Annual Review of Medicine - Volume 61, 2010

Humans have considerable genetic variation, as shown by their DNA sequence differences. Drug responsiveness and toxicity are affected by this variability. Genetic variation affects prodrug activation, drug targets, downstream activation pathways, drug elimination, and toxicity activation. Molecular diagnostic methods have discovered the genetic basis of several of these “outlier” drug responses. By predicting a patient's response, such diagnostics can improve both the safety and efficacy of drugs. The article illustrates the matching of molecular diagnosis to drug therapy for improved patient outcomes.

Nonsteroidal antinflammatory drugs (NSAIDs) inhibit prostaglandin formation by cyclooxygenases (COX) 1 and 2. NSAIDs selective for inhibition of COX-2 are less likely than traditional drugs to cause serious gastrointestinal adverse effects, but predispose to adverse cardiovascular events, such as heart failure, myocardial infarction, and stroke. Evidence from human pharmacology and genetics, genetically manipulated rodents, and other animal models and randomized trials indicates that this is consequent to suppression of COX-2-dependent cardioprotective prostagladins, particularly prostacyclin. Lessons drawn from how this saga unfolded are relevant to how we approach drug surveillance and regulation, integrate diversifed forms of information and might pursue a more personalized approach to drug efficacy and risk.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the white matter of the human brain caused by lytic infection of oligodendrocytes with the human polyomavirus JCV. Although the majority of PML cases occur in severely immune-suppressed individuals, with HIV-1 infection as the predominant factor, PML has been increasingly diagnosed in patients treated with biological therapies such as monoclonal antibodies that modulate immune system functions. Monoclonal antibodies that target the cell adhesion molecules VLA-4 (natalizumab; Tysabri® for multiple sclerosis and Crohn's disease) or LFA-1 (efalizumab; Raptiva® for severe forms of plaque psoriasis) to prevent extravasation of inflammatory T cells into tissues, or target the cell surface marker CD20 (rituximab; Rituxan® for hematologic malignancies and rheumatoid arthritis) to deplete peripheral circulating B cells, have all been associated with PML. The link between the effects of these therapies on the immune system and the occurrence of PML has prompted investigations on JCV sites of latency in the bone marrow, the migration of bone marrow derived cells into the circulation, and intracellular virus entry into the brain.

Mechanisms of platelet inhibition are reviewed with emphasis on the pharmacokinetic and pharmacodynamic determinants of clinical efficacy and safety of antiplatelet drugs. Current developments in antiplatelet therapy are discussed in relation to both primary and secondary prevention of atherothrombotic complications. Interindividual variability in response to antiplatelet agents and new drug targets are outlined within the context of optimizing the balance between the cardiovascular benefits and bleeding risks of antiplatelet therapy. Recent advances in the pharmacogenetics of thienopyridines open the realistic prospect of a personalized choice of the most appropriate antiplatelet agent and tailored dose adjustment for an individual patient.

Warfarin is a drug with a narrow therapeutic index and a wide interindividual variability in dose requirement. Because it is difficult to predict an accurate dose for an individual, patients starting the drug are at risk of thromboembolism or bleeding associated with underdosing or overdosing, respectively. Single nucleotide polymorphisms in the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKOR) genes have been shown to have a significant effect on warfarin dose requirement. Other genes mediating the action of warfarin make either little or no contribution to dose requirement. Although the polymorphisms in CYP2C9 and VKORC1 explain a significant proportion of the interindividual variability in warfarin dose requirement, currently available evidence based on a few small studies relating to the use of pharmacogenetics-guided dosing in the initiation of warfarin therapy has not shown improved outcomes in either safety or efficacy of therapy. Better clinical evidence of beneficial effects on patient outcome, particularly at the extremes of the dose requirements in geographically and ethnically diverse patient populations, is needed before the role of a pharmacogenomic approach to oral anticoagulation therapy in clinical practice can be established.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated hypercoagulable disorder caused by antibodies to platelet factor 4 (PF4) and heparin. HIT develops in temporal association with heparin therapy and manifests either as an unexplained thrombocytopenia or thrombocytopenia complicated by thrombosis. The propensity for thrombosis distinguishes HIT from other common drug-induced thrombocytopenias. Diagnosing HIT in hospitalized patients is often challenging because of the frequency of heparin use, occurrence of thrombocytopenia from other causes, and development of asymptomatic PF4/heparin antibodies in patients treated with heparin. This review summarizes our current understanding of the pathogenesis, clinical features, diagnostic criteria, and management approaches in HIT.

In contrast to the regulation of calcium homeostasis, which has been extensively studied over the past several decades, relatively little is known about the regulation of phosphate homeostasis. Fibroblast growth factor 23 (FGF23) is part of a previously unrecognized hormonal bone-parathyroid-kidney axis, which is modulated by PTH, 1,25(OH)2-vitamin D (1,25(OH)2D), dietary and serum phosphorus levels. Synthesis and secretion of FGF23 by osteocytes are positively regulated by 1,25(OH)2D and serum phosphorus and negatively regulated, through yet unknown mechanisms, by the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and by dentin matrix protein 1 (DMP1). In turn, FGF23 inhibits the synthesis of 1,25(OH)2D, and it may negatively regulate the secretion of parathyroid hormone (PTH) from the parathyroid glands. However, FGF23 synergizes with PTH to increase renal phosphate excretion by reducing expression of the renal sodium-phosphate cotransporters NaPi-IIa and NaPi-IIc in the proximal tubules. Most insights gained into the regulation of phosphate homeostasis by these factors are derived from human genetic disorders and genetically engineered mice, which are reviewed in this paper.

The alveolar region of the lung creates an extensive epithelial surface that mediates the transfer of oxygen and carbon dioxide required for respiration after birth. Maintenance of pulmonary function depends on the function of type II epithelial cells that synthesize and secrete pulmonary surfactant lipids and proteins, reducing the collapsing forces created at the air-liquid interface in the alveoli. Genetic and acquired disorders associated with the surfactant system cause both acute and chronic lung disease. Mutations in the ABCA3, SFTPA, SFTPB, SFTPC, SCL34A2, and TERT genes disrupt type II cell function and/or surfactant homeostasis, causing neonatal respiratory failure and chronic interstitial lung disease. Defects in GM-CSF receptor function disrupt surfactant clearance, causing pulmonary alveolar proteinosis. Abnormalities in the surfactant system and disruption of type II cell homeostasis underlie the pathogenesis of pulmonary disorders previously considered idiopathic, providing the basis for improved diagnosis and therapies of these rare lung diseases.

Neuropsychiatry is the subspecialty of psychiatry that deals with disorders at the intersection of neurology and psychiatry. Neuropsychiatric disorders are complex and incompletely understood. Neuroscience research is beginning to elucidate the biological underpinnings of many of these disorders. These advances have the potential to improve diagnosis, inform treatment selection, and facilitate development of new and better interventions.

Developing an HIV-1 vaccine that can elicit antibodies to prevent infection has been a formidable challenge. Although no single immunogen has generated antibodies that can neutralize diverse isolates, progress has been made in understanding (a) the structure of the HIV-1 envelope glycoprotein, which is targeted by neutralizing antibodies, (b) how HIV-1 evades antibodies made by an infected host, and (c) how rare monoclonal antibodies can exhibit broadly neutralizing activity. Advances in structural and molecular biology coupled with new approaches to isolate neutralizing antibodies from HIV-1-infected individuals are enhancing our understanding of what humoral immune responses will be required for a vaccine. This review summarizes progress in understanding the host antibody response to HIV-1 and current strategies for applying this information to develop an effective vaccine.

Despite more than 25 years of concerted worldwide research, the development of a safe and effective HIV-1 vaccine remains elusive. Prototype antibody-based and T cell–based HIV-1 vaccines have failed to show efficacy in clinical trials to date. Next-generation HIV-1 vaccine candidates are in various stages of preclinical and clinical development, but key scientific obstacles pose major challenges for the field. Critical hurdles include the enormous global diversity of the virus and the challenges associated with generating broadly reactive neutralizing antibody and cellular immune responses. We review the current state of the HIV-1 vaccine field and outline strategies that are being explored to overcome these roadblocks.

Tremendous success in the prevention and treatment of pediatric HIV in high-resource countries has changed the face of the epidemic. A perinatally HIV-infected child now faces a chronic disease rather than a progressive, fatal one. However, these successes pose new challenges as perinatally HIV-infected youth survive into adulthood. These include maintaining adherence to long-term, likely life-long therapy; selecting successive antiretroviral drug regimens, given the limited availability of pediatric formulations and the lack of pharmacokinetic and safety data in children; and overcoming extensive drug resistance in multi-drug-experienced children. Pediatric HIV care now focuses on morbidity related to long-term HIV infection and its treatment. Survival into adulthood of perinatally HIV-infected youth in high-resource countries encourages expansion of pediatric treatment programs in low-resource countries, where most HIV-infected children live, and provides important lessons about how the epidemic changes with increasing access to antiretroviral therapy for children.

Avian influenza H5N1 viruses that have spread to a number of countries in Asia, the Middle East, and Africa have the potential to cause a pandemic. The most effective public health intervention strategy is to combine preventive vaccination with nonpharmaceutical intervention strategies and enhanced surveillance activities. H5N1 vaccines are poorly immunogenic even at high doses; an adjuvant is needed for enhancement of immunogenicity and for dose-sparing. Lack of effective, yet safe, adjuvants is the limiting factor for candidate vaccines that utilize egg-dependent or egg-independent manufacturing technologies. Hence, developing novel adjuvants is crucial for pandemic influenza vaccine development. Although the use of antiviral drugs is also an important public health countermeasure for preventing and treating influenza, the emergence of drug-resistant strains of avian H5N1 viruses underscores the need to develop not only new drugs but other novel preventive and therapeutic strategies such as vaccines.

Coronary artery disease (CAD) is one manifestation of ischemic heart disease, which is the leading cause of mortality in the world. In addition to preventive medical therapy and lifestyle changes, consideration of revascularization of obstructed arteries to reduce ischemia, alleviate angina, and improve quality of life is a mainstay of current practice. However, the benefits of different methods of revascularization in particular patient populations are debated. Percutaneous coronary intervention (PCI), which involves placement of intracoronary stents in most patients, is a less invasive procedure than coronary artery bypass graft (CABG) surgery. Although it is generally accepted that patients with single-vessel obstructive CAD are best treated with PCI, patients with multivessel CAD have a higher ischemia burden, a greater risk for developing recurrent ischemic events, and a higher mortality. It is in this patient population where the debate over revascularization with stents versus surgery continues.

Acute myocardial infarction is a common and life-threatening presentation of coronary artery disease in adults. In the settings of ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction, significant mortality benefit has been observed in randomized trials of coronary stent procedures compared with medical therapy alone. However, data regarding procedural choices, and particularly stent choices, are limited, and significant controversy exists. Drug-eluting stents were introduced in the United States in 2003 and have been widely adopted based on profound reduction in restenosis. Yet recent years have witnessed a decline in use of drug-eluting stents in the setting of myocardial infarction due to long-term safety concerns. We review the current data regarding drug-eluting stent performance relative to bare metal stents in the setting of acute myocardial infarction with regard to effectiveness, safety, and the need for adjunctive long-term pharmacologic therapy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) has a prevalence of at least 1 in 1000, is a leading cause of sudden cardiac death in people aged ≤35 years, and accounts for up to 10% of deaths from undiagnosed cardiac disease in the <65 age group. The classic form of the disease has an early predilection for the right ventricle, but recognition of left-dominant and biventricular subtypes has prompted proposal of the broader term arrhythmogenic cardiomyopathy. The clinical profile of the disease bridges the gap between the cardiomyopathies and inherited arrhythmia syndromes. The early “concealed” phase is characterized by propensity toward ventricular tachyarrhythmia in the setting of well-preserved morphology, histology, and ventricular function. As the disease progresses, however, myocyte loss, inflammation, and fibroadiposis become evident. Up to 40% of cases harbor rare variants in genes encoding components of the desmosome, specialized intercellular junctions that confer mechanical strength to cardiac and epithelial tissue, and may also participate in signaling networks. Phenotypic heterogeneity and the nonspecific nature of associated features complicate clinical diagnosis, which requires multipronged cardiovascular investigation rather than a single test. Development of a prospectively validated risk-stratification algorithm for the full disease spectrum remains the foremost clinical challenge.

The introduction of the heart lung machine more than 50 years ago proved in principle that heart function can be replaced, albeit for short periods. This was followed by attempts to produce total or partial artificial hearts that could function for prolonged periods of time. Progress in this field has been intermittent but has accelerated considerably in the past 10 years, with ventricular assist devices (VADs) reaching an impressive degree of sophistication and complexity owing to the contributions from clinicians, engineers, scientists, industrialists, and others. This review describes the currently available types of VADs, their current clinical use, the patient selection process, the trend toward use of VADs in patients with less severe heart failure, and the use of VADs for myocardial recovery in combination with novel pharmacological strategies, gene therapy, and cell therapy.

Recently, an increasing number of cases of stress cardiomyopathy, mainly occurring in elderly women, have been documented in many parts of the world. In Japan, this disease is known as takotsubo cardiomyopathy (named after the fishing pot used for trapping octopus). Symptoms of this condition are akin to those of acute myocardial infarction, but no obstructive lesions are found in the coronary arteries, and left ventricular apical ballooning is present. Stress cardiomyopathy is now a well-recognized cause of acute heart failure, lethal ventricular arrhythmias, and ventricular rupture. Although the precise mechanism of onset of this condition is still controversial, two major pathogenic mechanisms have been proposed: catecholamine cardiotoxicity and neurogenic stunned myocardium. We summarize the findings of studies conducted to date on stress cardiomyopathy—from bench to bedside and bedside to bench.

Progenitor cells residing in bone marrow, adipose tissue, and skeletal muscle or circulating in the blood are capable of improving myocardial function in preclinical models. In contrast, early clinical studies using bone marrow cells have shown mixed results and reflect our incomplete understanding of underlying mechanisms. Recent identification of various cardiac precursor cells has suggested an endogenous reservoir for cell-based repair. However, confronted with massive cardiac cell loss, inventive strategies and enabling technologies are required to mobilize or deliver functionally competent progenitor cells to sites of injury or to effectively stimulate endogenous repair. We review our present knowledge in this promising and rapidly evolving development in cardiovascular medicine and highlight obstacles as well as opportunities.

Body mass index, as an approximation of body adiposity, is associated with increased risk of several common and less common malignancies in a sex- and site-specific manner. These findings implicate sex- and cancer site–specific biological mechanisms underpinning these associations, and it is unlikely that there is a “one system fits all” mechanism. Three main candidate systems have been proposed—insulin and the insulin-like growth factor–I axis, sex steroids, and adipokines—but there are shortfalls to these hypotheses. In this review, three novel candidate mechanisms are proposed: obesity-induced hypoxia, shared genetic susceptibility, and migrating adipose stromal cells. While public health policies aimed at curbing the underlying causes of the obesity epidemic are being implemented, there is a parallel need to better understand the biological processes linking obesity and cancer as a prerequisite to the development of new approaches to prevention and treatment.