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Heart. 2007 May; 93(5): 645–647.
PMCID: PMC1955538

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Monitoring Editor: Alistair Lindsay
Alastair Lindsay, Editor

GENERAL CARDIOLOGY

Do dopamine agonists cause valvular heart disease?

Previous studies have suggested that the ergot‐derived dopamine agonists pergolide and cabergoline may be associated with an increased risk of cardiac valve regurgitation. In addition, histological series have demonstrated valve abnormalities similar to those observed in carcinoid heart disease. Data from the UK General Practice Research Database were used to identify 11 417 individuals aged 40–80 years prescribed anti‐parkinsonian dopamine agonist drugs over a 17‐year period from 1988 to 2005. A total of 81 patients with newly diagnosed cardiac valve regurgitation were identified, of whom 50 were excluded. Of the remaining 31, six were currently taking pergolide, six cabergoline and 19 had not been exposed to a dopamine agonist within the preceding year. When compared with controls, the rate of cardiac valve regurgitation was increased with current use of pergolide (incident rate ratio 7.1, 95% CI 2.3 to 22.3) and cabergoline (incident rate ratio 4.9, 95% CI 1.5 to 15.6), but not with the use of other dopamine agonists. The risk was particularly high in patients who had taken daily doses of pergolide or cabergoline >3 mg/day, but only among individuals who had taken either drug for >6 months. One concurrent medication, amantadine, was also identified as a risk factor (adjusted incidence ratio 3.5, 95% CI 1.1 to 11.3). In a second paper, an echocardiographic prevalence study was performed on 155 patients taking dopamine agonists for Parkinson's disease (pergolide n = 64, cabergoline n = 49 and non‐ergot‐derived dopamine agonists n = 42). Among patients treated with ergot‐derived dopamine agonists, 17 cases of localised or diffuse leaflet thickening were identified in those treated with pergolide and 8 in those prescribed cabergoline. No cases of leaflet thickening were found in either the non‐ergot or the control group. Clinically significant valvular regurgitation (moderate to severe, grade 3–4) was demonstrated in 23.4% of individuals taking pergolide and in 28.6% taking cabergoline. This was not demonstrated in the non‐ergot dopamine agonist group (0%) when compared with controls (5.6%).

These two studies confirm the association of valvular heart disease with pergolide and cabergoline. Currently, approximately 1% of the US population aged >60 years have Parkinson's disease, and the findings of these two papers may have important therapeutic implications. Follow‐up echocardiographic monitoring may be advisable in all patients with Parkinson's disease undergoing dopamine agonist treatment.

[filled triangle] Schade R, Andersohn F, Suissa S, et al. Dopamine agonists and the risk of cardiac‐valve regurgitation. N Engl J Med 2007;356:29–30.

[filled triangle] Zanettini R, Antonini A, Gatto G, et al. Valvular heart disease and the use of dopamine agonists for Parkinson's disease. N Engl J Med 2007;356:39–46.

[filled triangle] Roth BL. Drugs and valvular heart disease. N Engl J Med 2007;356:6–9.

Alcohol, blood pressure and cardiovascular risk

Heavy alcohol consumption may increase the risk of cardiovascular disease (CVD) by increasing blood pressure. To investigate the relationship between alcohol intake and CVD in men with hypertension, 11 711 men with hypertension were recruited from the Health Professionals Follow‐Up Study. Alcohol consumption was assessed every 4 years by means of a questionnaire. End points documented were non‐fatal myocardial infarction (MI), fatal coronary heart disease and stroke over a 16‐year period. During this follow‐up period, 653 patients had a MI. The hazard ratio (HR) for MI in those patients consuming 0.1–4.9 g of alcohol/day was 1.09 (95% CI 0.86 to 1.37 g/day); for those consuming 5–9.9 g of alcohol/day was 0.81 (95% CI 0.60 to 1.08 g/day); for those consuming 10–14.9 g of alcohol/day was 0.68 (95% CI 0.51 to 0.91 g/day); for those consuming 15–29.9 g of alcohol/day was 0.72 (95% CI 0.54 to 0.97 g/day); for those consuming 30–49.9 g of alcohol/day was 0.67 (95% CI 0.48 to 0.94 g/day); and for those consuming [gt-or-equal, slanted]50 g of alcohol/day was 0.41 (95% CI 0.22 to 0.77 g/day; p<0.001 for trend). Similar associations were found for both fatal and non‐fatal MI; however, alcohol consumption was not associated with total death or death due to CVD. Risks for total and ischaemic stroke for patients consuming 10–29.9 g of alcohol/day were 1.40 (95% CI 0.93 to 2.12 g/day) and 1.55 (95% CI 0.90 to 2.68 g/day), respectively, compared with that of abstainers. Thus, in this population of men with hypertension, moderate alcohol consumption decreased the risk of MI but not the risk of overall death or death due to CVD specifically. On the basis of these data, the authors suggest that men with hypertension who drink moderately and safely may not need to change their drinking habits. However, one limitation of the study was that all alcohol consumption was self‐reported and may thus have been underestimated.

[filled triangle] Beulens JWJ, Rimm EB, Scherio A, et al. Alcohol consumption and risk for coronary heart disease among men with hypertension. Ann Intern Med 2007;146:10–19.

Improved heart failure performance measures required

The American College of Cardiology and the American Heart Association have recently released “clinical performance measures for adults with chronic heart failure”, which includes the following heart failure inpatient performance measures: discharge instructions, evaluation of left ventricular systolic function, use of ACE or angiotensin‐II receptor blockers for left ventricular systolic dysfunction, adult smoking cessation advice/counselling and anticoagulant at discharge for patients with atrial fibrillation. To validate the effect of these performance measures on actual clinical outcomes, Fonarow and colleagues prospectively collected 60–90 day discharge data on patients enrolled in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure registry. Data were collected from 5791 patients at 91 US hospitals between March 2003 and December 2004. The mean patient age was 72 years, 51% were men, 78% were white and 42% had heart failure of ischaemic aetiology.

Mortality during follow‐up was 8.6% and mortality/rehospitalisation was 36.2%. None of the five American College of Cardiology or American Heart Association heart failure performance measures was significantly associated with reduced risk of early mortality, and only use of ACE inhibitors or angiotensin receptor blockers at discharge was associated with 60–90‐day post‐discharge mortality or rehospitalisation. β Blockade at the time of hospital discharge, currently not a heart failure performance measure, was strongly associated with reduced risk of mortality (HR 0.48) and mortality/rehospitalisation during follow‐up. These current heart failure measures therefore seem to have little associations with patient mortality and combined mortality/rehospitalisation in the first 60–90 days after discharge. Improved measures for identifying and validating heart failure performance measures are required.

[filled triangle] Fonarow GC, Abraham WT, Albert NM, et al. Association between performance measures and clinical outcomes for patients hospitalized with heart failure. JAMA 2007;297:61–70.

Why do South Asians have more heart attacks?

What causes South Asians to have heart attacks at higher rates and at younger ages than people from other countries? A total of 1732 cases of first myocardial infarction (MI) from 15 medical centres in 5 South Asian countries and 2204 controls matched by age and sex were compared with 10 728 cases and 12 431 controls from other countries. The mean age for first MI was significantly lower in South Asian countries (53.0 years) than in other countries (58.8 years, p<0.001). Protective factors were noted to be lower in controls from South Asian countries than in controls from other countries. For example, moderate‐ or high‐intensity exercise was seen in 21.6% of controls, but only in 6.1% of South Asians. Similarly, daily intake of fruit and vegetables (45.2% vs 26.5%) and alcohol consumption more than once a week (26.0% vs 10.7%) were not as favourable. In addition, some harmful factors were more common in native South Asians than in individuals from other countries, including diabetes (9.55% vs 7.2%) and an increased apolipoprotein B100: apolipoprotein A–I ratio (43.8% vs 31.8%). Other classic risk factors showed similar relative associations between South Asians and individuals from other countries. Furthermore, the combined odds ratio for all nine risk factors studied was similar in South Asians and in individuals from other countries. However, when stratified by age, South Asians had more risk factors at ages <60 years. This may largely explain the earlier age of first MI in South Asians.

[filled triangle] Joshi P, Islam S, Pais P, et al. Risk factors for early myocardial infarction in South Asians compared with individuals in other countries. JAMA 2007;297:286–94.

ELECTROPHYSIOLOGY/PACING

Cardiac pacing for refractory vasovagal syncope: the placebo effect?

Vasovagal syncope is the most frequent cause of syncope where an aetiology is elicited and it usually follows a benign course. Permanent pacemaker (PPM) insertion has been used as a means to counteract the cardioinhibitory component of vasovagal syncope. However, clinical trials of pacing for this indication have shown conflicting results. A meta‐analysis of nine randomised controlled trials showed that permanent pacing reduced the risk of recurrent syncope in unblinded studies (Odds Ratio (OR) 0.09, 95% CI 0.04 to 0.22), and in studies that compared pacemaker algorithms (OR 0.04, 95% CI 0.0 to 0.23). No effect was demonstrated in double‐blinded trials (OR 0.83, 95% CI 0.41 to 1.70). The knowledge that a permanent pacemaker was inserted and functional, was associated with a significant expectation effect, which reduced the risk of syncope (OR 0.16, 95% CI 0.06 to 0.40, p<0.001). Similar results were seen when analysing the results of patients with a strong cardioinhibitory response on tilt‐table testing. Clinical diversity, particularly the variable inclusion criteria and protocols for tilt‐table testing, has been suggested as a cause for the conflicting results. Further, adequately powered studies are necessary to conclusively demonstrate the benefit of cardiac pacing as a preferred treatment for vasovagal syncope.

[filled triangle] Sud S, Massel D, Klein GJ, et al. The expectation effect and cardiac pacing for refractory vasovagal syncope. Am J Med 2007:120;54–62.

BASIC SCIENCE

Telomere length relates to cardiovascular risk

There is wide interindividual variability in susceptibility to coronary heart disease, even in patients with similar risk‐factor profiles. Could variations in the rate of biological aging be a factor? One way to estimate biological aging is to measure leucocyte telomere length. The West of Scotland Coronary Prevention Group looked at 484 individuals from the original West of Scotland Coronary Prevention Study trial who went on to develop coronary heart disease, and compared leucuocyte telomere length in these patients with 1058 matched controls who had not developed coronary disease. They also looked at whether telomere length correlated well with the observed clinical benefit of statin treatment. In the control group, mean telomere length declined by 9% each decade, much the same as in cases with coronary heart disease (−5.9%). However, individuals in the middle and lowest tertiles of telomere length were more at risk of developing a coronary heart disease event than were individuals in the highest tertile (odds ratio for coronary heart disease 1.44 for those in the lowest tertile). In the patients treated with placebo, the risk of coronary heart disease was almost double in those in the lower two tertiles of telomere length compared with those in the highest tertile. By contrast, in patients treated with pravastatin, the increased risk associated with short telomeres was substantially attenuated. The authors suggest that mean leucocyte telomere length could be used to identify individuals who would benefit from statin treatment. In addition, these findings support the hypothesis that different rates of biological ageing might contribute to the risk, and variability in age of onset, of coronary heart disease. Caution is required, however, before new markers of risk come into clinical use.

[filled triangle] Brouilette SW, Moore JS, McMahon AD, et al. Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case‐control study. Lancet 2007;369:107–14.

Long‐QT alleles more commonly transmitted to females

The most common forms of congenital long‐QT syndrome, types 1 and 2, are caused by mutations in the potassium channel genes KCNQ1 and KCNH2, respectively. Inheritance is autosomal dominant, but female preponderance has been observed. This study investigated the possibility of unbalanced genetic transmission. The distribution of alleles for the long‐QT syndrome was investigated in 484 nuclear families with type 1 disease and in 269 families with type 2 disease. All had fully genotyped offspring and were recruited from five European referral centres. Classic mendelian inheritance ratios were not observed in the offspring of either female carriers of the long‐QT syndrome type 1 or male and female carriers of the long‐QT syndrome type 2. Of the 1534 descendants, a significantly greater proportion was affected than expected according to mendelian inheritance: 870 (57%) carried a mutation and 664 were non‐carriers (43%, p<0.001). Among the 870 carriers, the allele for the long‐QT syndrome was transmitted more frequently to female (n = 476, 55%) than to male offspring (n = 394, 45%, p = 0.005). Increased maternal transmission of the long‐QT mutations to daughters was observed, possibly contributing to the excess of female patients with autosomal dominant long‐QT syndrome. Positive selection of the mutated alleles that cause the long‐QT syndrome leads to transmission distortion, with increased proportions of mutation carriers among the descendants of affected families. Alleles of the long‐QT syndrome are more often transmitted to daughters than to sons. The skewed segregation of the mutation from mothers to daughters may substantially contribute to the female predominance of this disorder.

[filled triangle] Imboden M, Swan H, Denjoy I, et al. Female predominance and transmission distortion in the long‐QT syndrome. N Engl J Med 2006;355:2744–51.

INTERVENTIONAL CARDIOLOGY

Complement inhibitor does not improve outcome in ST‐elevation myocardial infarction

Even with prompt re‐establishment of coronary blood flow by percutaneous coronary intervention (PCI), mortality remains high following ST‐elevation myocardial infarction (STEMI). Pexelizumab is a human monoclonal antibody that binds to the C5 component of complement. Could its anti‐inflammatory action improve the prognosis of patients with STEMI? In all, 5475 patients presenting with STEMI were randomly assigned to receive pexelizumab (n = 2860) given as a 2 mg/kg intravenous bolus before PCI followed by a 0.05 mg/kg/h infusion over the subsequent 24 h or placebo (n = 2885). All patients were randomised within 6 h of symptom onset. The primary end point was all‐cause mortality at 30 days. No difference in mortality was observed between the two treatment groups at 30 days; 116 patients treated with pexelizumab died, compared with 113 patients given placebo. The composite end points of death, shock or heart failure were also similar, with 257 patients (8.99%) receiving pexelizumab and 265 patients receiving placebo. In conclusion, in this large clinical trial of patients treated with primary PCI for STEMI, mortality was low and unaffected by the adminstration of pexelizumab.

[filled triangle] The APEX AMI Investigators. Pexelizumab for acute ST‐elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial. JAMA 2007;297:43–51.

PCI in total occlusions after myocardial infarction

Does reperfusion of the infarct‐related artery after >12 h improve patient outcome? Some trials (eg, International Study of Infarct Survival) showed improved survival with fibrinolytic treatment even 24 h after myocardial infarction when any myocardial salvage and hence improvement in left ventricular function was theoretically unlikely. This led to the establishment of “the open artery hypothesis” that the restoration of antegrade flow in the infarct‐related artery days, weeks or even months after myocardial infarction would improve survival even if left ventricular function did not improve. A total of 2166 stable patients, with total occlusion of the infarct‐related artery 3–28 days afer myocardial infarction, all of whom were deemed as high risk (ejection fraction <50% or proximal occlusion), were randomised to percutaneous coronary intervention (PCI) and stenting with optimisation of medical treatment (n = 1082) or optimisation of medical treatment alone (n = 1084). Exclusion criteria were New York Heart Association (NYHA) class III/IV heart failure, shock, serum creatinine >2.5 mg/dl (221 μmol/l), angiographically significant left main or three‐vessel coronary artery disease, angina at rest and severe ischaemia on stress testing. The primary end point was a composite of death, myocardial re‐infarction or NYHA class IV heart failure. The 4‐year cumulative primary event rate was 17.2% in the PCI group and 15.6% in the medical treatment group (hazard ratio (HR) for death, reinfarction or heart failure in the PCI group as compared with the medical treatment group 1.16, 95% CI 0.92 to 1.45, p = 0.20). Rates of myocardial re‐infarction (both fatal and non‐fatal) were 7.0% and 5.3%, respectively (HR 1.36, 95% CI 0.92 to 2.00, p = 0.13). Only 6 re‐infarctions (0.6%) were related to the assigned PCI procedure. Rates of NYHA class IV heart failure (4.4% vs 4.5%) and death (9.1% vs 9.4%) were similar. There was no interaction between treatment effect and any of the subgroup variables (age, sex, race, infarct‐related artery, ejection fraction, diabetes mellitus, Killip class and the time from myocardial infarction to randomisation). Although this study demonstrated a high procedural success rate with PCI and sustained vessel patency, it failed to demonstrate clinical benefit over an approximately 3 year follow‐up period with respect to death, reinfarction or heart failure. In other words, a patient whose artery was opened mechanically >12 h after an infarct did not have an improved outcome when compared with the individual treated with medical therapy alone.

[filled triangle] Hochman JS, Lamas, GA, Buller CE, et al. Coronary intervention for persistent occlusion after myocardial infarction. N Engl J Med 2006;355:2395–407.

[filled triangle] Hills LD, Lange RA, eds. Myocardial infarction and the open‐artery hypothesis. N Engl J Med 2006;355:2475–7.

Statistical bias may influence outcome of MI trials

When examining prognosis in post‐myocardial infarction (MI) trials, what is the significance of the statistical analytical method used? Stukel and colleagues from Canada reanalysed data from a cohort of 122 124 elderly patients aged 65–84 years, all of whom were hospitalised between 1994 and 1995 and were candidates for cardiac catheterisation. Patients were then followed up for 7 years to assess the association between long‐term survival and cardiac catheterisation within 30 days of hospital admission. Four main analytical methods were compared: multivariable model risk adjustment, propensity score risk adjustment, propensity‐based matching and instrumental variable analysis. After adjustment for prognostic factors using standard statistical adjustment methods, cardiac catheterisation was associated with a 50% relative decrease in mortality, giving an adjusted relative risk (RR) of 0.51. By contrast, instrumental variable analysis—which controls for hidden as well as overt bias—suggested a 16% relative decrease in mortality (RR 0.84). Therefore, in this study, estimates of the observational association of cardiac catheterisation with long‐term mortality from MI were highly sensitive to the analytical method used. Instrumental variable analysis may produce less biased estimates of treatment effects, but is more suited to answering policy questions rather than specific clinical questions.

[filled triangle] Stukel TA, Fisher ES, Wennberg DE, et al. Analysis of observational studies in the presence of treatment selection bias: effects of invasive cardiac management on AMI survival using propensity score and instrumental variable methods. JAMA 2007;297:278–85.

Journals scanned

American Journal of Medicine; American Journal of Physiology; Heart and Circulatory Physiology; Annals of Emergency Medicine; Annals of Thoracic Surgery; Archives of Internal Medicine; BMJ; Chest; European Journal of Cardiothoracic Surgery; Lancet; JAMA; Journal of Clinical Investigation; Journal of Diabetes and its Complications; Journal of Immunology; Journal of Thoracic and Cardiovascular Surgery; Nature Medicine; New England Journal of Medicine; Pharmacoeconomics; Thorax

Reviewers

Dr Alistair Lindsay, Dr Katie Qureshi


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