncement:
“Imagination is more important than knowledge.”