Rolf Steffensen

Pentanucleotide Repeat Polymorphism, Lipoprotein(a) Levels, and Risk of Ischemic Heart Disease

CONTEXTnLipoprotein(a) is a cardiovascular risk factor. Levels of lipoprotein(a) are predominantly determined by apolipoprotein(a) gene variation, including a pentanucleotide repeat promoter polymorphism.nnnOBJECTIVEnWe tested the hypothesis that apolipoprotein(a) pentanucleotide repeat genotype predicts elevated lipoprotein(a) levels and risk of myocardial infarction (MI) and ischemic heart disease (IHD) in the general population.nnnDESIGNnWe used a cohort study of the Danish general population, The Copenhagen City Heart Study, including 10,276 individuals of which 860 and 1,781 developed MI and IHD, respectively, during up to 31 yr of follow-up, and a case-control study including 1,814 IHD patients and 5,076 controls. Follow-up was 100% complete.nnnRESULTSnAllele frequencies were 0.0018, 0.0018, 0.6750, 0.1596, 0.1465, 0.0146, and 0.0004 for 6, 7, 8, 9, 10, 11, and 12 repeats, respectively. Mean lipoprotein(a) levels were 40, 36, and 27 mg/dl for individuals with 14-15, 16, and 17-22 repeats (sum of repeats on both alleles), respectively (trend, P < 0.001). Cumulative incidence of MI and IHD was increased for individuals with 14-15 vs. at least 16 repeats (log rank, P < 0.001 and P = 0.002). Multifactorially adjusted hazard ratios for 14-15 and 17-22 vs. 16 repeats were 3.1 (95% confidence interval, 1.6-5.8) and 1.0 (0.9-1.2) for MI and 2.2 (1.3-3.6) and 1.0 (0.9-1.1) for IHD. In the case-control study, multifactorially adjusted odds ratios for 14-15 and 17-22 vs. 16 repeats were 2.9 (1.1-7.8) and 0.9 (0.8-1.0) for MI and 2.5 (1.0-6.0) and 0.9 (0.8-1.0) for IHD.nnnCONCLUSIONSnApolipoprotein(a) 14-15 pentanucleotide repeats predict elevated levels of lipoprotein(a) and a 3- and 2-fold increased risk of MI and IHD in the general population.

Effects of atenolol and diltiazem on exercise tolerance and ambulatory ischaemia

Twenty-five normotensive patients with stable angina, angiographically documented coronary disease and normal left ventricular function were randomized to a crossover study comparing atenolol 100 mg x 1, sustained-release diltiazem 120 mg x 2, and their combination. A maximal symptom limited bicycle exercise test and a 24-h ambulatory electrocardiographic (ECG) monitoring were performed at the end of each treatment period. Exercise duration was increased equally in the different treatment groups. Time to onset of 1-mm ST-segment depression was longer with atenolol (P < 0.02) and combination therapy (P < 0.01) than with diltiazem. The maximal ST-segment depression was decreased with atenolol (P < 0.05) and combination therapy (P < 0.02), whereas, time to onset of angina was prolonged only with combination therapy (P < 0.03). The number of ischaemic episodes during ambulatory monitoring was lower with atenolol and combination therapy than with diltiazem (P < 0.01). The difference between atenolol and diltiazem was mainly due to lower ischaemic activity with atenolol between 06:00 h and 12:00 h (P < 0.05). Anginal frequency (P < 0.01) and nitroglycerin consumption (P < 0.05) were lower with combination therapy than with monotherapy. Thus, while comparable effects were achieved on clinical variables, atenolol appeared to be more effective than diltiazem, reducing myocardial ischaemia during exercise and ambulatory monitoring. With combination therapy, both clinical and electrocardiograph signs of ischaemia were improved.

Prothrombin and risk of venous thromboembolism, ischemic heart disease and ischemic cerebrovascular disease in the general population.

OBJECTIVEnWe tested the hypotheses that Prothrombin G20210A heterozygosity associate with increased risk of venous thromboembolism (VTE), ischemic heart disease (IHD), and ischemic cerebrovascular disease (ICVD) in the general population and re-tested risk of IHD and ICVD in two case-control studies.nnnMETHODSn9231 individuals from the Danish general population were followed for VTE (VTE=DVT+PE), deep venous thrombosis (DVT), pulmonary embolism (PE), IHD, myocardial infarction (MI), ICVD, and ischemic stroke (IS) for a median of 24 years. Case-control studies included 2461 IHD cases and 867 ICVD cases.nnnRESULTSnIn the general population, Prothrombin G20210A heterozygotes had1.3 (95% CI:0.6-2.9) fold risk for VTE, 0.6 (0.2-2.0) for DVT, 1.7(0.6-4.8) for PE, 1.5(1.1-2.1) for IHD, 1.7(1.1-2.7) for MI, 1.1(0.6-1.9) for ICVD, and 1.1(0.5-2.1) for IS compared to non-carriers. Double heterozygotes for Prothrombin G20210A and Factor V Leiden versus double non-carriers had a multifactorially adjusted hazard ratio for IHD of 6.0(2.0-19). In case-control studies, multifactorially adjusted odds ratios for Prothrombin G20210A heterozygotes versus non-carriers were 2.0(1.1-3.4) for IHD, 2.0(1.0-3.8) for MI, 1.4(0.7-3.1) for ICVD, and 2.1(0.8-5.4) for IS.nnnCONCLUSIONnProthrombin G20210A heterozygosity alone and in combination with Factor V Leiden R506Q heterozygosity predicts 1.5 and 6.0 fold risk of IHD compared to non-carriers.

Short-Term Effects of Captopril on Exercise Tolerance in Patients with Chronic Stable Angina pectoris and Normal Left Ventricular Function

A double-blind, placebo-controlled, crossover study was carried out to evaluate the short-term effects of captopril on exercise tolerance in 18 normotensive patients with chronic stable angina pectoris and normal left ventricular function. Captopril 25 mg (or placebo) was given twice, i.e. in the evening (10 p.m.) and the following morning (8 a.m.), prior to a maximal symptom-limited bicycle exercise test (11 a.m.). Captopril reduced the systolic and diastolic blood pressures at rest (p < 0.01) without causing any reflex tachycardia. The time to onset of S-T depression was prolonged (p < 0.05), and the maximal S-T depression was reduced (p < 0.02). No differences were found between captopril and placebo in total exercise duration or time to onset of angina. The effects of captopril on exercise-induced ischemia were demonstrated most clearly in patients who responded with a greater than 10 mm Hg fall in the resting systolic blood pressure. In conclusion, this study suggests that captopril has anti-ischemic properties, which may be of importance in the treatment of patients with chronic stable angina and normal left ventricular function. These beneficial effects probably relate to a reduction in afterload and myocardial wall stress and therefore a reduction in myocardial oxygen demand.

The Angiotensin Converting Enzyme Inhibition Post Revascularization Study (APRES): Effects of Ramipril in Patients with Reduced Left Ventricular Function. Rationale, Design, Methods, Baseline Characteristics and First-Year Experience

Invasive revascularization improves prognosis, functional status and quality of life in patients with severe angina pectoris and impaired left ventricular function, and treatment with ACE-I reduces the development of cardiac events and left ventricular dysfunction in patients without or with mild angina pectoris. However, the effects of a combined treatment strategy with invasive revascularization and subsequent long-term ACE-I therapy in patients with limiting angina pectoris and impaired left ventricular function have not previously been investigated. APRES is a long-term, prospective, randomized double-blind study that evaluates the effects of ramipril 10 mg o.d. on the long-term development of cardiac events, left ventricular function, functional status and quality of life following invasive revascularization in patients without recent AMI or clinical heart failure and with preoperative ejection fraction in the range 0.30-0.50. The rationale, design and power of APRES and the choice and relevance of outcome measures are discussed. Based on experience and results from the first year of the study for screening procedure, inclusion rate, patient compliance, reproducibility analyses and the magnitude of outcome measures, we conclude that the study is feasible and safe. The included patients match with the target population, the outcome measures seem appropriate and the power considerations valid for the majority of the outcome measures.

Effects of amlodipine and isosorbide dinitrate on exercise-induced and ambulatory ischemia in patients with chronic stable angina pectoris

This study was designed to compare once-daily administration of 5–10 mg amlodipine with two daily doses of 40 mg sustained-release isosorbide dinitrate in 59 patients with stable angina using a randomized, double-blind, crossover study design. Anginal episodes, nitroglycerin consumption, and possible adverse events were recorded in a diary. A maximal symptom-limited bicycle exercise test and 48-hour ambulatory ECG monitoring were performed at baseline and at the end of each 5-week period of therapy. Exercise time, time to angina, time to ST depression, and maximal ST depression were measured during exercise. During ambulatory monitoring, the number of ischemic episodes and the duration per hour of ST depression were assessed. Amlodipine significantly reduced anginal episodes (P < 0.001) when compared with isosorbide dinitrate. Furthermore, amlodipine prolonged time to ST depression (P < 0.001) and time to angina (P < 0.05) when compared with isosorbide dinitrate. The number and duration of ischemic episodes during ambulatory monitoring were significantly reduced with amlodipine when compared with baseline values (P < 0.05), whereas no differences were found between isosorbide dinitrate and baseline. Adverse events were reported more frequently with isosorbide dinitrate than with amlodipine (P < 0.02). Amlodipine appears to be more effective and tolerable than sustained-release isosorbide dinitrate as monotherapy for chronic stable angina.

958-95 Long-term Effects of Amlodipine and Isosorbiddinitrate on Exercise-induced and Ambulatory Ischaemia in Patients with Stable Angina Pectoris

Once-daily administration of 10xa0mg amlodipine has been compared with two daily doses of 40xa0mg sustained-release isosorbiddinitrate (ISDN) in 59 patients with stable angina, using a randomized, double-blind, double-placebo, crossover study design. Nine patients dropped out due to side effects (3 during amlodipine and 6 during ISDN therapy), and one patient was excluded for technical reasons. A maximal symptom limited supine bicycle tolerance test and a 48xa0h ambulatory ECG monitoring were performed at the end of each 5 week period of therapy. During exercise, exercise time, time to onset of angina, and time to onset of ischaemia, i.e., 1xa0mm ST segment depression were measured. During ambulatory monitoring, number of anginal episodes and duration per hour of ST deviation were assessed. Amlodipine significantly prolonged time to angina (320xa0±xa0155 vs 304xa0±xa0126 sec; pxa0lxa00.05) and time to ischaemia (292xa0±xa0153 vs 232xa0±xa0126 sec; pxa0lxa00.001). when compared with ISDN, while exercise time was similar for both treatments. Furthermore, amlodipine reduced anginal episodes (1.2xa0±xa01.6 vs 2.4xa0±xa03.0 attacks/48xa0h; pxa0lxa00.001), whereas, no difference was found between amlodipine and ISDN in duration of ST deviation during ambulatory monitoring. In conclusions, addressing the long-term treatment of patients with stable angina pectoris, once-daily dosing of amlodipine appears to be more effective than ISDN, as determined by its anti-anginal and anti-ischaemic effects during exercise tolerance testing and ambulatory ECG monitoring.