Gysèle S. Bleumink

Nonsteroidal Anti-Inflammatory Drugs and Heart Failure

Heart failure constitutes an increasing public health problem because of the growing incidence and prevalence, poor prognosis and high hospital (re)admission rates. Myocardial infarction is the underlying cause in the majority of patients, followed by hypertension, valvular heart disease and idiopathic cardio-myopathy.Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit the enzymes cyclo-oxygenase (COX) 1 and 2, have been associated with the occurrence of symptoms of heart failure in several case reports and quantitative studies, mainly in patients with a history of cardiovascular disease or left ventricular impairment. NSAIDs may impair renal function in patients with a decreased effective circulating volume by inhibiting prostaglandin synthesis. Consequently, water and sodium retention, and decreases in renal blood flow and glomerular filtration rate may occur, affecting the unstable cardiovascular homeostasis in these patients. In patients with pre-existing heart failure, this may lead to cardiac decompensation. Putative renal-sparing NSAIDs, such as COX-2 selective inhibitors have similar effects on renal function as the traditional NSAIDs, and can likewise be expected to increase the risk of heart failure in susceptible patients. NSAIDs are frequently prescribed to elderly patients, who are particularly at risk for the renal adverse effects. If treatment with NSAIDs in high risk patients cannot be avoided, intensive monitoring and patient education is important.

Treatment strategies, patterns of drug use and treatment discontinuation in men with LUTS suggestive of benign prostatic hyperplasia: The triumph project

OBJECTIVES We aimed to describe treatment strategies for lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH), adherence to and persistence with pharmacological treatment and the association between the type of LUTS/BPH complaints and early treatment discontinuation. METHODS Within a large GP database (IPCI) in the Netherlands we identified all males > or =45 years newly diagnosed with LUTS/BPH during 1995-2000. Details on treatment were assessed from the electronic patient records. Logistic regression analysis was used to estimate the association between the type of main urinary complaints and early treatment discontinuation. RESULTS Of the 2214 men with incident LUTS/BPH, 1075 received pharmacological treatment and 238 underwent prostate surgery. The average adherence differed slightly between drugs: 67% for alpha-blockers, 73% for 5alpha-reductase inhibitors and 71% for combination therapy. 26% of the treated patients discontinued treatment early. The probability of early discontinuation was higher if patients mainly expressed one type of complaint: voiding (OR(adj) 3.38; 95%CI: 1.89-6.04), post micturition (OR(adj) 2.37; 95%CI: 1.15-4.87) or storage symptoms (OR(adj) 1.85; 95%CI: 1.16-2.95) as compared to patients expressing a combination of symptoms. The risk of early discontinuation was higher if patients had a normal PSA measurement. Older age and a higher chronic disease score protected against early treatment discontinuation. CONCLUSIONS Almost half of newly diagnosed LUTS/BPH patients are pharmacologically treated, and a quarter discontinues very rapidly. Stopping early is more frequent among younger persons, persons with only one type of main urinary complaint, no other co-morbidity and a normal PSA.

The incidence of sudden cardiac death in the general population

BACKGROUND AND OBJECTIVES To determine the incidence of sudden cardiac death in a general (Dutch) population. METHODS Cohort study in the Integrated Primary Care Information (IPCI) project, a database with all medical data from 150 general practices in The Netherlands. The study population comprised 249,126 subjects with a mean follow-up of 2.54 years. RESULTS In this period 4,892 deaths were identified, 582 of which were classified as (probable) sudden cardiac death. The overall incidence of sudden cardiac death in this population was 0.92 cases per 1,000 person-years (95%CI: 0.85-0.99). The risk was 2.3-fold higher in men than in women, and increased with age. The incidence of sudden cardiac death peaked in October and was lowest in August. CONCLUSIONS The incidence of sudden cardiac death in the general Dutch population was almost 1 per 1,000 person-years per year during the period 1 January, 1995 to 1 April, 2001. Most of the cases occurred at home.

Genetic polymorphisms and heart failure

Heart failure is a complex clinical syndrome. There is evidence for a genetic contribution to the pathophysiology of heart failure. Considering the fundamental role of neurohormonal factors in the pathophysiology and progression of cardiac dysfunction and hypertrophy, variants of genes involved in this system are logical candidate genes in heart failure. In this report, genetic polymorphisms of the major neurohormonal systems in heart failure will be discussed. Studies on polymorphisms of the renin-angiotensin-aldosterone system (RAAS), adrenergic receptor polymorphisms, endothelin (receptor) polymorphisms, and a group of miscellaneous polymorphisms that may be involved in the development or phenotypic expression of heart failure will be reviewed. Research on left ventricular hypertrophy is also included. The majority of genetic association studies focused on the ACE I/D polymorphism. Initial genetic associations have often been difficult to replicate, mainly due to problems in study design and lack of power. Promising results have been obtained with genetic polymorphisms of the RAAS and sympathetic system. Considering the evidence so far, a modifying role for these polymorphisms seems more likely than a role of these variants as susceptibility genes. Besides the need for larger studies to examine the effects of single nucleotide polymorphisms and haplotypes, future studies also need to focus on the complexity of these systems and study gene-gene interactions and gene-environment interactions.

The risk of overanticoagulation in patients with heart failure on coumarin anticoagulants

Heart failure has been identified as a risk factor for increased coumarin anticoagulant responsiveness in several small‐scale experiments. Epidemiological studies quantifying the risk of overanticoagulation by heart failure in a non‐selected population on coumarins are scarce. Therefore, we investigated whether patients with heart failure have an increased risk of overanticoagulation and determined the effect of incidental heart failure on coumarin dose requirements. A cohort study of all patients was performed from an outpatient anticoagulation clinic treated with acenocoumarol or phenprocoumon between 1 January 1990 and 1 January 2000. All cohort members were followed until the first occurrence of an international normalized ratio (INR) ≥6·0, the last INR assessment, death, loss to follow‐up, or end of the study period. Of the 1077 patients in the cohort, 396 developed an INR ≥6·0. The risk of overanticoagulation was 1·66 [95% confidence interval (CI): 1·33–2·07] for cases of prevalent heart failure and 1·91 (95%CI: 1·31–2·79) for incidental cases. The decrease in dose requirements in patients with incidental heart failure showed a significant trend from the fifth INR measurement preceding the date of incidental heart failure to the third measurement after this date. Heart failure is an independent risk factor for overanticoagulation. Therefore, patients with heart failure should be closely monitored to prevent potential bleeding complications.

Mortality in patients with hypertension on angiotensin-I converting enzyme (ACE)-inhibitor treatment is influenced by the ACE insertion/deletion polymorphism.

Background The response to angiotensin-I converting enzyme (ACE)-inhibitor therapy is highly variable. Residual ACE activity during treatment, potentially modified by the ACE insertion/deletion (I/D) polymorphism, may explain part of this variability. We studied the possible interaction between ACE-inhibitor therapy in patients with hypertension and the ACE I/D polymorphism in incident heart failure and death. Methods We studied 3365 hypertensive participants of the population-based Rotterdam Study, without heart failure at baseline for whom ACE-genotyping was successful. Incident heart failure was defined according to established criteria. In addition, total and cardiovascular mortality were studied as endpoints. A Cox regression model with use of ACE-inhibitors defined as time-dependent covariates was used for data-analysis. Interaction was tested in this model assuming an allele-effect relationship. Results Although we could not demonstrate a beneficial effect of ACE-inhibitors, there was significant interaction between the ACE I/D polymorphism (II-ID-DD) and ACE-inhibitor use in the prediction of total and cardiovascular mortality. Mortality risk associated with treatment increased with the number of D alleles present; e.g. for total mortality in the II genotype group: RR=0.95 (95% CI 0.63–1.45), in the ID genotype group: RR=1.08 (95% CI 0.84–1.38) and in the DD genotype group: RR=1.61 (95% CI 1.18–2.18). No statistically significant interaction was found for incident heart failure. Conclusion The results of our study suggest a relative resistance to ACE-inhibitor therapy in subjects with hypertension and the DD genotype compared to the II genotype, with the ID genotype in an intermediate position.

A promoter polymorphism of the insulin-like growth factor-I gene is associated with left ventricular hypertrophy

Left ventricular hypertrophy (LVH) is a strong predictor of cardiovascular morbidity and mortality. Insulin-like growth factor-I (IGF-I) has an important role in the hypertrophic response of the myocardium.1 A polymorphism in the IGF-I gene promoter region has been identified which influences IGF-I production.2–4 Studying this polymorphism in relation to pathology may better reflect the effects of long term IGF-I exposure than studies on serum IGF-I concentrations, which may fluctuate considerably and are profoundly influenced by various factors. We investigated the association between this IGF-I promoter polymorphism and the occurrence of LVH on echocardiogram. The Rotterdam study is a population based cohort study in 7983 elderly people aged 55 years or over. The baseline examination was conducted in 1990–93, during which time information was obtained on age, sex, history of myocardial infarction, smoking, hypertension, diabetes mellitus, and body mass index (BMI). Cardiac ultrasound was performed in a random subpopulation of 2823 subjects. The present study was performed in subjects aged 55–75 years, without a history of myocardial infarction. The analyses were restricted to persons with an adequate echocardiogram and for whom blood specimens were available for IGF-I typing, a total of 1678 subjects. This is the first genetic case association study that uses the Rotterdam study database to investigate the phenotype of LVH on the echocardiogram. M mode echocardiography was performed …

Pergolide-induced pleuropulmonary fibrosis

Pleuropulmonary fibrosis is a rare, but well-recognized adverse effect of ergot alkaloids. We report on four patients who developed pleural and/or pulmonary fibrosis during treatment with pergolide and give characteristics of 87 cases with one or more symptoms of serosal fibrosis. Retroperitoneal and pleuropulmonary fibrosis are serious conditions, which are often irreversible after drug withdrawal. Increased awareness may help to diagnose these complications at an earlier stage and to minimize any permanent damage to the patient.

Heart failure and incident late-life depression.

OBJECTIVES: To assess whether heart failure (HF) increases the risk of developing depression and whether the use of loop diuretics in persons with HF alters this risk.