Joan G. Meeder

Management of Chronic Heart Failure Guided by Individual N-Terminal Pro-B-Type Natriuretic Peptide Targets Results of the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) Study

OBJECTIVES The purpose of this study was to assess whether management of heart failure (HF) guided by an individualized N-terminal pro-B-type natriuretic peptide (NT-proBNP) target would lead to improved outcome compared with HF management guided by clinical assessment alone. BACKGROUND Natriuretic peptides may be attractive biomarkers to guide management of heart failure (HF) and help select patients in need of more aggressive therapy. The PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study is, to our knowledge, the first large, prospective randomized study to address whether management of HF guided by an individualized target NT-proBNP level improves outcome. METHODS A total of 345 patients hospitalized for decompensated, symptomatic HF with elevated NT-proBNP levels at admission were included. After discharge, patients were randomized to either clinically-guided outpatient management (n = 171), or management guided by an individually set NT-proBNP (n = 174) defined by the lowest level at discharge or 2 weeks thereafter. The primary end point was defined as number of days alive outside the hospital after index admission. RESULTS HF management guided by this individualized NT-proBNP target increased the use of HF medication (p = 0.006), and 64% of HF-related events were preceded by an increase in NT-proBNP. Nevertheless, HF management guided by this individualized NT-proBNP target did not significantly improve the primary end point (685 vs. 664 days, p = 0.49), nor did it significantly improve any of the secondary end points. In the NT-proBNP-guided group mortality was lower, as 46 patients died (26.5%) versus 57 (33.3%) in the clinically-guided group, but this was not statistically significant (p = 0.206). CONCLUSIONS Serial NT-proBNP measurement and targeting to an individual NT-proBNP value did result in advanced detection of HF-related events and importantly influenced HF-therapy, but failed to provide significant clinical improvement in terms of mortality and morbidity. (Effect of NT-proBNP Guided Treatment of Chronic Heart Failure [PRIMA]; NCT00149422).

Coronary vasomotion in patients with syndrome X : Evaluation with positron emission tomography and parametric myocardial perfusion imaging

The aim of this study was to elucidate further the causative mechanism of abnormal coronary vasomotion in patients with syndrome X. In patients with syndrome X, defined as angina pectoris and documented myocardial ischaemia during stress testing with normal findings at coronary angiography, abnormal coronary vasomotion of either the micro- or the macrocirculation has been suggested as the causative mechanism. Accordingly, we evaluated endothelial function, vasodilator reserve, and perfusion heterogeneity in these patients. Twenty-five patients with syndrome X (definitely normal coronary arteriogram, group A), 15 patients with minimal coronary artery disease (group B) and 21 healthy volunteers underwent [13N]ammonia positron emission tomography at rest, during cold pressor stimulation (endothelial function) and during dipyridamole stress testing (vasodilator reserve). Heterogeneity of myocardial perfusion was analysed by parametric polar mapping using a 480-segment model. In both patient groups, resting perfusion was increased compared to the normal subjects: group A, 127±31 ml·min−1·100 g−1; group B, 124±30 ml·min−1·100 g−1 normal subjects, 105±21 ml·min−1·100 g−1 (groups A and B vs normals,P<0.05). These differences were abolished after correction for rate-pressure product. During cold pressor stimulation, the perfusion responses (ratio of cold pressor perfusion to resting perfusion) were similar among the patients and the control subjects (group A, 1.20±0.23; group B, 1.24±0.22; normal subjects, 1.23±0.14). Likewise, during dipyridamole stress testing, perfusion responses were similar among the three groups (group A, 2.71±0.67; group B, 2.77±1.29; normal subjects, 2.91±1.04). In group A the heterogeneity of resting perfusion, expressed as coefficient of variation, was significantly different from the volunteers (20.1±4.5 vs 17.0±3.0,P<0.05). In group B (coefficient of variation 19.4±3.9) the difference from normal volunteers was not significant. In this study, patients with syndrome X and patients with minimal coronary artery disease showed normal perfusion responses during cold pressor stimulation and dipyridamole stress testing. Our findings therefore suggest that endothelial dysfunction and impaired vasodilator reserve are of no major pathophysiological relevance in patients with syndrome X. Rather, other mechanisms such as increased sympathetic tone and focal release of vasoactive substances may play a role in the pathogenesis of syndrome X.

Comparison between positron emission tomography myocardial perfusion imaging and intracoronary Doppler flow velocity measurements at rest and during cold pressor testing in angiographically normal coronary arteries in patients with one-vessel coronary artery disease

With use of invasive methods, coronary endothelial function is generally studied by examining the response of epicardial coronary arteries to intracoronary administered acetylcholine or to cold pressor testing. Because invasive methods have substantial inherent limitations, studies should attempt to evaluate coronary endothelial function noninvasively. This study examines a noninvasive technique for endothelium-related coronary stress testing. In myocardial regions supplied by nonstenotic coronary arteries, we compared positron emission tomography (PET) myocardial perfusion imaging with intracoronary Doppler flow velocity measurements during endothelium-related stress testing. PET perfusion was examined at rest and during cold pressor testing in 10 patients with 1-vessel coronary artery disease. In nonstenotic coronary arteries, flow velocity measurements were obtained at rest, during cold pressor testing, and during intracoronary administered acetylcholine. Perfusion and flow velocity responses and stress/rest ratios were compared between the techniques during the various circumstances. Positive correlations were found between: (1) cold pressor Doppler flow velocity responses and acetylcholine Doppler flow velocity responses (r = 0.84, SEE = 0.19, p = 0.003); (2) cold pressor PET perfusion responses and cold pressor Doppler flow velocity responses (r = 0.70, SEE = 0.17, p = 0.02); and (3) cold pressor PET perfusion responses and acetylcholine Doppler flow velocity responses (r = 0.62, SEE = 0.19, p = 0.05). These results suggest that in angiographically normal coronary arteries, both the flow velocity and the perfusion responses during cold pressor testing may be related to the response to acetylcholine.

Long-term cigarette smoking is associated with increased myocardial perfusion heterogeneity assessed by positron emission tomography.

The pathophysiology of smoking-related coronary events in patients with normal coronary arteries is incompletely understood. This study was conducted to explore, in subjects without symptoms of cardiovascular disease, the long-term effects of smoking on regional coronary artery vasoactivity, especially during sympathetic stimulation. In ten smoking and ten non-smoking sex- and age-matched healthy volunteers, segmental myocardial perfusion was studied using dynamic parametric nitrogen-13 ammonia positron emission tomography at rest and during sympathetic stimulation evoked by the cold pressor stimulation. Smokers demonstrated a higher myocardial perfusion at rest (116±17 ml/min/100 g vs 96±20 ml/min/100 g,P <0.01) and an impaired myocardial perfusion increase during cold pressor stimulation (1.02±0.15 vs 1.18±0.17,P <0.05). The heterogeneity of perfusion, expressed as coefficient of variation, was significantly different between the smoking and the non-smoking group. The coefficient of variation of segmental myocardial perfusion was higher in smokers at rest (17.5%±4.2% vs 13.5%±1.9%,P <0.05) and during cold pressor stimulation (17.0%±3.2% vs 13.9%±1.8%,P <0.05). We conclude that the long-term effects of smoking in healthy volunteers are associated with (1) increased myocardial perfusion at rest, (2) impaired myocardial perfusion response to cold pressor stimulation, and (3) increased myocardial perfusion heterogeneity both at rest and during cold pressor stimulation. These results may suggest that in healthy subjects the longterm effect of smoking is related to abnormal coronary artery vasoactivity, presumably induced by an interplay of regional endothelial dysfunction and autonomic dysregulation.

Suitability of CGP-12177 and CGP-26505 for quantitative imaging of β-adrenoceptors

[3H]CGP-12177, a non-selective beta-adrenoceptor antagonist, and [3H]CGP-26505, a beta 1-selective beta-adrenoceptor antagonist, were intravenously administered to rats. 94-97% of the injected radioactivity disappeared from plasma with t1/2 0.2 and 0.5 min. Total/non-specific binding ratios of 5.4 and 6.9 (CGP-12177) or 2.0 and 2.8 (CGP-26505) were maintained in heart and lung from 10 to 40 min post-injection. Labelled plasma metabolites appeared after greater than 20 min (CGP-12177) or within 2 min (CGP-26505). No metabolites were found in the heart. CGP-12177 binds to blood cells, but CGP-26505 does not. CGP-12177 can be used for PET imaging of total (beta 1 and beta 2) adrenoceptors in the heart and lung of experimental animals, but CGP-26505 is less suitable for in vivo analysis of the beta 1-subpopulation.

Campylobacter jejuni: enterocolitis and myopericarditis.

Campylobacter jejuni enteritis is the commonest enteric infection in the developed world. There are only few reported cases in the medical literature of cardiac complications associated with C. jejuni enterocolitis, most of the patients in the reported literature were males and most of the cases followed a benign course. Severe left ventricular dysfunction complicated only two cases of C. jejuni myocarditis. We report here a young male with Campylobacter myopericarditis. We believe that this is the first reported case of Campylobacter associated myopericarditis in The Netherlands. The mechanism by which Campylobacter causes myo(peri)carditis remains uncertain, it may be caused by direct bacterial invasion of cardiac tissue, bacterial toxins, circulating immune complexes, or cytotoxic T-cells. Since the number of C. jejuni infection is increasing worldwide, cardiac complications, although rare, are a remarkable manifestation of this pathogen and should be always kept in mind.

LATE ONSET ATRIOVENTRICULAR NODAL TACHYCARDIA

AV nodal tachycardia may present at any age, but onset in late adulthood is considered uncommon. To evaluate whether onset of AV nodal tachycardias at older age is related to organic heart disease (possibly setting the stage for re-entry due to degenerative structural changes) 32 consecutive patients with symptomatic AV nodal tachycardia were studied. The age at onset of attacks showed a bimodal pattern, with 2 peaks: one between 15 and 35 years (22 patients) and one around 55 years (10 patients). Significantly more older patients had an underlying heart disease (60% versus 14%, P < 0.01), with coronary artery disease in 4 and hypertensive heart disease in 3. Frequent supraventricular ectopic activity was seen during baseline 24-h ambulatory monitoring in all the older patients, versus in only half of the younger patients (P = 0.005). These results indicate that late onset AV nodal tachycardia (i.e. > age 45 years) is not infrequent (33%). The frequent supraventricular arrhythmias on one hand and age-related structural AV nodal changes, potentially enhanced by underlying heart disease on the other, both may contribute to the development of late onset re-entrant AV nodal tachycardia.

Autoperfusion balloon catheter for complicated coronary angioplasty: a prospective study with retrospective controls

Prolonged angioplasty balloon inflation with an autoperfusion balloon for failed conventional coronary angioplasty, was compared with emergency surgery for this condition. Restenosis was assessed 6 weeks after successful intervention with the autoperfusion balloon. Forty consecutive patients with persistent acute occlusion and/or severe intimal dissection during conventional angioplasty, were treated with the autoperfusion balloon. They were candidates for emergency surgery if it failed. Total inflation time was significantly longer (p < 0.001) with the autoperfusion balloon (27.5; 10-180 min) than with the standard balloon (10; 1-20 min) (median; range). The number of inflations was significantly lower (p < 0.001) with the autoperfusion balloon (2; 1-5 times) than with the standard balloon (5; 2-14 times) (median; range). Two patients died, one before surgery could be performed. The autoperfusion balloon was successful in 26 patients (65%). After 6 weeks, 16 (62%) were asymptomatic without anti-anginal medication, 24 underwent repeat angiography, 10 (42%) had restenosis, 7 (27%) underwent elective bypass surgery. Emergency surgery remained necessary in 13 patients (33%), 9 received arterial grafts. In 31 retrospective controls, who had undergone immediate surgery for the same indication, only venous grafts could be used. Thus, prolonged autoperfusion balloon inflation was successful in 65% of the cases of failed, conventional angioplasty. The angiographic restenosis rate after 6 weeks was 42%. If emergency surgery remained necessary, the autoperfusion balloon facilitated the use of arterial bypass grafts.