Idiopathic dilated cardiomyopathy and chronic atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is common in idiopathic dilated cardiomyopathy (IDC). We explored the clinical characteristics of IDC patients with chronic AF compared with those with sinus rhythm (SR). METHODS: A group of patients with IDC underwent extensive non-invasive and invasive evaluation during a hospitalization period. The patients were further divided into two groups with AF (n = 19) and SR (n = 68). RESULTS: Left atrial diameter was greater (P<0·001), left ventricular end-diastolic diameter smaller (P<0·05), left ventricular end-diastolic and end-systolic volumes smaller (P<0·01 for all), mean pulmonary artery pressure and pulmonary capillary wedge pressure higher (P<0·05 for both), cardiac output and maximal oxygen consumption lower (P<0·01 and P<0·05, respectively), and the levels of N-terminal pro-brain natriuretic peptide and interleukin-6 higher (P<0·05 for both) in AF group compared with SR group. Left ventricular ejection fraction and left ventricular end-diastolic pressure were similar in both groups. CONCLUSIONS: In spite of otherwise more unfavourable prognostic factor profile, left ventricular size was observed to be smaller in chronic AF compared with SR in well-characterized patients with IDC. The confirmation and possible explainers of this paradoxical phenomenon need further studies in larger patient cohorts.

Intermittent levosimendan treatment in patients with severe congestive heart failure.

OBJECTIVE: Levosimendan (LS) is a novel inodilator for the treatment of severe congestive heart failure (CHF). In this study, we investigated the potential long-term effects of intermittent LS treatment on the pathophysiology of heart failure. METHODS: Thirteen patients with modest to severe CHF received three 24-h intravenous infusions of LS at 3-week intervals. Exercise capacity was determined by bicycle ergospirometry, well-being assessed by Minnesota Living with Heart Failure Questionnaire (MLHFQ) and laboratory parameters of interest measured before and after each treatment. RESULTS: One patient experienced non-sustained periods of ventricular tachycardia (VT) during the first infusion and had to discontinue the study. Otherwise the LS infusions were well tolerated. Exercise capacity (VO2max) did not improve significantly during the study although symptoms decreased (P < 0.0001). Levels of plasma NT-proANP, NT-proBNP and NT-proXNP decreased 30-50% during each infusion (P < 0.001 for all), but the changes disappeared within 3 weeks. Although norepinephrine (NE) appeared to increase during the first treatment (P = 0.019), no long-term changes were observed. CONCLUSION: Intermittent LS treatments decreased effectively and repetitively plasma vasoactive peptide levels, but no carryover effects were observed. Patients' symptoms decreased for the whole study period although there was no objective improvement of their exercise capacity. The prognostic significance of these effects needs to be further studied.

Cardiac MRI assessed left ventricular hypertrophy in differentiating hypertensive heart disease from hypertrophic cardiomyopathy attributable to a sarcomeric gene mutation.

OBJECTIVE: To evaluate the value of cardiac magnetic resonance imaging (CMRI)-assessed left ventricular hypertrophy (LVH) in differentiating between hypertensive heart disease and hypertrophic cardiomyopathy (HCM). METHODS: 95 unselected subjects with mild-to-moderate hypertension, 24 patients with HCM attributable to the D175N mutation of the α-tropomyosin gene and 17 control subjects were studied by cine CMRI. Left ventricular (LV) quantitative and qualitative characteristics were evaluated. RESULTS: LV maximal end-diastolic wall thickness, wall thickness-to-LV volume ratio, end-diastolic septum thickness and septum-to-lateral wall thickness ratio were useful measures for differentiating between LVH due to hypertension and HCM. The most accurate measure for identifying patients with HCM was the LV maximal wall thickness ≥ 17 mm, with a sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of 90%, 93%, 86%, 95% and 91%, respectively. LV maximal wall thickness in the anterior wall, or regional bulging in left ventricular wall was found only in patients with HCM. LV mass index was not discriminant between patients with HCM and those with LVH due to hypertension. CONCLUSION: LV maximal thickness measured by CMRI is the best anatomical parameter in differentiating between LVH due to mild-to-moderate hypertension and HCM attributable to a sarcomeric mutation. CMRI assessment of location and quality of LVH is also of value in differential diagnosis.

Metoprolol versus amiodarone in the prevention of atrial fibrillation after cardiac surgery: a randomized trial.

BACKGROUND: Current guidelines recommend ß-blockers as the first-line preventive treatment of atrial fibrillation (AF) after cardiac surgery. Despite this, 19% of physicians report using amiodarone as first-line prophylaxis of postoperative AF. Data directly comparing the efficacy of these agents in preventing postoperative AF are lacking. OBJECTIVE: To determine whether intravenous metoprolol and amiodarone are equally effective in preventing postoperative AF after cardiac surgery. DESIGN: Randomized, prospective, equivalence, open-label, multicenter study. (ClinicalTrials.gov registration number: NCT00784316) SETTING: 3 cardiac care referral centers in Finland. PATIENTS: 316 consecutive patients who were hemodynamically stable and free of mechanical ventilation and AF within 24 hours after cardiac surgery. INTERVENTION: Patients were randomly assigned to receive 48-hour infusion of metoprolol, 1 to 3 mg/h, according to heart rate, or amiodarone, 15 mg/kg of body weight daily, with a maximum daily dose of 1000 mg, starting 15 to 21 hours after cardiac surgery. MEASUREMENTS: The primary end point was the occurrence of the first AF episode or completion of the 48-hour infusion. RESULTS: Atrial fibrillation occurred in 38 of 159 (23.9%) patients in the metoprolol group and 39 of 157 (24.8%) patients in the amiodarone group (P = 0.85). However, the difference (-0.9 percentage point [90% CI, -8.9 to 7.0 percentage points]) does not meet the prespecified equivalence margin of 5 percentage points. The adjusted hazard ratio of the metoprolol group compared with the amiodarone group was 1.09 (95% CI, 0.67 to 1.76). LIMITATIONS: Caregivers were not blinded to treatment allocation, and the trial evaluated only stable patients who were not at particularly elevated risk for AF. The withdrawal of preoperative ß-blocker therapy may have increased the risk for AF in the amiodarone group. CONCLUSION: The occurrence of AF was similar in the metoprolol and amiodarone groups. However, because of the wide range of the CIs, the authors cannot conclude that the 2 treatments were equally effective. PRIMARY FUNDING SOURCE: The Finnish Foundation for Cardiovascular Research and the Kuopio University EVO Foundation.

Effect of levosimendan in experimental verapamil-induced myocardial depression.

BACKGROUND: Calcium antagonist overdose can cause severe deterioration of hemodynamics unresponsible to treatment with beta adrenergic inotropes. The aim of the study was to evaluate in an experimental model the effects of levosimendan during severe calcium antagonist intoxication. METHODS: Twelve landrace-pigs were intoxicated with intravenous verapamil at escalating infusion rates. The infusion containing 2.5 mg/ml verapamil was used aiming to a reduction of cardiac output by 40% from the baseline value. Intoxicated pigs were randomized into two groups: control (saline) and levosimendan (intravenous bolus). Inotropic effect was measured as a change in a maximum of the positive slope of the left ventricular pressure (LV dP/dt). The survival and hemodynamics of the animals were followed for 120 min after the targeted reduction of cardiac output. RESULTS: In the control group, five out of six pigs died during the experiment. In the levosimendan group, one pig died before completion of the experiment (p = 0.04). In the levosimendan group a change in LV dP/dt was positive in four out of six pigs compared to one out of six pigs in the control group (p = ns). CONCLUSIONS: In this experimental model, the use of levosimendan was associated with improved survival.

Cardiac sympathetic activity is associated with inflammation and neurohumoral activation in patients with idiopathic dilated cardiomyopathy.

BACKGROUND: Idiopathic dilated cardiomyopathy (IDC) is characterized by sympathetic nervous overactivity, inflammation and neurohumoral activation; however, their interrelationships are poorly understood. METHODS AND RESULTS: We studied 99 patients with IDC (age 54 +/- 1 years, left ventricular ejection fraction (EF) 40 +/- 1%, maximum oxygen uptake (VO(2)max) 20 +/- 1 ml kg(-1) min(-2), mean +/- SEM) by using (123)I-metaiodobenzylguanidine (MIBG) imaging. MIBG washout and MIBG heart/mediastinum (H/M)-ratio at 4 h postinjection were calculated. In addition, the plasma levels of interleukin (IL)-6 and N-terminal B-type natriuretic peptide (NT-proBNP) were measured. MIBG washout and MIBG H/M ratio had a significant correlation with IL-6 (r = 0.42, P<0.001 and r = -0.31, P<0.01) and NT-proBNP (r = 0.48, P<0.001 and r = -0.40, P<0.001). During a median follow-up of 4.1 years, 20 patients (20%) had an adverse cardiac event (death, heart transplantation or application of biventricular pacemaker or implantable cardioverter-defibrillator). In these patients, MIBG washout was higher (53 +/- 4 versus 40 +/- 2%, P = 0.01) and H/M ratio lower (1.38 +/- 0.04 versus 1.51 +/- 0.02, P = 0.01) than in patients without an event. CONCLUSIONS: In dilated cardiomyopathy, myocardial sympathetic innervation and activity are related to inflammation and neurohumoral activation. These relationships are at least partly independent of left ventricular function and exercise capacity.

Clinical significance of troponin I efflux and troponin autoantibodies in patients with dilated cardiomyopathy.

BACKGROUND: The appearance of circulating autoantibodies against cardiac troponin I (cTnAbs) in patients with heart failure has been reported. We sought to evaluate the role of circulating cardiac troponin I (cTnI) and cTnAbs in the pathophysiology and prognosis of idiopathic dilated cardiomyopathy. METHODS AND RESULTS: Circulating concentrations of cTnI and the presence of cTnAbs were determined in 95 patients with idiopathic dilated cardiomyopathy. The patients underwent laboratory testing, echocardiography, cardiopulmonary exercise testing, gated single photon emission computed tomography, and both-sided cardiac catheterization during a 3-day study period. Compared with cTnI- patients, the hearts of cTnI+ patients (cTnI > or = 0.01 ng/mL, n = 19) were significantly more dilated (left ventricular end-diastolic diameter 67 vs 61 mm, P < .05; left ventricular end-systolic dimension, 55 vs 49 mm, P < .01; echocardiography) and demonstrated greater intracardiac volumes (left ventricular end-diastolic volume 161 vs 132 mL, P = .060; left ventricular end-systolic volume 112 vs 82 mL, P < .05; gated single photon emission computed tomography), more disturbed systolic (ejection fraction 27 vs 33%, P < .05; gated single photon emission computed tomography) and cardiac sympathetic (123I-metaiodobenzylguanidine washout: 41% vs 34%; P < .05) function, and higher levels of vasoactive peptides (N-terminal proatrial natriuretic peptide 1030 vs 558 pmol/L, P < .05; N-terminal pro-B type natriuretic peptide 337 vs 115 pmol/L, P < .05). In addition, during a median follow-up time of 4.1 years, cTnI+ patients had clinical end points (cardiovascular death, heart transplantation, or clinical need for an automatic implantable cardioverter defibrillator) more often than cTnI- patients (37% vs 8%, P < .01). The presence of circulating cTnAbs (n = 15) was not associated with patients' clinical status or outcome. CONCLUSION: Patients with idiopathic dilated cardiomyopathy with cTnI efflux demonstrate more prominent changes in the indices of left ventricular remodeling and function than patients without signs of cTnI efflux. Moreover, elevated serum cTnI is associated with poor clinical outcome. The presence of circulating cTnAbs seems to have less utility in the clinical assessment of these patients. However, their pathogenic role in disease progression in the long term cannot be excluded.

Utility of cough response during hypertonic histamine challenge in diagnosing asthma.

Airway responses to bronchial provocation tests are traditionally assessed with spirometry which necessitates considerable patient co-operation. It has been shown that coughing during bronchial provocation tests is related to the degree of bronchoconstriction which, in turn, is independent of patient co-operation. The aim of the present study was to evaluate the utility of coughing induced by the hypertonic histamine challenge in the differential diagnosis of asthma in a clinically relevant patient population. The study population consisted of 25 healthy volunteers, 30 asthmatics, and 82 non-asthmatic subjects with respiratory symptoms due to other diseases. Hypertonic histamine solution was administered with ultrasonic nebuliser with the challenges being videotaped. The cough response was expressed as the cumulative number of coughs divided by the final histamine concentration administered (CCR). The geometric mean (95% CI) of CCR for asthmatics was 302 (166-562) coughs per mg/ml, for the symptomatic controls 29.5 (20.0-43.7) coughs per mg/ml (p<0.001) and for the healthy controls 6.61 (3.02-14.5) (p<0.001) coughs per mg/ml. According to the ROC curve, the optimal cut-off point for logCCR was 2.22, with the specificity and sensitivity to detect asthma among symptomatic subjects being 86% and 70%. Cough response to hyperosmolar challenge may be useful in the differential diagnosis of airway diseases.

Significance of plasma levels of N-terminal Pro-B-type natriuretic peptide on left ventricular remodeling in non-obstructive hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the alpha-tropomyosin gene.

Hypertrophic cardiomyopathy (HC) is an inherited heart disease characterized by left ventricular (LV) remodeling. The present study was conducted to investigate the association of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) levels with LV remodeling on magnetic resonance imaging and procollagen formation in 17 healthy controls and 24 patients with nonobstructive HC attributable to an identical Asp175Asn (aspartic acid to asparagine at codon 175) mutation in the alpha-tropomyosin gene. None of the patients had history of decompensated heart failure, and all patients had normal LV ejection fraction. Patients with HC had higher NT-pro-BNP levels compared with controls (median 60 pmol/L, range <40 to 359, vs <40 pmol/L; p <0.001), but 9 patients with HC had normal NT-pro-BNP levels (<40 pmol/L). In patients with HC, levels of NT-pro-BNP were correlated significantly with LV end-systolic volume index (r = 0.50, p <0.05), LV mass index (r = 0.47, p <0.05), proportion of hypokinetic segments (r = 0.50, p <0.05), and levels of serum aminoterminal propeptide of type III procollagen (r = 0.52, p <0.01). When patients with HC were divided into 3 groups on the basis of their NT-pro-BNP levels, there were statistically significant linear associations of LV end-systolic volume (test for linearity p = 0.034), LV mass index (p = 0.009), proportion of hypokinetic segments (p = 0.016), and levels of serum aminoterminal propeptide of type III procollagen (p = 0.020) with NT-pro-BNP levels over the 3 groups, suggesting a tight relation between LV remodeling and levels of NT-pro-BNP. In conclusion, in patients with nonobstructive HC attributable to an Asp175Asn mutation in the alpha-tropomyosin gene, elevated NT-pro-BNP levels are associated with incipient LV remodeling, suggesting that NT-pro-BNP could be used to diagnose insidious unfavorable LV remodeling in HC.

Cytokines, interstitial collagen and ventricular remodelling in dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is associated with myocardial fibrosis, and proinflammatory cytokines may play a role in this. METHODS: N-terminal type I and III procollagen propeptides (PINP, PIIINP) and cross-linked telopeptide of type I collagen (ICTP) were measured from serum samples of 73 patients with DCM and 56 age and sex matched controls. Circulating cytokine levels were determined in DCM patients. RESULTS: Serum levels of PINP and PIIINP were lower in patients than in controls (p<0.05 and p=0.001). In patients with DCM, the levels of PIIINP and ICTP correlated significantly with each other (p<0.01), and the proinflammatory cytokines, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6), correlated positively with ICTP (p<0.001, p<0.05), PIIINP/PINP ratio (p<0.05, p<0.01) and left atrial size (p<0.01, p<0.05). Presence of atrial fibrillation was associated with lower serum PINP level and higher PIIINP/PINP ratio (p<0.05). CONCLUSIONS: Our results suggest that interstitial myocardial collagen metabolism is altered in DCM patients and regulated by proinflammatory cytokines. These changes in collagen metabolism are associated with presence of atrial fibrillation, but do not reflect left ventricular remodelling. Treatment with beta-blockers and inhibitors of the renin angiotensin aldosterone system seem to effectively inhibit overall type I and III collagen syntheses.

Electrocardiographic left ventricular hypertrophy has low diagnostic accuracy in middle-aged subjects.

OBJECTIVE: To evaluate the usefulness of electrocardiographic left ventricular hypertrophy (ECG LVH) as a marker of LVH in middle-aged subjects. METHODS: LVH was determined by cardiovascular magnetic resonance imaging (MRI) in 188 apparently healthy middle-aged [97 men (45+/-7 years) and 91 women (47+/-6 years)]. Receiver operating characteristic (ROC) curves, test sensitivity, specificity, positive and negative predictive values for identifying LVH at different ECG criteria were calculated. RESULTS: Systolic and diastolic blood pressures were 142+/-13 mmHg and 90+/-8 mmHg in men and 139+/-10 mmHg and 90+/-8 mmHg in women, respectively. LVMI was 78+/-17 g/m2 in men and 67+/-12 g/m2 in women, and 14% of men and 22% of women had LVH in cardiac MRI. Only Sokolow-Lyon and Sokolow-Lyon product had the area under the ROC curve over 0.70. Sokolow-Lyon product had the highest sensitivity (47%). All ECG criteria had high negative predictive values, but the positive predictive values were below 46%. CONCLUSIONS: Commonly used ECG criteria of LVH have low discrimination ability in middle-aged subjects. ECG LVH alone should not be used as a marker of target organ damage in middle-aged, never treated and apparently healthy hypertensives.

Utility of plasma apelin and other indices of cardiac dysfunction in the clinical assessment of patients with dilated cardiomyopathy.

Apelin is a recently discovered peptide ligand reported to be involved in the regulation of cardiovascular homeostasis. The exact role of apelin in the pathophysiology of congestive heart failure has remained obscure, and the reported circulating levels of apelin in patients with heart failure have been contradictory. To establish the role of apelin in the assessment of cardiac dysfunction we measured plasma apelin levels in 65 patients with congestive heart failure caused by idiopathic dilated cardiomyopathy (IDC) and 14 healthy volunteers by specific radioimmunoassay. IDC patients were carefully examined including echocardiography, both-sided cardiac catheterization and cardiopulmonary exercise test. In addition, plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), N-terminal pro-atrial natriuretic peptide (NT-proANP), interleukin (IL)-6, tumor necrosis factor alpha (TNF-alpha), epinephrine and norepinephrine were determined. Plasma apelin levels were similar in IDC patients (median 26.5 pg/ml, range<3.40-97.6 pg/ml) and in control subjects (median 24.1 pg/ml, range 19.0-28.7 pg/ml; p=NS). Unlike the levels of NT-proBNP, IL-6, TNF-alpha, and norepinephrine, plasma apelin levels did not reflect the severity of heart failure. Our study demonstrates that although disturbed apelin-APJ signalling in heart may play a role in the pathophysiology of heart failure, circulating apelin levels cannot be applied in the clinical assessment of patients with chronic left ventricular dysfunction.

Utility of hypertonic histamine challenge in distinguishing difficult-to-diagnose asthma.

INTRODUCTION: Although classical asthma is associated with airway hyperresponsiveness (AHR), this condition is also present in many cardiopulmonary disorders undermining the rational basis of its measurement in the differential diagnosis of asthma. We have recently introduced a new method to investigate AHR, the hypertonic histamine challenge (HHC). OBJECTIVE: The aim of this study was to evaluate the differential diagnostic power of HHC in a clinically representative sample of 138 patients. METHODS: Fifty-seven patients from the outpatient clinic of the authors' hospital with symptoms indicative of asthma were consecutively recruited. Asthma was confirmed in 31 subjects. The remaining 26 subjects formed the control group, in conjunction with seven patients with COPD, 15 patients with interstitial lung disease, 21 patients with rhinitis, 13 patients with heart failure and 25 healthy controls. Hypertonic histamine solution was administered with an ultrasonic nebuliser. RESULTS: Only the PC(20) values of asthmatic subjects differed statistically significantly from those of the healthy group (P < 0.0001). The receiver operator characteristic curve indicated that a PC(20) value of 0.83 mg/mL would be the optimal cut-off point of HHC to separate the asthmatics from the symptomatic controls with a sensitivity of 81% and specificity of 70%. With the PC(20) values of 0.1 and 4.0 mg/mL, the sensitivities were 42% and 100%, and the specificities were 96% and 40%, respectively. In these limits, HHC either confirmed or excluded asthma in 64 out of 138 patients (46%). CONCLUSION: The authors' attempt to improve the accuracy of the airway challenge test by combining direct and indirect challenges did not overcome the diagnostic limitations of previously utilised airway challenges.

Molecular heterogeneity has a major impact on the measurement of circulating N-terminal fragments of A- and B-type natriuretic peptides.

BACKGROUND: The N-terminal fragments of A- and B-type natriuretic peptides (NT-proANP and NT-proBNP) are powerful markers of cardiac function. The current assays require refinement with regard to standardization with native calibrators and the ability to detect the actual circulating forms. METHODS: The following peptides were prepared with recombinant methods: NT-proANP, NT-proBNP, proBNP1-108, and Tyr0-proBNP77-108. Fifteen peptides of 13-22 amino acids, spanning the sequences of NT-proANP and NT-proBNP, were prepared by solid-phase peptide synthesis. Two immunoassays for NT-proANP and four for NT-proBNP were set up, each with a different epitope specificity. The assays were applied for the measurement of NT-proANP and NT-proBNP in healthy individuals and in patients with acute myocardial infarction. The circulating molecular forms were analyzed by gel-filtration and reversed-phase HPLC. RESULTS: According to the HPLC analyses, circulating NT-proANP consists mainly of the full-length peptide, with some degradation at both ends. In contrast, circulating NT-proBNP is very heterogeneous. Most immunoreactive NT-proBNP is significantly smaller in size than NT-proBNP1-76, with truncation at both termini. The smallest fragments can be detected by assays directed at the central part of NT-proBNP only; assays directed at the ends gave 30-40% lower values. Despite the difference, the various assays correlated reasonably well with each other (r2 = 0.77-0.85). In patients with acute myocardial infarction, NT-proANP and NT-proBNP concentrations were 1.8-2.3 and 4.2-4.5 times higher than in healthy individuals. The development of heart failure further increased the concentrations. CONCLUSIONS: Molecular heterogeneity of the circulating forms causes a serious risk of preanalytical errors in assays for NT-proBNP and, to a lesser extent, NT-proANP. The development of a sandwich assay for NT-proBNP would be especially challenging. The most robust and reliable assays use antibodies directed at the central portions of NT-proANP or NT-proBNP.

Atrial natriuretic peptide, B-type natriuretic peptide, and serum collagen markers after acute myocardial infarction.

Experimental data suggest that atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) act locally as antifibrotic factors in heart. We investigated the interrelationships of natriuretic peptides and collagen markers in 93 patients receiving thrombolytic treatment for their first acute myocardial infarction (AMI). Collagen formation following AMI, evaluated as serum levels of amino terminal propeptide of type III procollagen, correlated with NH(2)-terminal proANP (r = 0.45, P < 0.001), BNP (r = 0.55, P < 0.001) and NH(2)-terminal proBNP (r = 0.50, P < 0.01) on day 4 after thrombolysis. Levels of intact amino terminal propeptide of type I procollagen decreased by 34% (P < 0.001), and levels of carboxy terminal cross-linked telopeptide of type I collagen (ICTP) increased by 65% (P < 0.001). ICTP levels correlated with NH(2)-terminal proBNP (r = 0.25, P < 0.05) and BNP (r = 0.28, P < 0.05) on day 4. Our results suggest that ANP and BNP may act as regulators of collagen scar formation and left ventricular remodeling after AMI in humans. Furthermore, degradation of type I collagen is increased after AMI and may be regulated by BNP.

Acyl coenzyme A esters differentially activate cardiac and beta-cell adenosine triphosphate-sensitive potassium channels in a side-chain length-specific manner.

Recent evidence demonstrates that long-chain acyl coenzyme A esters (CoAs) activate cardiac and beta-cell plasma-membrane (pmK(ATP)) adenosine triphosphate (ATP)-sensitive potassium channels. In this study, we have investigated the differential effects of acyl CoAs of short and medium side-chain length on cardiac and beta-cell pmK(ATP) isoforms. At the single-channel level, the addition of acyl CoAs of differing side-chain length (2 to 16 carbons) to the inside face of membrane patches from ventricular myocytes caused varying increases in pmK(ATP) channel open probability proportional to increases in acyl side-chain length (20 mumol/L acetyl CoA: 310% +/- 90%, 20 mumol/L decanoyl CoA: 570% +/- 150%). A similar dependence of activation on side-chain length was observed in recombinant pmK(ATP) channels (SUR2A/Kir6.2) with full activation of current requiring both the acyl and CoA moieties in the esterified form. We found the recombinant beta-cell K(ATP) channel (SUR1/Kir6.2) to be much less sensitive to medium-chain acyl CoAs (decanoyl CoA: 124% +/- 15% v 231% +/- 25% in SUR2A/Kir6.2), suggesting a role for the cardiac sulfonylurea receptor, SUR2A, in the molecular mechanism of activation by these compounds. We propose that fatty acid metabolism, and the resultant generation of acyl CoAs of varying side-chain length, may be an important regulator of cellular excitability via interactions with the K(ATP) channel.

Interleukin-6 and tumor necrosis factor alpha in relation to myocardial infarct size and collagen formation.

BACKGROUND: Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) levels increase after acute myocardial infarction (AMI) in humans. Experimental data suggest that these cytokines regulate the initiation of scar formation after AMI. We investigated the interrelationships of IL-6 and TNF-alpha, tissue injury, infarct size, cardiac function, and collagen formation in humans. METHODS: Serum and plasma samples were taken on 93 patients receiving thrombolytic treatment for their first AMI. Collagen formation was evaluated by measuring concentrations of serum aminoterminal propeptide of type III procollagen (PIIINP). RESULTS: IL-6 levels increased by 44% (P<.001) and peaked at 24 hours. Peak IL-6 levels correlated positively with area under the curve of creatine kinase MB mass (r=.31, P<.01), peak troponin T level (r=.34, P<.005), and PIIINP measured at discharge (r=.46, P<.001). There were no changes in TNF-alpha levels, and patients with left ventricular dysfunction (EF<40%) had similar TNF-alpha levels as those with preserved left ventricular function. CONCLUSIONS: IL-6 may regulate collagen formation and thus remodeling of the left ventricle after AMI. In addition, TNF-alpha measurement is useless in the assessment of infarct size or left ventricular function during the immediate post-infarction period.