Looking for a particular review? Use Find in Page (Ctrl + F)
Bartlett, J. G. (2006). "Narrative review: the new epidemic of Clostridium difficile-associated enteric disease." Annals of Internal Medicine 145(10): 758-764.
Antibiotic-associated diarrhea and colitis were well established soon after antibiotics became available. Early work implicated Staphylococcus aureus, but in 1978 Clostridium difficile became the established pathogen in the vast majority of cases. In the first 5 years (1978 through 1983), the most common cause was clindamycin, the standard diagnostic test was the cytotoxin assay, and standard management was to withdraw the implicated antibiotic and treat with oral vancomycin. Most patients responded well, but 25% relapsed when vancomycin was withdrawn. During the next 20 years (1983 through 2003), the most commonly implicated antibiotics were the cephalosporins, which reflected the rates of use; the enzyme immunoassay replaced the cytotoxin assay because of speed of results and technical ease of performance; and metronidazole replaced vancomycin as standard treatment, and principles of containment hospitals became infection control and antibiotic control. During the recent past (2003 to 2006), C. difficile has been more frequent, more severe, more refractory to standard therapy, and more likely to relapse. This pattern is widly distributed in the United States, Canada, and Europe and is now attributed to a new strain of C. difficile designated BI, NAP1, or ribotype 027 (which are synonymous terms). This strain appears more virulent, possibly because of production of large amounts of toxins, and fluoroquinolones are now major inducing agents along with cephalosporins, which presumably reflects newly acquired in vitro resistance and escalating rates of use. The recent experience does not change principles of management of the individual patient, but it does serve to emphasize the need for better diagnostics, early recognition, improved methods to manage severe disease and relapsing disease, and greater attention to infection control and antibiotic restraint. [References: 77]
Committee, U. S. P. M. G. E. and U. S. Pharmacopeia (2006). "Narrative review: the U.S. Pharmacopeia and model guidelines for Medicare Part D formularies." Annals of Internal Medicine 145(6): 448-453.
The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 includes a provision directing the Secretary of the U.S. Department of Health and Human Services to request that the U.S. Pharmacopeia (USP) develop a list of categories and classes (the USP Model Guidelines) that can be used by prescription drug plans in developing their formularies for the Part D prescription drug benefit. The Centers for Medicare & Medicaid Services (CMS) used the Model Guidelines and USP's related listing, termed the Formulary Key Drug Types, to evaluate prescription drug plan formularies submitted by prescription drug plan sponsors intending to provide the new Part D benefit. This article recounts how USP's all-volunteer Model Guidelines Expert Committee developed the USP Model Guidelines and Formulary Key Drug Types, working under a cooperative agreement with CMS in response to the Secretary's request. The Model Guidelines and Formulary Key Drug Types are updated annually to reflect advances in evidence-based medicine, thereby offering timely guidance to CMS and to prescription drug plans based on USP's demonstrated expertise in setting standards. [References: 22]
Hayward, R. A., T. P. Hofer, et al. (2006). "Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem." Annals of Internal Medicine 145(7): 520-53
Recent national recommendations have proposed that physicians should titrate lipid therapy to achieve low-density lipoprotein (LDL) cholesterol levels less than 1.81 mmol/L (<70 mg/dL) for patients at very high cardiovascular risk and less than 2.59 mmol/L (<100 mg/dL) for patients at high cardiovascular risk. To examine the clinical evidence for these recommendations, the authors sought to review all controlled trials, cohort studies, and case-control studies that examined the independent relationship between LDL cholesterol and major cardiovascular outcomes in patients with LDL cholesterol levels less than 3.36 mmol/L (<130 mg/dL). For those with LDL cholesterol levels less than 3.36 mmol/L (<130 mg/dL), the authors found no clinical trial subgroup analyses or valid cohort or case-control analyses suggesting that the degree to which LDL cholesterol responds to a statin independently predicts the degree of cardiovascular risk reduction. Published studies had avoidable limitations, such as a reliance on ecological (aggregate) analyses, use of analyses that ignore statins' other proposed mechanisms of action, and failure to account for known confounders (especially healthy volunteer effects). Clear, compelling evidence supports near-universal empirical statin therapy in patients at high cardiovascular risk (regardless of their natural LDL cholesterol values), but current clinical evidence does not demonstrate that titrating lipid therapy to achieve proposed low LDL cholesterol levels is beneficial or safe. [References: 54]
Lloyd-Jones, D. M., K. Liu, et al. (2006)."Narrative review: Assessment of C-reactive protein in risk prediction for cardiovascular disease." Annals of Internal Medicine 145(1): 35-42.
Some experts propose C-reactive protein (CRP) as a screening tool for prediction of cardiovascular disease (CVD). Many epidemiologic studies show positive associations between elevated CRP levels and incident CVD. Assessment of the value of new prognostic tests, however, must rely on understanding of test characteristics rather than on associations measured by relative risks. In the case of CRP, test characteristics must be judged in the context of currently available CVD risk prediction algorithms. In this review of literature published before January 2006, the authors describe what is known about the additional utility of CRP in risk prediction. They find no definitive evidence that, for most individuals, CRP adds substantial predictive value above that provided by risk estimation using traditional risk factors for CVD. Use of CRP may add to risk estimation in a limited subset of individuals who are at intermediate predicted risk according to the Framingham risk score. The authors propose that many questions still must be addressed before CRP is incorporated into risk prediction algorithms and before universal screening with CRP can be recommended. [References: 49]
Mooradian, A. D., M. Bernbaum, et al. (2006). "Narrative review: a rational approach to starting insulin therapy." Annals of Internal Medicine 145(2): 125-134.
BACKGROUND: The emergence of multiple insulin products has provided new opportunities to achieve diabetes control. However, the number of options has raised concerns about the optimal choices of products. PURPOSE: To briefly review the pharmacologic characteristics of currently available insulin products and to suggest an initial insulin regimen based on common blood glucose profiles among patients with diabetes. DATA SOURCES: Relevant manuscripts were identified through a MEDLINE search (1996 to 25 February 2006) of the English-language literature. The key phrase used was therapeutic use of insulin. The literature search was limited to core clinical journals that have accessible full texts. STUDY SELECTION: Clinical trials and authoritative reviews published between 1996 and February 2006 were selected. A total of 420 manuscripts wasreviewed. DATA EXTRACTION: The authors independently reviewed the relevant available literature. This literature, along with the authors' clinical experience, was used to construct practical suggestions. DATA SYNTHESIS: Several new insulin and insulin analogue preparations are now available for clinical use. Used as prandial insulin (for example, insulin lispro, insulin aspart, or insulin glulisine) and basal insulin (for example, insulin glargine or insulin detemir), the analogues simulate physiologic insulin profiles more closely than the older conventional insulins. There is currently no strong rationale favoring glargine, neutral protamine Hagedorn insulin, insulin detemir, or fixed-ratio insulin preparations as the preferred agent for initiating insulin therapy. LIMITATIONS: This was a retrospective review of previously published manuscripts chosen at the authors' discretion. CONCLUSIONS: The advent of recombinant DNA technology made it possible to overcome limitations in the time-action profiles of conventional insulins. Insulin therapy must be individualized. Nevertheless, certain subgroups of patients with diabetes can be differentiated from each other according to the pattern of blood glucose changes during the day. On the basis of the blood glucose profile, the authors suggest an initial insulin regimen that can be used to evaluate individual responsiveness and plan a long-term regimen. [References: 54]
Reinstein, E. and A. Ciechanover (2006). "Narrative review: protein degradation and human diseases: the ubiquitin connection." Annals of Internal Medicine 145(9): 676-684.
Between the 1950s and 1980s, many scientists focused on the process by which the genetic code is translated into proteome. However, little attention was devoted to the mechanism responsible for protein degradation. When researchers discovered the organelle lysosome, they assumed that cellular proteins were degraded within it. However, several independent lines of evidence strongly suggested that intracellular proteolysis was largely nonlysosomal. The discovery of the ubiquitin proteasome system (UPS) resolved this enigma. It is now recognized that degradation of intracellular proteins by the UPS is involved in the regulation of a broad array of cellular processes, including cell-cycle division; DNA repair, growth, and differentiation; quality control; and regulation of membrane receptors and ion channels. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of numerous human diseases, and it seems that pharmacologic manipulation of the UPS might alter the outcome of many diseases, especially malignant conditions and possibly neurodegenerative and chronic inflammatory diseases. These findings have led to increasing efforts to develop mechanism-based drugs that modulate UPS activity, one of which is already on the market. In the near future, one can expect to see the development of new, potent, and highly specific drugs that target the degradation pathways of a single or a few proteins without affecting other proteins. [References: 76]
Shanafelt, T. D., J. C. Byrd, et al. (2006). "Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia." Annals of Internal Medicine 145(6): 435-447.
Chronic lymphocytic leukemia is one of the most common malignant lymphoid diseases in the western world and is frequently diagnosed by internists. There have been clinically significant changes in method of diagnosis, prognostic tools, supportive care, and treatment over the past 2 decades. Most patients with chronic lymphocytic leukemia now have Rai stage 0 or I disease at diagnosis. Patients with early-stage disease are a heterogeneous group: Approximately 30% to 50% will have accelerated disease progression, and the remainder may live for decades and possibly never require therapy. Recent insights into the biological characteristics of leukemic B cells have led to the discovery of new prognostic tools (immunoglobulin variable-region heavy chain gene mutation status, cytogenetic abnormalities assessed by fluorescent in situ hybridization, and Z-chain-associated protein kinase-70 protein expression) that can identify patients with early-stage disease who are at high risk for early disease progression. These tools allow physicians to individualize counseling, follow-up, and management on the basis of disease risk. In addition, new treatments developed over the past 2 decades (purine nucleoside analogues, monoclonal antibodies, and combination chemoimmunotherapy regimens) have dramatically improved response rates and appear to prolong survival. In this review, the authors discuss the current work-up of lymphocytosis and highlight how to use recently identified prognostic tools to stratify risk in patients with newly diagnosed, early-stage chronic lymphocytic leukemia. Recommendations for patient counseling, follow-up, supportive care, and initial treatment are presented for each risk category. [References: 90]
Spies, C. and R. G. Trohman (2006). "Narrative review: Electrocution and life-threatening electrical injuries." Annals of Internal Medicine 145(7): 531-537.
The authors reviewed the mechanisms and pathophysiology of typically encountered electrical injuries by searching English-language publications listed in MEDLINE and reference lists from identified articles. They included relevant retrospective studies, case reports, and review articles published between 1966 and 2005. The authors also searched the Internet for information related to electrocution and life-threatening electrical injuries. They found that familiarity with basic principles of physics elucidates the typical injuries sustained by patients who experience electrical shock. Death due to electrocution occurs frequently. However, patients successfully resuscitated after cardiopulmonary arrest often have a favorable prognosis. Approximately 3000 patients who survive electrical shock are admitted to specialized burn units annually. Patients with serious electrical burns admitted to the intensive care unit are trauma patients and should be treated accordingly. Initial prediction of outcome for patients who have experienced electrical shock is difficult, as the full degree of injury is often not apparent. [References: 65]
Steinman, M. A., L. A. Bero, et al. (2006). "Narrative review: the promotion of gabapentin: an analysis of internal industry documents." Annals of Internal Medicine 145(4): 284-293.
BACKGROUND: Internal documents from the pharmaceutical industry provide a unique window for understanding the structure and methods of pharmaceutical promotion. Such documents have become available through litigation concerning the promotion of gabapentin (Neurontin, Pfizer, Inc., New York, New York) for off-label uses. PURPOSE: To describe how gabapentin was promoted, focusing on the use of medical education, research, and publication. DATA SOURCES: Court documents available to the public from United States ex. rel David Franklin vs. Pfizer, Inc., and Parke-Davis, Division of Warner-Lambert Company, mostly from 1994-1998. DATA EXTRACTION: All documents were reviewed by 1 author, with selected review by coauthors. Marketing strategies and tactics were identified by using an iterative process of review, discussion, and re-review of selected documents. DATA SYNTHESIS: The promotion of gabapentin was a comprehensive and multifaceted process. Advisory boards, consultants meetings, and accredited continuing medical education events organized by third-party vendors were used to deliver promotional messages. These tactics were augmented by the recruitment of local champions and engagement of thought leaders, who could be used to communicate favorable messages about gabapentin to their physician colleagues. Research and scholarship were also used for marketing by encouraging "key customers" to participate in research, using a large study to advance promotional themes and build market share, paying medical communication companies to develop and publish articles about gabapentin for the medical literature, and planning to suppress unfavorable study results. LIMITATIONS: Most available documents were submitted by the plaintiff and may not represent a complete picture of marketing practices. CONCLUSION: Activities traditionally considered independent of promotional intent, including continuing medical education and research, were extensively used to promote gabapentin. New strategies are needed to ensure a clear separation between scientific and commercial activity. [References: 124]
Ting, H. H., E. H. Yang, et al. (2006). "Narrative review: reperfusion strategies for ST-segment elevation myocardial infarction." Annals of Internal Medicine 145(8): 610-617.
Optimal treatment for ST-segment elevation myocardial infarction depends on early diagnosis and rapid selection of the appropriate reperfusion strategy. Primary percutaneous coronary intervention (PCI) is the preferred reperfusion strategy at PCI-capable hospitals. For hospitals without PCI capability, there are 2 reperfusion strategies, primary PCI and thrombolytic therapy, which are both supported by clinical evidence and national guidelines. Transferring patients for primary PCI may cause delays and requires established, proven protocols, systems, and networks to achieve minimal door-to-balloon times. The authors review the available data and present a systematic, evidence-based approach in a simple framework to enable noncardiovascular and cardiovascular physicians to select the optimal reperfusion strategy. The framework is based on available data from clinical trials and local circumstances from clinical practice by incorporating duration of symptoms (fixed ischemia time) and anticipated transport delays to a PCI-capable facility (incurred ischemia time). [References: 72]
Tung, R., S. Kaul, et al. (2006). "Narrative review: drug-eluting stents for the management of restenosis: a critical appraisal of the evidence." Annals of Internal Medicine 144(12): 913-919.
Interventional cardiologists have quickly replaced bare metal stents with intravascular drug-eluting stents for treating and preventing restenosis, largely on the basis of empirical evidence that shows profound reduction in angiographic and clinical restenosis. A critical reassessment of the published evidence, however, suggests that the putative superiority of intravascular drug-eluting stents is founded on questionable premises, including 1) overestimation of restenosis benefit, 2) underestimation of the risk for stent thrombosis, 3) overreliance on "soft" rather than "hard" outcomes (need for repeated revascularization vs. death or myocardial infarction), and 4) the attendant overestimation of cost-effectiveness. Because the long-term incremental risks, benefits, and costs of drug-eluting stents have not yet been optimally evaluated in a broad spectrum of patient and lesion cohorts, the rational role of these devices in clinical management warrants reappraisal. [References: 34]
Umpierrez, G. E., D. Smiley, et al. (2006). "Narrative review: ketosis-prone type 2 diabetes mellitus." Annals of Internal Medicine 144(5): 350-357.
Several investigators have reported that more than half of African-American persons with new diagnoses of diabetic ketoacidosis have clinical, metabolic, and immunologic features of type 2 diabetes during follow-up. These patients are usually obese, have a strong family history of diabetes, have a low prevalence of autoimmune markers, and lack a genetic association with HLA. Their initial presentation is acute, with a few days to weeks of polyuria, polydipsia, and weight loss and lack of a precipitating cause of metabolic decompensation. At presentation, they have markedly impaired insulin secretion and insulin action, but intensified diabetic management results in significant improvement in beta-cell function and insulin sensitivity sufficient to allow discontinuation of insulin therapy within a few months of follow-up. On discontinuation of insulin therapy, the period of near-normoglycemic remission may last for a few months to several years. The absence of autoimmune markers and the presence of measurable insulin secretion have proven useful in predicting near-normoglycemic remission and long-term insulin dependence in adult patients with a history of diabetic ketoacidosis. This clinical presentation is commonly reported in African and African-American persons but is also observed in Hispanic persons and those from other minority ethnic groups. The underlying mechanisms for beta-cell dysfunction in ketosis-prone type 2 diabetes are not known; however, preliminary evidence suggests an increased susceptibility to glucose desensitization. [References: 76]
Alaedini, A. and P. H. R. Green (2005). "Narrative review: celiac disease: understanding a complex autoimmune disorder." Annals of Internal Medicine 142(4): 289-298.
Celiac disease is a common autoimmune disorder that has genetic, environmental, and immunologic components. It is characterized by an immune response to ingested wheat gluten and related proteins of rye and barley that leads to inflammation, villous atrophy, and crypt hyperplasia in the intestine. The disease is closely associated with genes that code for human leukocyte antigens DQ2 and DQ8. Transglutaminase 2 appears to be an important component of the disease, both as a deamidating enzyme that can enhance the immunostimulatory effect of gluten and as a target autoantigen in the immune response. Sensitive and specific serologic tests, including those for anti-transglutaminase antibody, are facilitating fast and noninvasive screening for celiac disease. Thus, they are contributing to a more accurate estimate of the prevalence of the disease and its association with other disorders. Celiac disease is associated with increased rates of anemia, osteoporosis, cancer, neurologic deficits, and additional autoimmune disorders. A gluten-free diet is the mainstay of safe and effective treatment of celiac disease, although its effect on some of the extraintestinal manifestations of the disease remains to be determined. [References: 122]
Eisen, G. M. and D. S. Weinberg (2005). "Narrative review: screening for colorectal cancer in patients with a first-degree relative with colonic neoplasia." Annals of Internal Medicine 143(3): 190-198.
Many patients and providers are aware that colorectal cancer (CRC) "runs in families." A patient with 1 first-degree relative with CRC has approximately twice the personal risk for CRC as a similar person without this family history. Colorectal cancer is the third most common type of cancer in the United States. When providers neglect to collect information on family history, they may fail to appropriately tailor recommendations for screening for CRC for many patients. This review considers the existing data and summarizes an evidence-based approach to the common clinical problem of how and when to implement screening for CRC in a patient with a family history of colonic neoplasia. The authors discuss the varying risks for CRC given the patient's age, health habits, and personal and family histories. In the context of a clinical case that focuses on the effect of a single affected first-degree relative, the authors weigh the risks and benefits of various screening alternatives and briefly address chemoprevention, genetic testing, and future directions in screening for CRC.
Falagas, M. E. and P. I. Vergidis (2005). "Narrative review: diseases that masquerade as infectious cellulitis." Annals of Internal Medicine 142(1): 47-55.
For cellulitis that does not respond to conventional antimicrobial treatment, clinicians should consider, among other explanations, several noninfectious disorders that might masquerade as infectious cellulitis. Diseases that commonly masquerade as this condition include thrombophlebitis, contact dermatitis, insect stings, drug reactions, eosinophilic cellulitis (the Wells syndrome), gouty arthritis, carcinoma erysipelatoides, familial Mediterranean fever, and foreign-body reactions. Diseases that uncommonly masquerade as infectious cellulitis include urticaria, lymphedema, lupus erythematosus, sarcoidosis, lymphoma, leukemia, Paget disease, and panniculitis. Clinicians should do an initial diagnostic work-up directed by the findings from a detailed history and complete physical examination. In many cases, skin biopsy is the only tool that helps identify the correct diagnosis. Special tests may also be needed. [References: 126]
Jeremias, A. and C. M. Gibson (2005). "Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded." Annals of Internal Medicine 142(9): 786-791.
Current guidelines for the diagnosis of non-ST-segment elevation myocardial infarction are largely based on an elevated troponin level. While this rapid and sensitive blood test is certainly valuable in the appropriate setting, its widespread use in a variety of clinical scenarios may lead to the detection of troponin elevation in the absence of thrombotic acute coronary syndromes. Many diseases, such as sepsis, hypovolemia, atrial fibrillation, congestive heart failure, pulmonary embolism, myocarditis, myocardial contusion, and renal failure, can be associated with an increase in troponin level. These elevations may arise from various causes other than thrombotic coronary artery occlusion. Given the lack of any supportive data at present, patients with nonthrombotic troponin elevation should not be treated with antithrombotic and antiplatelet agents. Rather, the underlying cause of the troponin elevation should be targeted. However, troponin elevation in the absence of thrombotic acute coronary syndromes still retains prognostic value. Thus, cardiac troponin elevations are common in numerous disease states and do not necessarily indicate the presence of a thrombotic acute coronary syndrome. While troponin is a sensitive biomarker to "rule out" non-ST-segment elevation myocardial infarction, it is less useful to "rule in" this event because it may lack specificity for acute coronary syndromes. [References: 48]
Sanderson, S., J. Emery, et al. (2005). "Narrative review: aspirin resistance and its clinical implications." Annals of Internal Medicine 142(5): 370-380.
Aspirin is currently the most cost-effective drug for the secondary prevention of cardiovascular disease, but treatment failures are relatively common. Several factors have been linked to these recurrent vascular events in patients prescribed aspirin, including smoking, drug interactions, nonadherence, comorbid conditions, and aspirin resistance. The term aspirin resistance has been used to describe not only an absence of the expected pharmacologic effects of aspirin on platelets but also poor clinical outcomes, such as recurrent vascular events, in patients treated with aspirin. Aspirin resistance is perhaps more precisely understood as the phenomenon of measurable, persisting platelet activation that occurs in patients prescribed a therapeutic dose of aspirin and may underlie an unknown proportion of aspirin treatment failures. Key challenges for future research are to standardize a definition of aspirin resistance and to compare whether different measures of platelet activation, either alone or in combination, independently predict cardiovascular events. These challenges must be met before researchers conduct studies to assess the clinical utility of testing on patient outcomes and cost-effective prescribing. [References: 68]
Yan, A. T., R. T. Yan, et al. (2005). "Narrative review: pharmacotherapy for chronic heart failure: evidence from recent clinical trials." Annals of Internal Medicine 142(2): 132-145.
Heart failure is an important cause of morbidity and mortality. Clinical trials over the past 2 decades have revolutionized the care of patients with systolic heart failure, and substantial data support the use of angiotensin-converting enzyme inhibitors, beta-blockers, angiotensin-receptor blockers, and aldosterone blockers in the management of this serious condition. This article reviews the evidence on the pharmacologic treatment of heart failure, with a focus on recent clinical trials. [References: 149]
Tolman, K. G., V. Fonseca, et al. (2004). "Narrative review: hepatobiliary disease in type 2 diabetes mellitus." Annals of Internal Medicine 141(12): 946-956.
Diabetes mellitus is the fifth leading cause of death in the United States; 17 million people are affected. Liver disease is one of the leading causes of death in persons with type 2 diabetes. The standardized mortality rate for death from liver disease is greater than that for cardiovascular disease. The spectrum of liver disease in type 2 diabetes ranges from nonalcoholic fatty liver disease to cirrhosis and hepatocellular carcinoma. The incidence of hepatitis C and acute liver failure is also increased. Nonalcoholic fatty liver disease is now considered part of the metabolic syndrome, and, with alcohol and hepatitis C, is the most common cause of chronic liver disease in the United States. Weight reduction and exercise are the mainstays of treatment for nonalcoholic fatty liver disease, but there are promising results with the new thiazolidinediones (pioglitazone and rosiglitazone) as well as metformin and 3-hydroxy-3-methylglutaryl coenzyme A inhibitors. [References: 150]
Andreoli, T. E. (2001). "Arrhythmias: introductory comments." The American Journal of Medicine 110(1): 49-49.
This issue of the American Journal of Medicine contains the first of a group of articles in the “Physiology in Medicine” series that will focus on arrhythmias. About a century ago, little was known about arrhythmias except for the notion of so-called “circus movements.” The earliest examples of the latter were drawn from experiments on the Portuguese man-of-war. A burn on the mantle of a man-of-war followed by electrical stimulation of the mantle produced what are now recognized as the requisite characteristics for a circus, or reentrant, arrhythmia: a single excitatory beat with different rates of radial propagation so that annular conduction occurs. In his classic 1933 textbook Diseases of the Heart(New York: MacMillan), Sir Thomas Lewis described circus rhythm as accounting for atrial fibrillation, but no information was available about the actual pathways for conduction.It is reasonable to argue that modern electrophysiology began with the triumphant experiments of Hodgkin and Huxley, culminating in their classic series of papers (for which they were awarded the Nobel Prize) in 1952 in which they described voltage-gated ionic channels and the ways in which these channels produced impulse propagation in excitable tissues. The channels Hodgkin and Huxley dealt with in exquisitely quantitative detail were sodium channels and potassium channels. There followed Sir Bernard Katz’ description of voltage-gated calcium channels, thus setting much of the stage, again at a membrane but not molecular level, for understanding arrhythmias. By the early 1970s, it was well known that impulse formation in the sinus node and in the atrioventricular node was regulated by voltage-gated calcium channels, while the spread of the cardiac impulse in atrial musculature and in the Purkinje system occurred by way of voltage-gated sodium channels.In the last 2 decades, the explosion of knowledge at the molecular level with the cloning and description of the structure of, in particular, voltage-gated sodium channels, potassium channels, and calcium channels has provided us with insights into the molecular mechanisms of arrhythmia formation. Thus, this series provides an overview of the molecular biology of some of these channels; their role in arrhythmias; some specific derangements in channel molecular biology in certain arrhythmias; and the development of devices such as automatic implantable cardiac defibrillators (AICDs) for the treatment of cardiac arrhythmias.The series begins with an article by M. G. Sanguinetti from the University of Utah on the role of calcium channels in the pathogenesis of cardiac arrhythmias. The second article, a close companion to the first, is by C. W. Balke of the University of Maryland School of Medicine and focuses on the molecular biology of calcium channels. The third article, by A. O. Grant of Duke University, considers the molecular biology of sodium channels and how sodium channels are involved directly in cardiac arrhythmias.The fourth article in the series, by J. A. Towbin of the Baylor College of Medicine, deals with the family of disorders grouped under the term “prolonged QT syndromes,” and the molecular biology of some of these disorders. In subsequent articles, G. V. Naccarelli of Penn State University discusses the molecular biology of the Brugatta syndrome, and E. N. Prystowsky of St. Vincent Hospital, Indianapolis, provides an overview of derangements of channel biology in arrhythmias.Finally, the series closes with an article by M. Estes of Tufts University on implantable devices such as AICDs in the management of arrhythmias. This article will also provide insights into the emerging new strategies for the therapy of arrhythmias.
Grant, A. O. (2001). "Molecular biology of sodium channels and their role in cardiac arrhythmias." The American Journal of Medicine 110(4): 296-305.
The sodium channel is an integral membrane protein that plays a central role in conduction of the cardiac impulse in working cardiac myocytes and cells of the His-Purkinje system. The channel has two fundamental properties, ion conduction and gating. Specific domains of the channel protein control each of these functions. Ion conduction describes the mechanisms of the selective movement of sodium ion across the pore in the cell membrane. The selectivity of the channel for sodium ions is at least 10 times greater than that for other monovalent cations; the channel does not normally conduct divalent cations. Gating describes the opening and closing of the sodium channel pore. Sodium channels open transiently during membrane depolarization and close by a process termed inactivation. The cardiac sodium channel protein is a multimeric complex consisting of an [alpha] and an auxiliary [beta]-subunit. The genes encoding the sodium channel have been cloned and sequenced. The [alpha] subunit gene, SCN5A is sufficient to express a functional channel. However, [beta] subunit co-expression increases the level of channel expression and alters the voltage dependence of inactivation. Mutations of the sodium channel may result in incomplete inactivation during maintained depolarization, a decrease in the level of channel expression or acceleration of inactivation. The resulting clinical phenotypes include long QT syndrome, type III (LQT III), Brugada syndrome, and heart block. LQT III and Brugada syndromes have a high case fatality rate and are best treated with an implantable defibrillator.
Naccarelli, G. V. and C. Antzelevitch (2001). "The Brugada syndrome: clinical, genetic, cellular, and molecular abnormalities." The American Journal of Medicine 110(7): 573-581.
The Brugada syndrome is an arrhythmic syndrome characterized by a right bundle branch block pattern and ST segment elevation in the right precordial leads of the electrocardiogram in conjunction with a high incidence of sudden death secondary to ventricular tachyarrhythmias. No evidence of structural heart disease is noted during diagnostic evaluation of these patients. In 25% of families, there appears to be an autosomal dominant mode of transmission with variable expression of the abnormal gene. Mutations have been identified in the gene that encodes the alpha subunit of the sodium channel (SCN5A) on chromosome 3. This genetic defect causes a reduction in the density of the sodium current and explains the worsening of the above electrocardiographic abnormalities when patients are treated with sodium channel blocking antiarrhythmic agents, which further diminish the already reduced sodium current. The prognosis is poor with up to a 10% per year mortality. Antiarrhythmic drugs including beta-blockers and amiodarone have no benefit in prolonging survival. The treatment of choice is the insertion of an implantable cardioverter-defibrillator.
Shorofsky, S. R. and C. W. Balke (2001). "Calcium currents and arrhythmias: insights from molecular biology." The American Journal of Medicine 110(2): 127-140.
Calcium channels are critical to normal cardiac function. They are involved in the generation and conduction of the action potential and in contraction. Three surface membrane channels have been identified. The L-type Ca channel is most abundant and is responsible for Ca entry into the cell that triggers contraction. T-type Ca channels are most prevalent in the conduction system and are probably involved in automaticity. A newly described TTX-sensitive calcium current may be important in "boosting" or enhancing conduction and contraction. The main intracellular Ca channel resides in the sarcoplasmic reticulum and is responsible for the release of the Ca that activates contraction. Oscillatory behavior of this channel influences the sarcolemmal membrane, causing delayed aftercontractions and arrhythmias such as those seen in digoxin toxicity. The on-going molecular characterization of these channels will enhance our knowledge of their normal function and dysfunction in disease states, leading to the development of new therapeutic agents to treat arrhythmias and contractile dysfunction.
Towbin, J. A. and M. Vatta (2001). "Molecular biology and the prolonged QT syndromes." The American Journal of Medicine 110(5): 385-398.
The prolonged QT syndromes are characterized by prolongation of the QT interval corrected for heart rate (QTc) on the surface electrocardiogram associated with T-wave abnormalities, relative bradycardia, and ventricular tachyarrhythmias, including polymorphic ventricular tachycardia and torsades de pointes. These patients tend to present with episodes of syncope, seizures, or sudden death typically triggered by exercise, emotion, noise, or, in some cases, sleep. These disorders of cardiac repolarization are commonly inherited, with the autosomal dominant form, Romano-Ward syndrome, mostcommon. A rare autosomal recessive form associated with sensorineural deafness, Jervell and Lange-Nielsen syndrome, in which the cardiac disorder is autosomal dominant and deafness is a recessive trait, also occurs. The underlying genetic causes of these forms of prolonged QT interval syndromes are heterogeneous, with at least seven genes responsible for the clinical syndromes. All of the five genes identified to date encode ion channel proteins, suggesting this to be an ion channelopathy. In this review, the genetic basis of the prolonged QT interval syndromes will be discussed, genotype-phenotype correlations identified, and the approaches to genetic testing and treatments will be outlined.
Tristani-Firouzi, M., J. Chen, et al. (2001). "Molecular biology of K+ channels and their role in cardiac arrhythmias." The American Journal of Medicine 110(1): 50-59.
The configuration of cardiac action potentials varies considerably from one region of the heart to another. These differences are caused by differential cellular expression of several types of K+ channel genes. The channels encoded by these genes can be grouped into several classes depending on the stimulus that permits the channels to open and conduct potassium ions. K+ channels are activated by changes in transmembrane voltage or binding of ligands. Voltage-gated channels are normally the most important players in determining the shape and duration of action potentials and include the delayed rectifiers and the transient outward potassium channels. Ligand-gated channels include those that probably have only minor roles in shaping repolarization under normal conditions but, when activated by extracellular acetylcholine or a decrease in the intracellular concentration of ATP, can substantially shorten action potential duration. Inward rectifier K+ channels are unique in that they are basically stuck in the open state but can be blocked in a voltage-dependent manner by intracellular Mg2+, Ca2+, and polyamines. Other K+ channels have been described that provide a small background leak conductance. Many of these cardiac K+ channels have been cloned in the past decade, permitting detailed studies of the molecular basis of their function and facilitating the discovery of the molecular basis of several forms of congenital arrhythmias. Drugs that block cardiac K+ channels and prolong action potential duration have been developed as antiarrhythmic agents. However, many of these same drugs, as well as other common medications that are structurally unrelated, can also cause long QT syndrome and induce ventricular arrhythmia.