Pathophysiology and medical management of systemic hypertension and pre-eclampsia in pregnancy.

Hypertension in pregnancy includes a group of distinct disorders that require special consideration in both prevention and pharmacological treatment. In recent years, there have been few advances regarding the pathophysiology and prevention of pre-eclampsia, however there have been some promising studies regarding possible modes of screening women for preeclampsia before clinical signs and symptoms are apparent. The recommendations for first-line drug therapy for the hypertensive complications of pre-eclampsia, and the recommendations for pharmacological treatment of women with chronic hypertension antedating pregnancy, have changed little primarily because first-line medications have the advantage of having had more extensive research experience. Recent clinical trials have demonstrated the efficacy and safety of various second-line drugs for the hypertensive disorders of pregnancy; whether these therapies can eventually replace the standard recommended medications will require more extensive long-term investigation.

One-year study of felodipine or placebo for stage 1 isolated systolic hypertension.

Asubstantial number of older hypertensive patients have stage 1 isolated systolic hypertension (systolic blood pressure between 140 and 159 mm Hg and diastolic blood pressure <90 mm Hg), but there are currently no data showing that drug treatment is effective, safe, and/or beneficial. To compare the effects of active treatment compared with placebo on blood pressure, left ventricular hypertrophy, and quality of life among older stage 1 isolated systolic hypertensive patients, a randomized, double-blind, parallel-group, multicenter clinical trial comparing felodipine (2.5, 5, or 10 mg once daily) and matching placebo was performed in 171 patients (49% male, average age 66+/-7 years, with 49% white and 30% Hispanic) with a baseline blood pressure of 149+/-7/83+/-6 mm Hg. During 52 weeks of treatment, patients randomized to active treatment achieved significantly lower blood pressures (137.0+/-11.7/80.2+/-7.6 mm Hg for extended-release felodipine versus 147.5+/-16.0/83.5+/-9.7 mm Hg for placebo, P<0.01 for each), a reduced incidence of left ventricular hypertrophy (7% for extended release felodipine versus 24% for placebo, P<0.04), and improved quality of life (change in Psychological General Well-Being index, 3.0+/-6.8 for extended-release felodipine versus -0.8+/-10.3 for placebo, P<0.01) versus baseline. There were no clinically significant differences between treatments in tolerability or adverse effects. Stage 1 isolated systolic hypertension can be effectively and safely treated pharmacologically. Treatment reduced progression to the higher stages of hypertension, reduced the incidence of left ventricular hypertrophy, and improved an overall measure of the quality of life. Larger and longer studies will be needed to document any long-term reduction in cardiovascular event rates associated with treating stage 1 systolic hypertension.

Antioxidant vitamins and enzymatic and synthetic oxygen-derived free radical scavengers in the prevention and treatment of cardiovascular disease.

Oxygen-derived free radical formation can lead to cellular injury and death. Under normal situations, the human body has a free radical scavenger system (catalase, superoxide dismutase) that can detoxify free radicals. Antioxidant vitamins and enzymatic and synthetic oxygen-derived free radical scavengers have been used clinically to prevent the formation of oxidized LDL and to prevent reperfusion injury, which is often caused by free radicals. In this article, the pathogenesis of free radical production and cell injury are discussed, and therapeutic approaches for disease prevention are presented.

Innovative pharmacologic approaches to cardiopulmonary resuscitation.

The survival rate of patients undergoing cardiopulmonary resuscitation is 5 to 15%. New cardiopulmonary resuscitation treatment approaches under investigation include the use of vasopressin as a vasopressor, amiodarone for the treatment of ventricular tachyarrhythmias, and adenosine antagonists (i.e., theophylline) for bradyasystolic rhythms. More innovative approaches include the use of thyroid hormone and endothelin.

Unstable angina pectoris and non-Q-wave myocardial infarction.

Unstable angina pectoris and non-Q-wave myocardial infarction are clinical syndromes that share many pathophysiologic and clinical features. In the spectrum of coronary artery disease, these syndromes lie between chronic stable angina and Q-wave myocardial infarction. Although both conditions are associated with significant morbidity and mortality, patients presenting with these syndromes can be further risk stratified into higher and lower risk based on a number of readily available clinical features and biochemical parameters. Such risk stratification can allow for more tailored treatment and better resource allocation. Although routine early coronary angiography and revascularization has not been shown to be superior to conservative management, certain high-risk patients may benefit from a more aggressive strategy. Medical therapy with the use of antiplatelet, anticoagulant, and antiischemic agents remains the cornerstone of emergent treatment for patients presenting with these syndromes. The recent demonstration of a reduction in both morbidity and mortality with the glycoprotein IIb/IIIa antagonists has further expanded the armamentarium of available agents. Following initial stabilization, risk stratification with stress testing can help identify patients with a large residual ischemic burden who may benefit from coronary angiography with revascularization if feasible.

Student research projects and theses: should they be a requirement for medical school graduation?

From 1981 to 1994, 69 fourth-year students at the Albert Einstein College of Medicine participated in a 6-month medical school research project (MSRP) with the same mentor. Students could choose an original project or library project, and were required to prepare a written report suitable for submission to a peer-reviewed journal. In this article, it is assessed whether a mandatory fourth-year MSRP might substitute for traditional clinical electives. Student reactions to the experience were ascertained by using the responses to an open- and closed-ended questionnaire regarding skills gained by doing MSRPs, the impact on their careers, and their relationship to the mentor. Eighty-nine percent of the students responded that MSRPs increased their ability to formulate a hypothesis, 91% reported that this project increased their ability to conduct a literature search, 95% felt that MSRPs increased their knowledge of research techniques, and 91% reported having improved data collection skills after completing these projects. Students also reported that MSRPs increased their ability to critically evaluate the literature (95%) or to work independently (93%), and 89% responded that the project improved their ability to evaluate their individual strengths and weaknesses. Eighty-nine percent reported that the project increased their ability to write a research paper (34% of projects were original research, 35% were literature reviews, and 30% both original research and literature reviews). Thirty-three percent of respondents reported having some kind of problem completing their projects, and 90% of project reports were accepted for publication in peer-reviewed journals. Ninety-one percent of students responded that they had received appropriate guidance from their mentor, and 73% met with him at least once a week. Seventy-three percent described a relationship with the mentor that went beyond project advising. Eighty-five percent responded that the project impacted their careers in medicine, 97% felt that the research experience was a useful replacement for fourth-year electives, and 91% felt they were as well prepared for residency training as their classmates who had regular fourth-year electives without research. Fifty percent of students indicated that completion of an independent research project should not be required for graduation, whereas 18% responded it should be a requirement and 32% were undecided. Incorporating an MSRP in the fourth year appears to increase research skills and is considered to be a useful replacement for traditional elective rotations. The MSRP impacts favorably on future careers; however, many students do not think it should be a mandatory requirement for graduation from medical school.

Cardiovascular considerations with anthracycline use in patients with cancer.

Anthracyclines are important chemotherapeutic agents that are used for the treatment of various malignancies in both adults and children, but their usefulness has been limited by cardiotoxicity that is usually dose related. Oxidative injury appears to be the cause of myocardial dysfunction when using these drugs. Screening for early myocardial injury with troponin testing, echocardiography, and radionuclide examinations has reduced the incidence of chronic cardiac dysfunction. Various anthracycline analogues have been developed that have less cardiotoxicity. Dexrazoxane, an iron chelator, and the radioprotective agent amifostine protect against cardiac injury, thus allowing the use of higher doses of anthracyclines. Other strategies that have been evaluated are dietary glutamine supplementation and the use of the antioxidant probucol.

Endothelin as a therapeutic target in the treatment of cardiovascular disease.

Endothelins, a family of peptides derived from the vascular endothelium and smooth muscle cells possess vasoconstrictor and mitogenic properties. By acting predominantly in a paracrine fashion, these peptides activate specific receptors and have protean effects in normal and diseased organ systems. The wide distribution of these receptors in various tissues mediate the multiplicity of physiologic actions attributed to endothelins. Much of our understanding about endothelins has come from the development of an array of receptor-specific and mixed receptor antagonists. Based on the promising results from animal studies, active research and drug development programs are under way to investigate the clinical potential of endothelin antagonism for treatment of cardiovascular disease.

Ticlopidine-associated thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura is a rare complication of ticlopidine treatment. This syndrome has been reported to occur typically within the first few weeks after the initiation of therapy. The authors describe a case of a 72-year-old woman in whom thrombotic thrombocytopenic purpura developed just 2 days after starting ticlopidine therapy for a new-onset ischemic stroke. The patient responded successfully to plasmapheresis. The authors are reporting this case to emphasize the unpredictable nature of the association between the drug and the disease, which necessitates careful hematologic monitoring.

Alternative approaches to the medical management of angina pectoris: acupuncture, electrical nerve stimulation, and spinal cord stimulation.

Complementary or alternative modalities of medical treatment have been gaining attention as primary or supplementary therapies in cardiovascular disease pain management. However, definitive research in these areas has been limited by the inability to perform placebo-controlled trials when evaluating these treatments. Preliminary studies have suggested a possible benefit from acupuncture, electrical nerve stimulation, and spinal cord stimulation in the treatment of patients with angina pectoris and coronary artery disease.

Inhibition of myocardial apoptosis as a therapeutic target in cardiovascular disease prevention: focus on caspase inhibition.

Apoptosis is a type of programmed cell death that is evident during embryonic development and normal tissue turnover. When the apoptotic activity extends beyond physiologic limits, it can determine and/or contribute to those pathologic states characterized by excessive cell loss and impairment of organ function. The clinical development of caspase inhibitors may represent a potential therapeutic strategy for influencing the onset and progression of ventricular dysfunction to terminal failure. This article focuses on the caspase cascade, a fundamental enzymatic system for apoptotic cell death. Caspases do not constitute the death signals, but are implicated in their transmission. These cytoplasmic cysteine proteases have a dual role in apoptosis. Caspases can operate as initiators, activating an endonuclease that catalyzes deoxyribonucleic acid fragmentation. Alternatively, caspases can act as effectors, participating in the total disassembly of cell structures. For example, apoptosis represents the principal form of myocyte death in the region of an acute myocardial infarction. In addition, apoptosis in the region bordering the infarct can influence the development of ischemic cardiomyopathy and ventricular dilation.

The role of tumor necrosis factor in cardiac disease.

Tumor necrosis factor (TNF) is a proinflammatory cytokine that can produce widespread deleterious effects when expressed in large amounts. It is produced in the heart by both cardiac myocytes and resident macrophages under conditions of cardiac stress, and is thought to be responsible for many of the untoward manifestations of cardiac disease. This article discusses the role of TNF in heart disease and some potential therapeutic modalities that can influence the cytokine activity. The results of controlled studies would suggest that TNF inhibition does not influence the clinical course of patients with heart failure.

Systemic inflammation as a cardiovascular disease risk factor and as a potential target for drug therapy.

Inflammation-related processes play a key role the current etiologic model of atherosclerosis and its acute complications. Recent evidence suggests that blood-based biomarkers that reflect systemic inflammation may contribute to our ability to predict future risk of cardiovascular disease. Global markers of inflammation, such as C-reactive protein and fibrinogen, have been well studied as potential cardiovascular risk factors. A variety of additional markers that reflect various elements of the complex systems governing inflammation, including proinflammatory and antiinflammatory cytokines, mediators of cellular adhesion, and matrix degradation enzymes, are also worthy of study. Although many previous studies have examined the relation of inflammation to myocardial infarction, emerging evidence suggests that other cardiovascular phenotypes such as ischemic stroke and early-stage atherosclerosis may also be related to inflammation. Further elucidating the role of inflammation in cardiovascular disease may lead to the identification of new targets for preventive or therapeutic interventions. In addition, markers of inflammation may be useful as a means to predict or monitor an individual's response to currently available cardiovascular therapies, such as aspirin or HMG coenzyme A reductase inhibitors, that may act via antiinflammatory mechanisms.