Infarct-related chronic total coronary occlusion and the risk of ventricular tachyarrhythmic events in out-of-hospital cardiac arrest survivors.

INTRODUCTION: Chronic total coronary occlusion (CTO) has been identified as a risk factor for ventricular arrhythmias, especially a CTO in an infarct-related artery (IRA). This study aimed to evaluate the effect of an IRA-CTO on the occurrence of ventricular tachyarrhythmic events (VTEs) in out-of-hospital cardiac arrest survivors without ST-segment elevation. METHODS: We conducted a post hoc analysis of the COACT trial, a multicentre randomised controlled trial. Patients were included when they survived index hospitalisation after cardiac arrest and demonstrated coronary artery disease on coronary angiography. The primary endpoint was the occurrence of a VTE, defined as appropriate implantable cardioverter-defibrillator (ICD) therapy, sustained ventricular tachyarrhythmia or sudden cardiac death. RESULTS: A total of 163 patients from ten centres were included. Unrevascularised IRA-CTO in a main vessel was present in 43 patients (26%). Overall, 61% of the study population received an ICD for secondary prevention. During a follow-up of 1 year, 12 patients (7.4%) experienced at least one VTE. The cumulative incidence rate of VTEs was higher in patients with an IRA-CTO compared to patients without an IRA-CTO (17.4% vs 5.6%, log-rank p = 0.03). However, multivariable analysis only identified left ventricular ejection fraction < 35% as an independent factor associated with VTEs (adjusted hazard ratio 8.7, 95% confidence interval 2.2-35.4). A subanalysis focusing on CTO, with or without an infarct in the CTO territory, did not change the results. CONCLUSION: In out-of-hospital cardiac arrest survivors with coronary artery disease without ST-segment elevation, an IRA-CTO was not an independent factor associated with VTEs in the 1st year after the index event.

Encouraging survival rates in patients with acute myocardial infarction treated with an intra-aortic balloon pump.

OBJECTIVE: To evaluate a 30-day and long-term outcome of patients with acute myocardial infarction (AMI) treated with intra-aortic balloon pump (IABP) counterpulsation and to identify predictors of a 30-day and long-term all-cause mortality. METHODS: Retrospective cohort study of 437 consecutive AMI patients treated with IABP between January 1990 and June 2004. A Cox proportional hazards model was used to identify predictors of a 30-day and long-term all-cause mortality. RESULTS: Mean age of the study population was 61 ± 11 years, 80% of the patients were male, and 68% had cardiogenic shock. Survival until IABP removal after successful haemodynamic stabilisation was 78% (n = 341). Cumulative 30-day survival was 68%. Median follow-up was 2.9 years (range, 6 months to 15 years). In patients who survived until IABP removal, cumulative 1-, 5-, and 10-year survival was 75%, 61%, and 39%, respectively. Independent predictors of higher long-term mortality were prior cerebrovascular accident (hazard ratio (HR), 1.8; 95% confidence interval (CI), 1.0-3.4), need for antiarrhythmic drugs (HR, 2.3; 95% CI, 1.5-3.3), and need for renal replacement therapy (HR, 2.3; 95% CI, 1.2-4.3). Independent predictors of lower long-term mortality were primary percutaneous coronary intervention (PCI; HR, 0.6; 95% CI, 0.4-1.0), failed thrombolysis with rescue PCI (HR, 0.5; 95% CI, 0.3-0.9), and coronary artery bypass grafting (HR, 0.3; 95% CI, 0.1-0.5). CONCLUSIONS: Despite high in-hospital mortality in patients with AMI treated with IABP, a favourable number of patients survived in the long-term. These results underscore the value of aggressive haemodynamic support of patients throughout the acute phase of AMI.

Evaluation of a single-tube real-time PCR for detection and identification of 11 dermatophyte species in clinical material.

We developed a dermatophyte-specific single-tube real-time PCR assay based on internal transcribed sequences. This assay allows the rapid detection and identification of 11 clinically relevant species within the three dermatophyte genera Trichophyton, Microsporum and Epidermophyton in nail, skin and hair samples within a few hours. Analysis of 145 clinical samples (107 nail, 36 skin scale, and two hair) by both real-time PCR and a PCR-reverse line blot (PCR-RLB) assay described earlier revealed that 133 of the 145 samples had concordant real-time PCR and PCR-RLB detection results (83 positive, 49 negative, and one inhibited). Six samples were positive by real-time PCR and negative by PCR-RLB, and two were negative by real-time PCR and positive by PCR-RLB. Four samples demonstrated inhibition in one of the two PCR assays. Only one of 83 positive samples had discordant identification results between both assays (Trichophyton verrucosum and Trichophyton erinacei by real-time PCR and Trichophyton erinacei by PCR-RLB). Dermatophytes present in seven positive samples that were incompletely identified as Trichophyton sp. by PCR-RLB were identified to the species level by real-time PCR as Trichophyton interdigitale and Trichophyton rubrum in six cases and one case, respectively. One hundred and twenty of 145 samples were also analysed by conventional dermatophyte culture and by direct microscopy. Our single-tube real-time PCR assay proved to be suitable for direct detection and identification of dermatophytes in nail, skin and hair samples with minimal total assay time (4 h after overnight lysis) and hands-on time, without the need for post-PCR analysis, and with good sensitivity and specificity.

Validation of PCR-reverse line blot, a method for rapid detection and identification of nine dermatophyte species in nail, skin and hair samples.

A dermatophyte-specific PCR-reverse line blot (PCR-RLB) assay based on internal transcribed sequences was developed. This assay allows the rapid detection and identification of nine clinically relevant species within the three dermatophyte genera Trichophyton, Microsporum and Epidermophyton in nail, skin and hair samples within 1 day. Analysis of 819 clinical samples (596 nail, 203 skin and 20 hair) revealed a positive PCR-RLB result in 93.6% of 172 culture-positive and microscopy-positive samples. PCR-RLB was superior to culture and direct microscopy, in both detection and species identification. Comparison of identification results of 208 PCR-positive and culture-positive clinical samples showed five discrepancies (2.4%) between PCR-RLB identification and classical microscopic/biochemical identification of isolates. Comparison of PCR-RLB identification and classical identification of 98 other isolates (dermatophytes and non-dermatophytes) revealed 13 discrepancies (13.3%) and five incomplete identifications of Trichophyton spp. Sequence analysis of ITS1 regions of 23 samples with discrepant or incomplete identification results (four Centraalbureau voor Schimmelcultures dermatophyte strains, four clinical samples and 15 clinical isolates) confirmed identification results of PCR-RLB in 21 of the 23 analyzed samples. PCR-RLB proved to be extremely suitable for routine detection and identification of dermatophytes directly in nail, skin and hair samples because it is rapid, sensitive, specific and accurate.

Upregulation of platelet derived endothelial cell growth factor/thymidine phosphorylase by interferon alpha.

Thymidine phosphorylase (TP) catalyzes the phosphorolytic cleavage of thymidine to thymine and deoxyribose-1-phosphate. TP, which is overexpressed in a wide variety of solid tumors, is involved in the activation and inactivation of fluoropyrimidines. TP is known to be regulated by several cytokines and interferons. In our HT29 cell line the TP mRNA and activity expression increased 2-3 fold after treatment with interferon alpha.

Differential anti-ischaemic effects of muscarinic receptor blockade in patients with obstructive coronary artery disease; impaired vs normal left ventricular function.

AIMS: In patients with coronary artery disease acetylcholine (a muscarinic agonist) causes vasoconstriction. The effect of atropine (a muscarinic antagonist) on coronary vasotone in patients with normal or impaired left ventricular function is unknown. METHODS AND RESULTS: Twenty-four patients who required atropine infusion (to supplement heart rate response) during atrial pacing (pacing was conducted to assess ischaemia as part of an experimental protocol) were studied; 17 patients had normal and seven impaired left ventricular function (ejection fraction < or =0.40). Two control groups were selected from a large database (from patients in whom atrial pacing was carried out but to whom atropine was not administered) to match the normal (n=20) and dysfunction (n=10) groups. In the normal left ventricular function group atropine increased rate pressure product by 12 +/- 4%, as compared to those without atropine (P < 0.05). Left ventricular end diastolic pressure increased less in the atropine group (+40 +/- 8% vs +78 +/- 6%;P < 0.05). Arterial norepinephrine increased similarly in both groups, but coronary flow (as assessed by using a thermodiluting method in the coronary sinus) increased 23 +/ -4% more in the atropine group (P < 0.05). Further, there were lower levels of myocardial lactate production and ST-segment depression in the atropine group [lactate extraction +13 +/- 6% (atropine) vs -19 +/- 4% (controls), ST-segment depression 1. 3 +/- 0.6 (atropine) vs 1.8 +/- 0.2 mm (control), both P < 0.05 between groups]. In contrast, in the dysfunction group the overall effect of atropine was less pronounced. CONCLUSION: In patients with normal left ventricular function atropine improves coronary flow and reduces myocardial lactate production and ST-segment depression during atrial pacing, suggesting a reduction in myocardial ischaemia.

Acute anti-ischemic effects of perindoprilat in men with coronary artery disease and their relation with left ventricular function.

Long-term angiotensin-converting enzyme (ACE) inhibition may reduce ischemic events in patients with coronary artery disease, but whether it protects against acute ischemia or the effects of preexisting left ventricular (LV) dysfunction on potential anti-ischemic properties is unknown. We performed a double-blind trial in 25 patients with exercise-induced ischemia. The effects of perindoprilat on pacing-induced myocardial ischemia were examined. Fourteen patients received perindoprilat and 11 patients received placebo. Based on LV function, 2 subgroups were formed in the perindoprilat group: 7 patients with LV dysfunction (LV ejection fraction <0.40), and 7 patients with normal LV function. After receiving the study medication, the pacing test was repeated. During the first pacing test both groups developed ischemia. After perindoprilat administration, the increase in systemic vascular resistance and LV end-diastolic pressure were significantly blunted (p <0.05). Further, the ischemia-induced increase in arterial and cardiac uptake of norepinephrine was inhibited by perindoprilat, and the increase in atrial natriuretic peptide was less pronounced; also, ST-segment depression was reduced by 32% compared with placebo (all p <0.05). In the group with LV dysfunction, perindoprilat reduced LV end-diastolic pressure significantly by 67% and myocardial lactate production was prevented, but this did not happen in the group with normal LV function. In addition, the increase in arterial norepinephrine was reduced by 74% and 33%, respectively (p <0.05). These results indicate that perindoprilat reduced acute, pacing-induced ischemia in normotensive patients. In patients with (asymptomatic) LV dysfunction these effects were more pronounced than in patients with normal LV function.

Neurohumoral response to carmoxirole, a selective dopamine (D2) receptor agonist, in patients with chronic moderate heart failure.

Neurohormonal activation and elevated ventricular filling pressures are prominent features in heart failure. Carmoxirole is a DA2 receptor agonist with limited central activity that modulates sympathetic activation and subsequently reduces pre-load and afterload in animals. The effect of carmoxirole on neurohormones and hemodynamics in humans was evaluated in 12 normotensive patients with NYHA class III-IV heart failure on stable ACE 1 and diuretic therapy. Carmoxirole (0.25-1.00 mg) was administered on 2 consecutive days, and hemodynamic and neurohormonal measurements were carried out. Values given are maximal percent changes from prestudy baseline (significance level P < 0.05). The lower dose on day 1 (0.25-0.50 mg) reduced circulating norepinephrine, vasopressin, and ANP by 40%, 19%, and 25%, respectively. In addition, on day 2, at a dose level of 0.75-1.00 mg, plasma renin activity decreased by 30%. Mean arterial pressure and systemic vascular resistance were reduced by 10% and 18%, and pulmonary wedge and right atrial pressure by 38% and 39%, respectively. Cardiac index improved by 20%. Despite a concomitant 12% reduction in heart rate, both stroke volume and stroke work index increased by 32% and 31%, respectively. Mean pulmonary artery pressure decreased by 21%, whereas pulmonary resistance was not affected. Thus, carmoxirole modulates sympathetic activation, accompanied by changes in vasopressin and ANP, and the renin-angiotensin system at higher dosages. These effects lead to a reduction in systemic resistance and heart rate, and an improvement in cardiac pump function and left and right ventricular filling pressures. It is concluded that carmoxirole induces beneficial effects on hemodynamic and neurohumoral parameters in heart failure.

Renal hemodynamic effects in patients with moderate to severe heart failure during chronic treatment with trandolapril.

Treatment of patients with severe heart failure by ACE inhibition is often limited by worsening of renal function. To evaluate whether trandolapril, a potent lipophilic ACE inhibitor, affects renal function in severe heart failure, we studied 12 patients with severe heart failure treated with only diuretics and digoxin. Patients received increasing oral dosages of trandolapril (0, 1, and 2 mg) on 3 consecutive days (A). Patients were then discharged on 2 mg trandolapril bid and re-evaluated 8 weeks later (B). Mean arterial and pulmonary wedge pressures decreased by maximal 14% and 43%, and stroke volume and work indexes increased by 24% and 20% at A and similarly at B (11, 45, and 25 ns and 33%, respectively). In contrast, heart rate, systemic resistance, pulmonary artery pressure, and cardiac index decreased by 6%, 23%, 29%, and 17%, respectively, at only A. Renal blood flow improved by approximately 40% both at A and B. In contrast, the glomerular filtration rate decreased by 25% at only B, whereas serum creatinine, creatinine clearance, and urine osmolality were unaffected during the study. Norepinephrine, angiotensin II, and aldosterone levels decreased by approximately 30%, 60%, and 65%, respectively, at both A and B. Renin levels increased by 136% at A and remained elevated at B. Thus, whereas the initial systemic vasodilating and inotropic effects did not persist, long-term trandolapril results in sustained neurohormonal modulation, reduced preload, and improved organ perfusion, indicated by a persistent increase in renal blood flow and preservation of renal function in severe heart failure.

Effects of epanolol, a selective beta1-blocker with intrinsic sympathomimetic activity, in patients with ischemic left ventricular dysfunction.

Recently, different beta-blockers have been shown to be effective in the treatment of chronic heart failure (CHF), but the importance of their ancillary properties is not clear. Epanolol is a selective beta1-blocker with intrinsic sympathomimetic activity, which has been shown useful in angina pectoris, but its value in patients with left ventricular (LV) dysfunction and CHF is unknown. We examined the effects of epanolol in patients with LV dysfunction (n = 8; mean LV ejection fraction, 0.33 +/- 0.08) and compared them with patients with normal LV function (n = 8; mean LV ejection fraction, 0.52 +/- 0.04). Measurement of invasive hemodynamics and neurohormones was performed at rest and during myocardial ischemia, which was induced by atrial pacing. All measurements were performed before and after epanolol. Before epanolol, pacing-induced ischemia led to a similar increase in norepinephrine and coronary sinus blood flow in both groups. After epanolol, the increase in neurohormones was more pronounced in the group with LV dysfunction (norepinephrine, 1,130 +/- 164 pg/ml for patients with LV dysfunction vs. 637 +/- 41 pg/ml for normal subjects; p < 0.05). A similar effect was observed for angiotensin II. Further, in the LV-dysfunction group, coronary sinus blood flow increased less, and coronary vascular resistance decreased less (both values, p < 0.05). Despite the fact that the increase in double product was decreased to a similar extent in both groups, ischemia was reduced only in normal LV function (p < 0.05). In ischemic LV dysfunction, neurohumoral activation after epanolol may impair adequate coronary flow response, and this may limit its antiischemic properties. Because of the small size of the study, no definitive inference on the clinical benefit of epanolol in patients with ischemic LV function can be made from this study.

A non-invasive selective assessment of type I fibre mitochondrial function using 31P NMR spectroscopy. Evidence for impaired oxidative phosphorylation rate in skeletal muscle in patients with chronic heart failure.

BACKGROUND: Skeletal muscle abnormalities contribute considerably to the clinical expression of heart failure. Deconditioning, underperfusion and an increased number of type IIb glycolytical fibres lead to early lactate production and muscle fatigue at low exercise levels. Aerobic muscle metabolism may also be impaired, as suggested by biopsy studies. Thus far, no data are available from non-invasive studies to indicate the extent of aerobic muscle dysfunction during low-grade exercise which does not induce acidosis. METHODS AND RESULTS: Mitochondrial function of skeletal muscle during fibre type I activation was studied in 22 patients with chronic heart failure [NYHA class III, left ventricular ejection fraction 28 +/- 2%, (patients)] on ACE inhibitors, diuretics and digoxin, and in 20 normal subjects, using 31P NMR spectroscopy of a single right forearm flexor muscle during three mild intermittent exercise levels (0-40% of maximum voluntary contraction) and recovery time. At rest, the inorganic phosphate/phosphocreatine ratio was different [0.13 +/- 0.005 (patients) vs 0.09 +/- 0.002 (normal subjects), P = 0.0001]. However, intracellular pH was comparable. Local acidosis (tissue pH < 6.9) was avoided to prevent fibre type IIb activation. Calculated resting phosphate potential levels were comparable, but the slope and intercept of the linear relationship of phosphate potential and workload were significantly lower in patients than in normal subjects (11.7 +/- 0.7 vs 15.8 +/- 0.6 and 139 +/- 7 vs 196 +/- 7, patients vs normal subjects, indicating early exhaustion of intracellular energy at lower exercise levels. Also, maximum calculated workload at which tissue ADP stabilized was lower in patients than in normal subjects (88 +/- 7% vs 120 +/- 4% of maximum voluntary workload, patients vs normal subjects, P < 0.05). Time to recovery to pre-test phosphocreatine levels was prolonged by 46% in patients compared to normal subjects (P < 0.05). CONCLUSIONS: In heart failure, oxidative fibre mitochondrial function in skeletal muscle is impaired, as reflected by the reduced phosphate potential and oxidative phosphorylation rate, early exhaustion and slowed recovery of intracellular energy reserve at workloads, which do not affect intracellular pH.

Early administration of ramipril in acute myocardial infarction: neurohormonal and hemodynamic effects and tolerability.

Although several large studies indicate a beneficial effect of angiotensin-converting enzyme (ACE) inhibitors after myocardial infarction, the optimal timing of therapy in terms of safety and the effects on neurohormones during myocardial infarction are less well known. In order to investigate the effect of ramipril, administered within 24 h after myocardial infarction, on hemodynamics and neurohormones and its safety, 20 patients with a myocardial infarction were studied. Nine patients had an anterior, 10 an inferior, and 1 a non-Q-wave infarction. Fourteen patients received thrombolytic therapy, whereas 6 did not. The initial dose of ramipril was 1.25 mg, but was gradually increased to 5 mg during the next 4 days. Side effects did not occur. The mean arterial pressure decreased 8 h after the first dose from 84 +/- 2 mm Hg (control) to 77 +/- 2 mm Hg (p < 0.05) and remained decreased thereafter. This was accompanied by a reduction in systemic resistance of 8% after 8 h and of 12% on day 2. Heart rate, cardiac and stroke indexes, and pulmonary artery and wedge pressures did not change. The ACE activity decreased within 1 h of ramipril administration with a maximum of 71% at 4 h after the second dose and remained at this level throughout the study. Angiotensin II decreased by 34% (day 2) and by 41% (day 5). The renin activity gradually increased from 33 +/- 7.5 to 75.4 +/- 11.5 microM/ml on day 5, whereas epinephrine was reduced from day 2 onwards, with a maximal reduction of 71% on day 5. Arginine vasopressin was significantly reduced 5 h after ramipril administration until the end of the study, with a maximum of 77% on day 3. Moreover, a late but significant decrease in norepinephrine occurred on day 5. Thus, oral ramipril results in early ACE inhibition, followed by progressive attenuation of the neuroendocrine activation and a reduction in afterload during the acute phase of myocardial infarction. It is well tolerated, also in combination with nitroglycerin and thrombolytic therapy.

Contrasting preload-dependent hemodynamic and neurohumoral effects of isomazole, a partial phosphodiesterase inhibitor and calcium sensitizer.

BACKGROUND: Currently evaluated positive inotropic agents that act predominantly through phosphodiesterase III-inhibiting properties, have been disappointing in the treatment of heart failure. Lack of efficacy as a result of diminished cellular cyclic adenosine monophosphate and vasodilating tolerance and side effects are prevalent. In contrast, calcium sensitization is preserved in heart failure and agents that combine phosphodiesterase-inhibiting and calcium-sensitizing properties may be more efficacious. Isomazole is such a novel agent with combined properties. This study investigated the acute hemodynamic and neurohormonal effects of intravenous isomazole (3 micrograms/kg/min for 30 minutes). METHODS AND RESULTS: The effects of preexisting preload were evaluated in 18 patients with heart failure, New York Heart Association class II/III, and elevated (> 15 mmHg, n = 11, group I) and normal; (n = 7, group II) pulmonary wedge pressure at baseline. In the overall group, isomazole increased myocardial contractility and relaxation and decreased systemic resistance by 20%. Left and right filling pressures fell by 35-45%, accompanied by a 69% reduction in cardiac atrial natriuretic peptide release. In contrast, levels of arterial norepinephrine and renin both increased by 27%. Cardiac output increased in group I (23%), but fell in group II (18%), accompanied by a 51% increase in arterial norepinephrine. Cardiac atrial natriuretic peptide decreased in group I, but not in group II. CONCLUSIONS: Isomazole induced positive inotropic and lusitropic effects and arterial vasodilation in all patients. Cardiac pump function improved only in group I, accompanied by a reduction in sympathetic activity and renin-angiotensin and aldosterone levels and a more pronounced decrease in cardiac atrial natriuretic peptide release. In contrast, in patients with normal to low preload, the further reduction in preload led to a deterioration of pump function and increased sympathetic tone.

Acute hemodynamic effects and preload-dependent cardiovascular profile of the partial phosphodiesterase inhibitor nanterinone in patients with mild to moderate heart failure.

Nanterinone (UK-61,260) is a novel positive inotropic and balanced-type vasodilating drug, only partially based on phosphodiesterase III inhibition. Preliminary data from controlled studies suggest satisfactory long-term efficacy and safety. As its acute hemodynamic effects in humans are unknown, an oral dose of 2 mg nanterinone was studied in 14 patients with heart failure (NYHA class II-III) on chronic diuretic and angiotensin-converting enzyme (ACE) inhibitor treatment. Before the study, patients were on a 2 g salt-balanced diet, and they received their last medication 16 hours before each study day. Hemodynamic measurements were carried out before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours after administration of the study drug. All patients received placebo and nanterinone on 2 consecutive days. Following nanterinone, systemic vascular resistance decreased immediately from 1699 +/- 82 (mean +/- SEM) at baseline to 1368 +/- 80 at 1 hour. Changes persisted for 12 hours. Concomitantly, there was an immediate and significant fall in pulmonary wedge pressure to 38% of baseline at 1.5 hours, together with a 20% reduction in pulmonary artery pressure. Heart rate remained unchanged and arterial pressures showed only a short, significant decrease. Cardiac index rose significantly from 2.28 +/- 0.15 at baseline to a highest value of 2.65 +/- 0.14 1/min/m2 at 1 hour. Changes persisted for 3 hours. Placebo had no effect on these variables. As, in view of its potential venodilating properties, hemodynamic improvement by nanterinone may depend on pre-existing left ventricular filling pressure, patients were subsequently grouped according to baseline pulmonary wedge pressure of > 12 mmHg (H-PCWP) and < or = 12 mmHg (L-PCWP). Cardiac index improved by 26% in H-PCWP and by 17% in L-PCWP (NS). In contrast, PCWP fell more markedly in H-PWCP than in L-PCWP (40% and 23%, respectively, p < 0.05). Thus, oral nanterinone results in a significant acute hemodynamic improvement and is well tolerated. Although changes in left ventricular filling pressure are more pronounced in patients with elevated pre-existing PCWP, cardiac pump function improves equally in patients with normal or low left ventricular filling pressure at baseline.