Peak oxygen uptake during cardiopulmonary exercise testing determines response to cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) is an established treatment modality for advanced heart failure (HF) but 20-30% of patients treated with CRT do not experience clinical improvement. Hence, in this study we aimed to investigate whether baseline cardiopulmonary exercise testing (CPX) can help improve the prediction of a positive functional CRT response. METHODS: This prospective observational study included 76 HF patients undergoing elective CRT implantation and clinical CPX and echocardiographic assessment were performed at baseline, 6, and 12 months. RESULTS: Peak VO2 increased from 11.0±2.5 ml/min/kg to 12.0±4.1 ml/min/kg and 12.2±3.5 ml/min/kg at 6 and 12 months after CRT, respectively. The number of patients classified as "CRT-responders" (Δ peak VO2≥1 ml/kg/min) was 33 (46%) and 36 (52%) at 6 and 12 months after CRT, respectively. Patients with baseline peak VO2<40% of predicted (lowest tertile) demonstrated a 68% and 69% response rate at 6 and 12 months, respectively, as compared to a 35% and 42% response rate among patients with baseline peak VO2≥40% of predicted (p=0.01 and p=0.02, respectively). In multivariate analysis patients with baseline peak VO2<40% of predicted had an adjusted odds ratio of 4.4 (95% CI 1.6-12.5; p<0.01) and 3.1 (95% CI 1.1-8.8; p=0.03) for positive CRT response at 6 and 12 months, respectively. CONCLUSIONS: Treatment with CRT improves exercise capacity but this increase is most substantial among patients with a lower baseline peak VO2 (% of predicted). Baseline CPX can, therefore, be utilized to identify patients more likely to exhibit a functional improvement after CRT.

Prognostic value of cardiac troponin T in patients with moderate to severe heart failure scheduled for cardiac resynchronization therapy.

BACKGROUND: Predicting response to cardiac resynchronization therapy (CRT) is challenging. Highly sensitive cardiac troponin T (hsTnT) might predict response to CRT and identify patients at a high risk of experiencing severe cardiovascular events. We investigated whether baseline levels of hsTnT were associated with response to CRT and with severe cardiovascular events after long-term follow-up. METHODS: Eighty-one consecutive patients were included according to the current guidelines for CRT. Biochemical, functional, and clinical parameters were assessed at baseline and at 3, 6, and 12 months of follow-up; and mortality/cardiac transplantation after 46 ± 6 months of follow-up was investigated. Cardiac magnetic resonance imaging and echocardiography were used to assess left ventricular function including viability and remodeling. RESULTS: Seventy-five patients completed 12 months of follow-up; and after a follow-up of 46 ± 6 months, a total of 15 patients died, 13 of these from cardiovascular causes, and 7 underwent heart transplantation. Baseline hsTnT <15 ng/L predicted response to CRT and was associated with a more favorable outcome with regard to severe cardiovascular events. Multivariate analysis found that presence of transmural scar tissue/fibrosis on magnetic resonance imaging and use of statins were independently associated with higher concentrations of hsTnT at baseline. There was a strong correlation between hsTnT and N-terminal pro-B-type natriuretic peptide levels. CONCLUSIONS: Highly sensitive TnT levels were elevated in the majority of heart failure patients who were scheduled for CRT. The HsTnT levels predicted response to CRT as well as long-time survival.

Assessment of response criteria to cardiac resynchronization therapy (CRT) and prediction of response.

AIMS: Approximately 30% of patients treated with cardiac resynchronization therapy (CRT) do not respond. We evaluated response to CRT at six and 12 months, tested a novel response criterion and evaluated different clinical and echocardiographic predictors of response. METHODS AND RESULTS: Eighty one patients were enrolled. A definition of response to CRT was predefined as a combination of 1) a reduction of LV end-systolic volume of ≥10% and 2) either an improvement in NYHA class by ≥1 or an increase in peak oxygen consumption of ≥1 ml/kg/min. Pre-and postoperatively at six and 12 months we also evaluated the most commonly employed definitions of response in our material: NYHA class, quality of life, left ventricular (LV) performance and functional capacity. After six and 12 months of CRT, 42 (52%) and 48 patients (59%) were responders, respectively. Employing different criteria, response ranged from 33-96% and 31-94% at six and 12 months, respectively. In our material a large pre-operative interventricular motion delay (IVMD) was a predictor of response to CRT (p<0.05). CONCLUSIONS: Fifty two percent and 59% were responders to CRT at six months and one year given a predefined novel endpoint. Different response criteria to CRT gave response rates ranging from 33-96% and 31-94% at six and 12 months, respectively. A large IVMD predicts response to CRT at six and 12 months.

Aetiology-specific patterns in end-stage heart failure patients identified by functional annotation and classification of microarray data.

BACKGROUND: The objective of the present study was to use gene expression profiling, functional annotations and classification to identify aetiology-specific biological processes and potential molecular markers for different aetiologies of end-stage heart failure. METHODS AND RESULTS: Individual left ventricular myocardial samples from eleven coronary artery disease and nine dilated cardiomyopathy transplant patients were co-hybridized with pooled RNA from four non-failing hearts on custom-made arrays of 7000 human genes. Significance analysis identified differential expression of 153 and 147 genes, respectively, in coronary artery disease or dilated cardiomyopathy versus non-failing hearts. Analysis of Gene Ontology biological process annotations indicated aetiology-specific patterns, primarily related to genes involved in catabolism and in regulation of protein kinase activity. Gene expression classifiers were obtained and used for class prediction of random samples of coronary artery diseased and dilated cardiomyopathic hearts. Best classifiers frequently included matrix metalloproteinase 3, fibulin 1, ATP-binding cassette, sub-family B member 1 and iroquois homeobox protein 5. CONCLUSION: Combining functional annotation from microarray data and classification analysis constitutes a potent strategy to identify disease-specific biological processes and gene expression markers in e.g. end-stage coronary artery disease and dilated cardiomyopathy.

Presence and development of atrial fibrillation in chronic heart failure. Experiences from the MERIT-HF Study.

BACKGROUND: Atrial fibrillation is common in heart failure, but data regarding beta-blockade in these patients and its ability to prevent new occurrence of atrial fibrillation are scarce. METHODS: Baseline ECGs in MERIT-HF were coded regarding baseline rhythm, and outcome was analyzed in relation to rhythm. Occurrence of atrial fibrillation during follow-up was also analyzed. RESULTS: At baseline atrial fibrillation was diagnosed in 556 patients (13.9%). Mean metoprolol CR/XL dose in patients in atrial fibrillation (154 mg) and sinus rhythm (158 mg) was similar, as well as decrease in heart rate (14.8 and 13.7 bpm, respectively). Only 61 (total of 362) deaths occurred in those in atrial fibrillation at baseline, 31 on placebo and 30 on metoprolol (RR 1.0; 95% CI 0.61-1.65). During follow-up, new atrial fibrillation was observed in 85 patients on placebo and 47 patients on metoprolol (RR 0.53; 95% CI 0.37-0.76; p=0.0005). CONCLUSION: First, given the wide confidence interval, it was impossible to detect an interaction between metoprolol and mortality in patients with atrial fibrillation and heart failure. Second, in patients with sinus rhythm at baseline, metoprolol reduced the incidence of atrial fibrillation during follow-up. However, we must be extremely cautious in over-interpreting effects in these subgroups.

Functional serotonin 5-HT4 receptors in porcine and human ventricular myocardium with increased 5-HT4 mRNA in heart failure.

Serotonin (5-hydroxytryptamine, 5-HT) increases contractile force and elicits arrhythmias through 5-HT(4) receptors in porcine and human atrium, but its ventricular effects are unknown. We now report functional 5-HT(4) receptors in porcine and human ventricle. 5-HT(4) mRNA levels were determined in porcine and human ventricles and contractility studied in ventricular trabeculae. Cyclic AMP-dependent protein kinase (PKA) activity was measured in porcine ventricle. Porcine and human ventricles expressed 5-HT(4) receptor mRNA. Ventricular 5-HT(4(b)) mRNA was increased by four times in 20 failing human hearts compared with five donor hearts. 5-HT increased contractile force maximally by 16% (EC(50)=890 nM) and PKA activity by 20% of the effects of (-)-isoproterenol (200 microM) in ventricular trabeculae from new-born piglets in the presence of the phosphodiesterase-inhibitor 3-isobutyl-1-methylxanthine. In ventricular trabeculae from adult pigs (3-isobutyl-1-methylxanthine present) 5-HT increased force by 32% (EC(50)=60 nM) and PKA activity by 39% of (-)-isoproterenol. In right and left ventricular trabeculae from failing hearts, exposed to modified Krebs solution, 5-HT produced variable increases in contractile force in right ventricular trabeculae from 4 out of 6 hearts and in left ventricular trabeculae from 3 out of 3 hearts- range 1-39% of (-)-isoproterenol, average 8%. In 11 left ventricular trabeculae from the failing hearts of four beta-blocker-treated patients, pre-exposed to a relaxant solution with 0.5 mM Ca(2+) and 1.2 mM Mg(2+) followed by a switch to 2.5 mM Ca(2+) and 1 mM Mg(2+), 5-HT (1-100 microM, 3-isobutyl-1-methylxanthine present) consistently increased contractile force and hastened relaxation by 46% and 25% of (-)-isoproterenol respectively. 5-HT caused arrhythmias in three trabeculae from 3 out of 11 patients. In the absence of phosphodiesterase inhibitor, 5-HT increased force in two trabeculae, but not in another six trabeculae from 4 patients. All 5-HT responses were blocked by 5-HT(4) receptor antagonists. We conclude that phosphodiesterase inhibition uncovers functional ventricular 5-HT(4) receptors, coupled to a PKA pathway, through which 5-HT enhances contractility, hastens relaxation and can potentially cause arrhythmias.

Soluble CD40 ligand in pulmonary arterial hypertension: possible pathogenic role of the interaction between platelets and endothelial cells.

BACKGROUND: Inflammatory processes seem to be involved in pulmonary arterial hypertension (PAH). CD40 ligand (L) may promote inflammation and thrombus formation, and we hypothesized that CD40L could be involved in the pathogenesis of PAH. METHODS AND RESULTS: Several significant findings were revealed when examining the possible role of CD40L in PAH. (1) Patients with primary (n=13) and secondary (n=11) PAH but not those with chronic thromboembolic pulmonary hypertension (n=8) had increased plasma levels of soluble (s) CD40L compared with control subjects (n=8). (2) PAH patients using warfarin had markedly lower sCD40L levels than those without such therapy. (3) sCD40L levels were higher in arterial (femoral artery) compared with mixed venous blood (pulmonary artery), suggesting enhanced release or reduced clearance in the pulmonary vasculature. (4) Platelets from PAH patients showed enhanced spontaneous and SFLLRN-stimulated release of sCD40L compared with control subjects. (5) In vitro, recombinant sCD40L induced monocyte chemoattractant protein (MCP)-1 and interleukin-8 gene expression in endothelial cells, and plasma levels of these chemokines were raised in all PAH groups, significantly correlated to sCD40L and hemodynamic parameters. (6) Although prostacyclin therapy (3 months) showed clinical benefit, this therapy had no effect on sCD40L and increased MCP-1 levels in PAH patients, and prostacyclin enhanced MCP-1 in CD40L-stimulated endothelial cells. CONCLUSIONS: Our findings suggest a role for CD40L in the pathogenesis of PAH, possibly operating through an interaction between platelets and endothelial cells involving chemokine-related mechanisms.

Implantable cardioverter defibrillator dysfunction during and after magnetic resonance imaging.

This report describes a patient in whom a MRI of the brain was performed without realizing that an ICD had been implanted 8 days previously. Electromagnetic noise induced during the MRI was detected as ventricular fibrillation and nearly caused inappropriate shocks. Charge time during MRI was prolonged. The battery indicator switched to "end of life," but this was reversed by capacitor reformation. These problems could have been avoided by inactivating the ICD prior to MRI. Three months later, the pacing threshold increased from 0.4 V per 0.5 ms at implantation to 2.8 V per 0.5. It is still uncertain whether radiofrequency current heating at the electrode tip caused the increased pacing threshold or if this would have occurred independently of the MRI. MRI of patients with an active ICD may cause life-threatening complications, and it is unknown if MRI may be safely performed if the ICD is inactivated. Therefore, MRI of patients with an ICD remains contraindicated.

Alpha(1)-AR-induced positive inotropic response in heart is dependent on myosin light chain phosphorylation.

The possible involvement of different kinases in the alpha(1)-adrenoreceptor (AR)-mediated positive inotropic effect (PIE) was investigated in rat papillary muscle and compared with beta-AR-, endothelin receptor- and phorbol ester-induced changes in contractility. The alpha(1)-AR-induced PIE was not reduced by the inhibitors of protein kinase C (PKC), MAPK (ERK and p38), phosphatidyl inositol 3-kinase, or calmodulin kinase II. However, PKC inhibition attenuated the effect of phorbol 12-myristate 13-acetate (PMA) on contractility. alpha(1)-AR-induced PIE was reduced by approximately 90% during inhibition of myosin light chain kinase (MLCK) by 1-(5-chloronaphthalene-1-sulfonyl)1H-hexahydro-1,4-diazepine (ML-9). Endothelin-induced PIE was also reduced by ML-9, but ML-9 had no effect on beta-AR-induced PIE. The Rho kinase inhibitor Y-27632 also reduced the alpha(1)-AR-induced PIE. The alpha(1)-AR-induced PIE in muscle strips from explanted failing human hearts was also sensitive to MLCK inhibition. alpha(1)-AR induced a modest increase in (32)P incorporation into myosin light chain in isolated rat cardiomyocytes. This effect was eliminated by ML-9. The PIE of alpha(1)-AR stimulation seems to be dependent on MLCK phosphorylation.

Short and medium time experience with a tined, multilumen steroid eluting defibrillation lead.

Both leads and pulse generators of implantable defibrillators have undergone important improvements during the last years. New leads should be tested against previous models to demonstrate safety and reliability. When introduced in 1995, the Medtronic 6932 pace, sense and defibrillation lead was compared to the alternative larger 6936 lead in a short-term randomized study with a mean follow-up of 2.4 +/- 2.0 months. A subgroup of patients were followed for 23.9 +/- 9.0 months. Three hundred and thirty-six patients were randomized to receive either the 6932 or the 6936 lead. Defibrillation threshold at implant, tested using a binary search protocol, was similar for the two leads. The pacing threshold was significantly lower for the 6932 lead both at implant and at follow-up, probably due to the steroid eluting tip of the electrode. R-wave amplitudes were similar for the leads, as were the complication rates. During about two years of follow-up, both leads performed well, with a slightly lower pacing threshold for the 6932 lead.