Oligonucleotide-based gene therapy for cardiovascular disease

Gene therapy is emerging as a potential strategy for the treatment of cardiovascular disease such as restenosis after angioplasty, vascular bypass graft occlusion, transplant coronary vasculopathy, homozygous familial hypercholesterolemia and cystic fibrosis, for which no known effective therapy exists. Gene therapy requires efficient in vivo gene transfer technology. During the past decade, many gene transfer methods including viral transfer techniques have been developed, and some are being applied clinically in human gene therapy studies. Molecular biology and pathophysiology of the cardiovascular system have started to emerge, and the time is ripe for the introduction of gene therapy to the management of cardiovascular disorders. In this review, we have focused on the future potential of oligonucleotide-based gene therapy for the treatment of cardiovascular disease.     

Aspirin for primary prevention of cardiovascular events

OBJECTIVE: The use of aspirin for primary prevention of cardiovascular events in the general population is controversial. The purpose of this study was to create a versatile model to evaluate the effects of aspirin in the primary prevention of cardiovascular events in patients with different risk profiles. DESIGN: A Markov decision-analytic model evaluated the expected length and quality of life for the cohort's next 10 years as measured by quality-adjusted survival for the options of taking or not taking aspirin. SETTING: Hypothetical model of patients in a primary care setting. PATIENTS: Several cohorts of patients with a range of risk profiles typically seen in a primary care setting were considered. Risk factors considered included gender, age, cholesterol levels, systolic blood pressure, smoking status, diabetes, and presence of left ventricular hypertrophy. The cohorts were followed for 10 years. Outcomes were myocardial infarction, stroke, gastrointestinal bleed, ulcer, and death. MAIN RESULTS: For the cases considered, the effects of aspirin varied according to the cohort's risk profile. By taking aspirin, the lowest-risk cohort would be the most harmed with a loss of 1.8 quality-adjusted life days by taking aspirin; the highest risk cohort would achieve the most benefit with a gain of 11.3 quality-adjusted life days. Results without quality adjustment favored taking aspirin in all the cohorts, with a gain of 0.73 to 8.04 days. The decision was extremely sensitive to variations in the utility of taking aspirin and to aspirin's effects on cardiovascular mortality. The model was robust to other probability and utility changes within reasonable parameters. CONCLUSIONS: The decision of whether to take aspirin as primary prevention for cardiovascular events depends on patient risk. It is a harmful intervention for patients with no risk factors, and it is beneficial in moderate and high-risk patients. The benefits of aspirin in this population are comparable to those of other widely accepted preventive strategies. It is especially dependent on the patient's risk profile, patient preferences for the adverse effects of aspirin, and on the level of beneficial effects of aspirin on cardiovascular-related mortality.     

Postmenopausal hormone replacement therapy and cardiovascular disease

Cardiovascular disease is the leading cause of mortality in postmenopausal women in developed countries. A possible cardioprotective role of hormone replacement therapy (HRT) is suggested by epidemiologic studies of HRT and reduced risk of coronary heart disease, as well as by randomized trials of HRT and lipid subfractions. Estrogen has beneficial effects on the lipid profile, raising high-density lipoprotein cholesterol levels and reducing low-density lipoprotein cholesterol levels each by approximately 10%. Other possible biologic mechanisms include beneficial effects on vascular function, oxidative status, endothelial-dependent vasodilation, intimal hyperplasia and insulin sensitivity. Estrogen's net effects on coagulation and fibrinolysis are less clear. Estrogen replacement therapy is associated with decreased atherosclerosis in several animal models. However, most of the available data on HRT derive from observational studies or small randomized trials assessing biologic intermediates rather than clinical events. Further research, including large-scale randomized clinical trials, are required to evaluate definitively the role of estrogen replacement therapy, especially given uncertainties about the effects of combined estrogen-progestin therapy and the balance of benefits and risk of this common intervention in postmenopausal women.     

Aspirin use in middle-aged men with cardiovascular disease: are opportunities being missed?

BACKGROUND: Since the 1980s, clinical trial evidence has supported aspirin use in the secondary prevention of cardiovascular disease (CVD). AIM: To explore aspirin use among British men with known CVD in a population-based study. METHOD: Longitudinal study (British Regional Heart Study), in which subjects have been followed up for cardiovascular morbidity and mortality since 1978-1980. Aspirin use was assessed by questionnaires to study participants in November 1992 (Q92); cardiovascular diagnoses are based on general practice notifications to October 1992. A total of 5751 men aged 52-73 years (87% of survivors) completed questions on aspirin use. RESULTS: Overall, 547 men (9.5%) were taking aspirin daily, of whom 321 (59%) had documented CVD. Among men with pre-existing disease, 153 out of 345 (44%) men with myocardial infarction, 42 out of 109 (39%) with stroke, and 75 out of 247 (29%) with angina were taking aspirin daily. Among men with angina (54% versus 26%) or myocardial infarction (59% versus 42%), those who had undergone coronary artery bypass surgery (CABG) or angioplasty were more likely to be receiving aspirin. Higher rates of aspirin use were also found in those whose last major event occurred after January 1990 (47% versus 34%). There was no association between aspirin use and social class or region of residence. CONCLUSION: Despite strong evidence of its effectiveness, many patients with established CVD were not receiving aspirin. Daily aspirin treatment was less likely in men with less recent major CVD events and in those who had not received invasive treatment.     

Chronotherapeutics for cardiovascular disease

Chronotherapeutics, or delivery of a medication in concentrations that vary according to physiological need at different times during the dosage period, is a relatively new practice in clinical medicine. Epidemiological studies document that the incidence of many cardiovascular diseases, including myocardial infarction and stroke, varies predictably in time over 24 hours (the circadian period). Advanced diagnostic technologies using ambulatory monitoring of the blood pressure and electrocardiogram have also demonstrated that there is marked variability in the level of pressure in hypertensive patients and the degree of myocardial ischaemia in patients with coronary disease. These diagnostic techniques also allow us to study the effects of varying the timing of administration or delivery of a concentration of a drug on end-points such as changes in blood pressure, heart rate or intensity of angina. The first chronotherapeutic agent for hypertension and angina pectoris, controlled onset, extended release (COER-24) verapamil, has recently been developed and registered in the US, Brazil, Canada and Mexico. The theoretical advantage of this formulation is that delivery of the active drug, verapamil, has been tailored to the typical circadian rhythm of blood pressure and heart rate in patients with hypertension and angina to better cover the early morning hours when cardiovascular need appears to be the greatest. An outcome study (CONVINCE) that evaluates primary prevention of cardiovascular events with this chronotherapy versus standard of care therapy is under way in several countries in North and South America and Europe.     

Transdermal estrogen replacement therapy: beneficial effects on hemostatic risk factors for cardiovascular disease

OBJECTIVES: To assess the effect of estrogen replacement therapy on hemostatic risk factors for cardiovascular disease (CVD) in postmenopausal women during 2 years of treatment. METHODS: In an open prospective study, patients (n = 42) were investigated before and during 2 years of treatment, and compared to an untreated postmenopausal control group (n = 18) followed during the same period, healthy premenopausal women (n = 20) being included as a reference group for premenopausal values. The patients underwent treatment with transdermal 17 beta-estradiol (E2) (50 micrograms/24 h), oral medroxyprogesterone acetate (5 mg/day) being added for 12 days every second month. RESULTS: After 2 years of treatment there was a significant increase in t-PA antigen (P = 0.01) and a significant decrease in F VII antigen (P = 0.01). PAI-1 antigen concentrations decreased slightly. Fibrinogen concentrations were already significantly decreased at 3-month follow-up (P = 0.01), and were still low after 2 years. By contrast, at 2-year follow-up the postmenopausal control group manifested significant increases in F VII and PAI-1 antigen and slight increases in fibrinogen, which resulted in significant differences between patients and controls. Regression analysis showed the increase in the serum estradiol concentrations to be inversely correlated to the decreases in the plasma concentrations of F VII antigen (r = -0.34, P = 0.001) and fibrinogen (r = -0.35, P = 0.001). There were no changes in AT III or protein C in any group. CONCLUSIONS: The increase in serum estradiol concentrations due to replacement therapy did not adversely affect the studied components of the fibrinolytic and protein C defense system against thrombosis, and resulted in beneficial decreases in F VII antigen and fibrinogen. These findings may help to explain the beneficial effects of estrogen replacement therapy in terms of protection from cardiovascular disease.     

Reducing risk for cardiovascular disease.

The focus of this review article is to examine the importance of psychological and social factors in the development and maintenance of cardiovascular diseases, primarily coronary heart and artery disease, and to provide an overview of the effectiveness of psychosocial risk reduction interventions. First we summarize the prevalence and economic burden of cardiovascular disease, as well as the role of psychosocial factors in disease development and progression. We then examine the primary modifiable risk factors and evaluate the role of psychotherapists in the treatment of heart disease. Finally, we assess the effectiveness of risk factor modification and rehabilitation interventions, describe the potential costs and benefits of these programs, and discuss the role of primary prevention programs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Aspirin therapy in nonarteritic anterior ischemic optic neuropathy

Swiss mice fed commercial or elemental diets and an oral short-chain fatty acid (SCFA) solution or saline were treated with the cytostatic drug Ara-C (cytarabine, 3.6 mg/mouse/day) for two or four days. Histopathological examination revealed less damage (atrophy, inflammation, or necrosis) to the small intestine and colon caused by Ara-C when SCFA was administered. Accordingly, protein and nucleotide concentrations in the intestinal mucosa were higher in the group receiving SCFA than in the group receiving a placebo of the same pH and osmolarity. Improvement by SCFA treatment was correlated with an increase in the height of the intestinal villi, with no alterations of the crypts. Furthermore, the number of intraepithelial lymphocytes was similar to normal values in animals receiving SCFA and Ara-C. When large doses of SCFA were administered, xanthomized enterocytes appeared, suggesting an accumulation of fatty acids in these cells. We conclude that oral administration of SCFA at close to physiological proportions reduces the inflammation and necrosis caused by Ara-C administration, thus representing a potential factor for the improvement of patients with mucositis caused by cancer treatment.     

Lessons from human arteries: how to design a gene therapy strategy for treatment of cardiovascular disease

The histological and ultrastructural characteristics of an adenocarcinoma of the lung are described in an about 16-year-old female Steller sea lion with a 1.5 month history of cough and anorexia. The animal had multiple neoplastic nodules in the lungs and diaphragmatic pleura. The bronchial and mediastinal lymph nodes were replaced by neoplastic tissue, and there were several metastatic lesions in the liver and spleen. The lung tumor was characterized by accumulations of encapsulated lesions with central necrosis, and the neoplastic cells showing a papillary growth pattern produced small amounts of mucin. Ultrastructurally, some cells contained basal bodies, and cilia were rarely seen. This neoplasm was considered to be of ciliated bronchial or bronchiolar epithelium origin.     

Thrombosis and cardiovascular disease

The use of combinatorial chemistry for the generation of new lead molecules is now a well established strategy in the drug discovery process. Central to the use of combinatorial chemistry is the design and availability of high quality building blocks which are likely to afford hits from the libraries that they generate. Herein we describe "RECAP" (Retrosynthetic Combinatorial Analysis Procedure), a new computational technique designed to address this building block issue. RECAP electronically fragments molecules based on chemical knowledge. When applied to databases of biologically active molecules this allows the identification of building block fragments rich in biologically recognized elements and privileged motifs and structures. This allows the design of building blocks and the synthesis of libraries rich in biological motifs. Application of RECAP to the Derwent World Drug Index (WDI) and the molecular fragments/ building blocks that this generates are discussed. We also describe a WDI fragment knowledge base which we have built which stores the drug motifs and mention its potential application in structure based drug design programs.     

Hormone replacement therapy: cardiovascular benefits for aging women

Observational studies suggest that hormone replacement therapy (HRT) reduces the risk of coronary artery disease by approximately 50%. This review focuses on possible mechanisms for this reduction in disease risk. HRT reverses many of the lipid and lipoprotein change associated with menopause, and the route of hormone delivery influences these changes. Oral HRT improves serum markers of clotting, although it may increase the risk of deep vein thrombosis. Endothelial function, particularly endothelium-dependent vasodilation, improves with estrogen. Central body fat appears to be reduced with oral HRT, possibly reducing the risk of coronary artery disease. Insulin sensitivity, which worsens after menopause, may be improved with HRT. Global systolic function, as measured by ejection fraction, may improve with oral HRT. Understanding how HRT regimens influence cardiovascular risk may allow physicians to make intelligent choices about HRT for particular patients.     

Providing dental treatment for patients with cardiovascular disease

The appropriate management of dental patients with cardiovascular disease is contingent on appropriate assessment and evaluation. Baseline vital signs, a good medical history and medical evaluation are all essential for the safe delivery of care. All patients with cardiovascular disease can be managed using the following guidelines: 1. Properly assess the patient. This should include an assessment by the dentist and also a medical consultation if required. 2. Establish what medications the patient is taking along with the dose and timing and note any potential drug interactions and side effects. 3. Use short appointments (less than one hour), preferably in the morning. 4. Premedication should be considered to alleviate anxiety. The intraoperative use of nitrous oxide and oxygen is also a reasonable strategy for patients with cardiovascular disease, particularly those with ischemic heart disease. 5. Effective local anesthesia is important in order to avoid undue stress during the appointment as long as the guidelines for the administration of epinephrine are followed. The use of epinephrine impregnated gingival displacement cord should be strictly avoided in patients with cardiovascular disease. 6. For patients with angina pectoris, a fresh supply of nitroglycerin should be available at the time of the appointment. Prophylactic nitroglycerin has been shown to be effective in the prevention of both hypertension and angina pectoris during dental treatment. The appointment should be terminated early if the patient becomes overly anxious. In the event of cardiovascular symptoms during dental treatment, all work should be stopped. Emergency measures should be instituted if necessary. Preparations for emergencies should be undertaken by all dentists. The treatment of patients with cardiovascular disease is relatively simple if the proper steps are taken. The use of blood pressure measurements on all patients will help to screen for undiagnosed hypertension and all patients who are potentially hypertensive should be referred for medical evaluation. A preventive approach to the treatment of these patients will serve to prevent untoward outcomes and provide safe and simple delivery of dental care for cardiovascular patients.     

Hyperlipidaemia and cardiovascular disease

Seasonal variations in mood and behavior (seasonality) and seasonal affective disorder (SAD) have been attributed to seasonal fluctuations in brain serotonin (5-HT). the short (s), as opposed to the long (l), allele of the 5-HT transporter linked polymorphism (5-HTTLPR) has been associated with neuroticism and depression. We hypothesized that this short allele would also be associated with SAD and with higher levels of seasonality. Ninety-seven SAD patients and 71 non-seasonal healthy controls with low seasonality levels were genotyped for 5-HTTLPR and compared statistically. Patients with SAD were less likely to have the l/l genotype (27.8% vs 47.9%; P < 0.01) and more likely to have the s allele (44.8% vs 32.4%; P < 0.02) as compared to controls. The three 5-HTTLPR genotypes were also differentially distributed in patients and controls (P < 0.03). The SAD patients with the l/l genotype had a lower mean seasonality score than did patients with the other two genotypes (mean +/- s.d. = 15.3 +/- 2.8 vs 17.1 +/- 3.4 respectively; P < 0.02). The 5-HTTLPR short allele contributes to the trait of seasonality and is a risk factor for SAD, providing further evidence for a relationship between genetic variation in the 5-HT transporter (5-HTT) and behavior.