The role of cardiorenal biomarkers for risk stratification in the early follow-up after hospitalisation for acute heart failure.

CONTEXT: Cardiorenal biomarkers (CBs) predict outcome in acute heart failure (AHF). OBJECTIVE: To evaluate CBs in early follow-up prognostication. METHODS: In 124 AHF patients, levels of CystatinC, NT-proBNP and TroponinI measured five weeks from admission (W5) and relative change from day 2 (D2) were assessed for 6-month prognosis (mortality/HF hospitalization). RESULTS: The combined end-point occurred in 33 patients (27%). D2-, W5-cystatin≥ median, and lack of ≥30%decrease in NT-proBNP were independent predictors of outcome. Additionally, a risk score established from W5 CBs identified patients with very high event rate. CONCLUSIONS: CBs at early follow-up of AHF may guide risk stratification.

Effect of weight loss on inflammation in patients with mild obstructive sleep apnea.

BACKGROUND AND AIMS: Inflammation may be one mediating mechanism for cardiovascular diseases in obstructive sleep apnea (OSA). However, little is known about subclinical inflammation or the effect of lifestyle intervention on inflammation in early stages of OSA. The aim of this substudy of an existing randomized controlled trial, with post hoc analyses, was to determine the impact of lifestyle changes aimed at weight reduction on inflammatory biomarkers in overweight patients with mild OSA. METHODS AND RESULTS: Patients were randomized to supervised intensive lifestyle intervention group (N=28) or to control group (N=31), which received routine lifestyle advices. Circulating concentrations of pro- and anti-inflammatory mediators were measured before and after the 1-year intervention. The concentrations of two pro-inflammatory mediators, high-sensitivity C-reactive protein (hsCRP) and interleukin (IL)-6, decreased significantly in both groups. Although the changes in inflammatory biomarkers favored the supervised lifestyle intervention, the only significant reduction observed between the groups was for the anti-inflammatory IL-1 receptor antagonist (IL-1RA). The change in hsCRP was associated with apnea-hypopnea index, and improving night-time oxygen saturation was related to tumor necrosis factor alpha. IL-1RA and IL-6 were associated with insulin metabolism. CONCLUSION: Weight loss resulted in reductions in concentrations of some pro- and anti-inflammatory mediators in overweight patients with mild OSA, overall favoring the supervised lifestyle intervention. These findings suggest that more intensive treatment of obesity in OSA patients might be well-justified.

Cystatin C, NT-proBNP, and inflammatory markers in acute heart failure: insights into the cardiorenal syndrome.

BACKGROUND: Inflammation is thought to be a mediator in the pathophysiology of the cardiorenal syndrome. We evaluated the interactions between kidney function, cardiac stress, and various inflammatory cytokines in patients with acute heart failure (AHF). The effect on 1-year mortality was also assessed. METHODS AND RESULTS: Plasma levels of cystatin C, NT-proBNP, and inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor-α [TNF-α], IL-10) were measured in consecutive patients (n = 465) hospitalized for AHF. After adjustment for demographic characteristics and comorbidities, TNF-α had the strongest relation with renal function (ß = 0.39, P < 0.0001). Elevated TNF-α levels were seen in patients with high cystatin C, irrespective of NT-proBNP. Levels of IL-6 (ß = 0.26, P < 0.0001) and IL-10 (ß = 0.15, P < 0.01), but not TNF-α, were associated with NT-proBNP. Moreover, the most elevated levels of IL-6 were seen in patients with combined high NT-proBNP and high cystatin C. Cox regression analysis found IL-6 above median to be independently predictive of mortality (hazard ratio 1.9; 95% CI 1.2-2.9, P = 0.003). TNF-α was not significantly associated with prognosis in the overall population after adjustment for multiple covariates, but improved risk stratification in the subgroup with low cystatin C and NT-proBNP. CONCLUSION: Levels of TNF-α in AHF are related to kidney function, but not to NT-proBNP. IL-6 seems to be more associated with cardiac stress. Patients with severe dual organ dysfunction have the highest levels of IL-6 and TNF-α. Different relations of inflammatory cytokines to renal function and cardiac stress need to be considered when evaluating heart--kidney interactions.

N-terminal pro-atrial natriuretic peptide reflects cardiac remodelling in stage 1 hypertension.

Early detection of left ventricular hypertrophy (LVH) is beneficial, since treatment-induced regression of LVH has been unequivocally associated with a better prognosis. Our aim was to study the relation of cardiac remodelling and natriuretic peptides (NPs) in stage 1 hypertension. We studied 175 (46±7 years, 87 women and 88 men) apparently healthy middle-aged that had never been treated for hypertension. Left ventricular and atrial parameters were determined by magnetic resonance imaging. Systolic blood pressure (BP) correlated with left ventricular mass index (LVMI) (r=0.23, P<0.01) and ventricular septum thickness index (IVSI) (r=0.29, P<0.001). N-terminal pro-B-type NP (NT-proBNP) or N-terminal pro-atrial NP (NT-proANP) did not correlate with BP, LVMI or IVSI. NT-proANP correlated with left atrial area index (LAAI) (r=0.38, P<0.001), and subjects with LVH had higher LAAI than subjects with normal left ventricular geometry and no LVH (11.2±0.3 vs 10.0±0.2 cm(2) m(-2), P<0.001). In conclusion, measurement of NT-proBNP or NT-proANP does not appear to discriminate LVH in middle-aged, never treated and apparently healthy hypertensives. NT-proANP, but not NT-proBNP, reflects early cardiac remodelling in hypertensive heart disease.

A 3-year clinical follow-up of adult patients with 3243A>G in mitochondrial DNA.

OBJECTIVE: To follow the clinical course of patients with the mitochondrial DNA mutation 3243A>G for 3 years. METHODS: Thirty-three adult patients with the 3243A>G mutation entered a 3-year follow-up study. They were clinically evaluated annually, audiometry was performed, and samples were drawn for the analysis of blood chemistry and mutation heteroplasmy in leukocytes. Holter recording was performed three times during the follow-up and echocardiography, neuropsychological assessment, and quantitative EEG and brain imaging conducted at entry and after 3 years. RESULTS: The incidence of new neurologic events was low during the 3-year follow-up. Sensorineural hearing impairment (SNHI) progressed, left ventricular wall thickness increased, mean alpha frequency in the occipital and parietal regions decreased, and the severity of disease index (modified Rankin score) progressed significantly. The rate of SNHI progression correlated with mutation heteroplasmy in muscle. The increase in left ventricular wall thickness was seen almost exclusively in diabetic patients. Seven patients died during the follow-up, and they were generally more severely affected than those who survived. CONCLUSIONS: Significant changes in the severity of disease, sensorineural hearing impairment, left ventricular hypertrophy, and quantitative EEG were seen in adult patients with 3243A>G during the 3-year follow-up.

Improved adherence to practice guidelines yields better outcome in high-risk patients with acute coronary syndrome without ST elevation: findings from nationwide FINACS studies.

OBJECTIVES: Treatment options for acute coronary syndrome (ACS) without ST elevation have evolved rapidly during the recent years, but the successful implementation of practice guidelines incorporating new treatments into practice has been challenging. In this study, we evaluate whether targeted educational intervention could improve adherence to treatment guidelines of ACS without ST elevation. DESIGN, SETTING AND SUBJECTS: A previous study, FINACS I, evaluated the treatment and outcome of 501 consecutive non-ST elevation ACS patients that were referred in early 2001 to nine hospitals, covering nearly half of the Finnish population. That study revealed poor adherence to ESC guidelines, so targeted educational intervention on optimal practice was arranged before the second study (FINACS II), which was performed in the same hospitals using the same protocol as FINACS I. FINACS II, undertaken in early 2003, evaluated 540 consecutive patients. Interventions. Targeted educational programmes on optimal practice. MAIN OUTCOME MEASURES: The use of evidence-based therapies in non-ST elevation ACS patients. In-hospital event-free (death, new myocardial infarction, refractory angina, readmission with unstable angina and transient cerebral ischaemia/stroke) survival, and event-free survival at 6 months. RESULTS: Baseline characteristics and risk markers were similar in both studies, and no significant changes in resources were seen. In 2003, the in-hospital use of statins, ACE-inhibitors, clopidogrel and glycoprotein (GP) IIb/IIIa receptor antagonists increased significantly, and in-hospital angiography was performed more often, especially in high-risk patients (59% vs. 45%, P < 0.05); waiting time also shortened (4.2 +/- 5.5 vs. 5.8 +/- 4.7 days, P < 0.01). Overall no significant change was seen in the frequency of death either in-hospital (2% vs. 4%, P = NS) or at 6 months (7% vs. 10%, P = NS) in FINACS II. However, the survival of high-risk patients improved both in-hospital (95% vs. 90%, P = 0.05) and at 6 months (89% vs. 78%, P = 0.05). CONCLUSION: In patients with non-ST elevation ACS-targeted educational interventions appeared to be associated with improved adherence to practical guidelines, which yielded a better outcome in high-risk ACS patients.

Inducibility of life-threatening ventricular arrhythmias is related to maximum left ventricular thickness and clinical markers of sudden cardiac death in patients with hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the alpha-tropomyosin gene.

We investigated inducibility of life-threatening arrhythmias with programmed ventricular stimulation (PVS) in relation to clinical markers of sudden cardiac death (SCD) in subjects with hypertrophic cardiomyopathy (HCM) attributable to the Asp175Asn mutation in the alpha-tropomyosin gene (TPM1-Asp175Asn). PVS was performed with up to three extrastimuli and distribution of markers of SCD was evaluated in 21 adult subjects with the TPM1-Asp175Asn. Sustained polymorphic ventricular tachycardia (VT) or ventricular fibrillation (VF) was induced in seven of 21 subjects (33%). Inducible subjects had more severe left ventricular hypertrophy (LVH) and an increased number of markers of SCD (family history of SCD, syncope or presyncope, fall in systolic blood pressure (BP) during exercise, documented non-sustained VT (NSVT), and marked LVH) compared to non-inducible subjects (IVS 2.4 +/- 0.3 cm vs. 1.6 +/- 0.5 cm, P < 0.001; and two to three vs. one to two markers of SCD, P = 0.007, respectively). In conclusion, in HCM attributable to the Asp175Asn mutation in the alpha-tropomyosin gene, life-threatening arrhythmias were induced in one third of the patients. Inducibility was associated with the maximum left ventricular (LV) thickness and the number of markers of SCD, suggesting that in HCM patients with an identical causative mutation, susceptibility to ventricular arrhythmias is related to the cardiomyopathic phenotype.

Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial.

BACKGROUND: Levosimendan, a novel calcium sensitiser, improves myocardial contractility without causing an increase in myocardial oxygen demand. We compared the effects of levosimendan and dobutamine on haemodynamic performance and clinical outcome in patients with low-output heart failure. METHODS: Patients were recruited into a multicentre, randomised, double-blind, double-dummy, parallel-group trial. Under continuous haemodynamic monitoring, an initial loading dose of levosimendan of 24 microg/kg was infused over 10 min, followed by a continuous infusion of 0.1 microg kg(-1) min(-1) for 24 h. Dobutamine was infused for 24 h at an initial dose of 5 microg kg(-1) min(-1) without a loading dose. The infusion rate was doubled if the response was inadequate at 2h. The primary endpoint was the proportion of patients with haemodynamic improvement (defined as an increase of 30% or more in cardiac output and a decrease of 25% or more in pulmonary-capillary wedge pressure) at 24 h. Analyses were by intention to treat. FINDINGS: 103 patients were assigned levosimendan and 100 dobutamine. The primary haemodynamic endpoint was achieved in 29 (28%) levosimendan-group patients and 15 (15%) in the dobutamine group (hazard ratio 1.9 [95% CI 1.1-3.3]; p=0.022). At 180 days, 27 (26%) levosimendan-group patients had died, compared with 38 (38%) in the dobutamine group (0.57 [0.34-0.95]; p=0.029). INTERPRETATION: In patients with severe, low-output heart failure, levosimendan improved haemodynamic performance more effectively than dobutamine. This benefit was accompanied by lower mortality in the levosimendan group than in the dobutamine group for up to 180 days.

Myocardial preservation during coronary surgery with and without cardiopulmonary bypass.

BACKGROUND: There is increased interest in coronary artery bypass grafting (CABG) without cardiopulmonary bypass (CPB), although the preservation of the myocardium under such circumstances has not been properly investigated. The aim of this randomized study was to compare the changes in myocardial metabolism during CABG with and without CPB. METHODS: Myocardial energy metabolism and tissue injury during CABG was monitored in a series of 22 patients (11 with and 11 without CPB). RESULTS: The maximum myocardial lactate production was significantly higher (p = 0.02) in the group operated with CPB (0.56 mmol/L) than without it (0.17 mmol/L). A similar phenomenon was seen in the transcardiac pH differences (0.085 and 0.034 with and without CPB, p = 0.007). The postoperative peak values of creatine kinase-MB mass (15.1 vs 6.3 microg/L) and troponin I (13.8 vs 5.2 microg/L) were significantly higher (p < 0.001 and p = 0.008) with than without CPB. CONCLUSIONS: CABG on a beating heart is associated with better myocardial energy preservation and less myocardial damage compared with conventional CABG with CPB and intermittent antegrade mild hypothermic blood cardioplegia.

Reversible ischemic inhibition of F(1)F(0)-ATPase in rat and human myocardium.

The physiological role of F(1)F(0)-ATPase inhibition in ischemia may be to retard ATP depletion although views of the significance of IF(1) are at variance. We corroborate here a method for measuring the ex vivo activity of F(1)F(0)-ATPase in perfused rat heart and show that observation of ischemic F(1)F(0)-ATPase inhibition in rat heart is critically dependent on the sample preparation and assay conditions, and that the methods can be applied to assay the ischemic and reperfused human heart during coronary by-pass surgery. A 5-min period of ischemia inhibited F(1)F(0)-ATPase by 20% in both rat and human myocardium. After a 15-min reperfusion a subsequent 5-min period of ischemia doubled the inhibition in the rat heart but this potentiation was lost after 120 min of reperfusion. Experiments with isolated rat heart mitochondria showed that ATP hydrolysis is required for effective inhibition by uncoupling. The concentration of oligomycin for 50% inhibition (I(50)) for oxygen consumption was five times higher than its I(50) for F(1)F(0)-ATPase. Because of the different control strengths of F(1)F(0)-ATPase in oxidative phosphorylation and ATP hydrolysis an inhibition of the F(1)F(0)-ATPase activity in ischemia with the resultant ATP-sparing has an advantage even in an ischemia/reperfusion situation.

Clinical relevance of ischemic preconditioning.

The mechanisms of ischemic cell death and reperfusion injury in the myocardium and the ways to limit these have been under extensive research for decades. The discovery of the phenomenon of ischemic preconditioning, i.e. endogenous protection against ischemia-reperfusion injury obtained by one or more brief preceding episodes of ischemia, really boosted this research 15 years ago. Even though extensive research in experimental animals has provided data on the cellular mechanisms of ischemic preconditioning, such as adenosine receptor activation, opening of mitochondrial adenosine triphosphate (ATP)-sensitive potassium channels and production of endogenous protective stress proteins, direct clinical applications are still missing. The purpose of this study is to summarize the latest progress in solving the cellular and molecular mechanisms of the phenomenon, as well as the evidence for the existence of this phenomenon in humans and its clinical relevance.

Adaptation to myocardial ischemia during repeated ventricular pacing in patients with coronary artery disease.

OBJECTIVE: The purpose of our study was to evaluate whether repeated ventricular pacing is able to induce adaptation against ischemia in coronary artery disease patients. DESIGN: Fifteen patients with documented coronary artery disease were subjected to two successive periods of rapid ventricular pacing (150 bpm) of equal length (295+/-33 s), the first being limited by intolerable anginal pain. The second pacing period, of the same length as the first, was initiated after the disappearance of angina and ST depression, the mean resting time being 433+/-30 s. Blood samples for the determination of transcardiac differences in glucose, lactate, free fatty acids, K+, pCO2, pH, oxygen saturation and noradrenaline were taken from the femoral artery and coronary sinus before and at the end of each pacing period. The mechanical performance of the hearts was followed by continuous monitoring of intra-arterial blood pressure and pulmonary capillary wedge pressure, and the observed adaptation in the measured variables during the successive pacing tests was correlated with the duration of angina, severity of coronary artery disease and degree of collateralization. RESULTS: Changes in the transcardiac pH and K+ differences, ST segment and pulmonary capillary wedge pressure were less pronounced during the second pacing period. The subgroup with net lactate production before or after the first pacing period demonstrated metabolic adaptation manifested as improved lactate extraction during the second pacing period. Rate-pressure product and oxygen extraction, and thus presumably also overall oxygen consumption and oxygen delivery, were similar during both tests. The magnitude of adaptation did not correlate with the duration of angina, severity of coronary artery disease or overall collateral score. CONCLUSION: Rapid ventricular pacing is able to induce adaptation to myocardial ischemia, but the exact mechanisms in this process remain to be elucidated.

Intracellular free calcium and mitochondrial membrane potential in ischemia/reperfusion and preconditioning.

Moderation of calcium perturbations has been implicated in ischemic preconditioning. As mitochondria possess an effective Ca(2+)transporting system driven by the mitochondrial membrane potential, experiments were performed to study time-averaged intracellular free calcium and the mitochondrial membrane potential during preconditioning and ischemia-reperfusion. Isolated rat hearts were subjected to 5 min of preconditioning, a 9-min intervening reperfusion and 21 min of ischemia with subsequent reperfusion. The hearts were preloaded with the Ca(2+)indicator Fura-2 or the mitochondrial membrane potential probe safranine. A method was devised for correction for NADH autofluorescence in time-averaged Ca(2+)probing with Fura-2. The pH dependence of the apparent dissociation constant of the Ca(2+)complex of Fura-2 was determined. Intracellular free Ca(2+)increased during the 5-min ischemia, and this was reversed upon reperfusion. During protracted ischemia a continual Ca(2+)rise was observed when the fluorescence data were corrected for changes in pH. An initial sharp Fura-2 fluorescence spike upon final reperfusion was caused by a pH-dependent change in the dissociation constant of the Ca(2+)complex of Fura-2. In preconditioned hearts the free Ca(2+)was somewhat lower during reperfusion, but a major effect of preconditioning was observed during the prolonged ischemia. The decrease in mitochondrial membrane potential during prolonged ischemia was faster in the preconditioned heart with no difference during the final reperfusion. The effect of preconditioning on cell survival was reflected in a decrease in the post-ischemic washout of creatine kinase. The moderation of the ischemic and post-ischemic intracellular Ca(2+)increase, and the acceleration of the ischemic mitochondrial membrane potential decrease by ischemic preconditioning is in accord with the notion of the involvement of mitochondrial ATP sensitive K(+)channels in preconditioning. In studies on ischemia it is absolutely necessary to correct for the pH-sensitivity of the apparent dissociation constant of the calcium complex of Fura-2 to obtain reliable data for intracellular free calcium.

Effectiveness of amiodarone as a single oral dose for recent-onset atrial fibrillation.

The efficacy of amiodarone has been proved in long-term maintenance of sinus rhythm (SR) in patients with paroxysmal atrial fibrillation (AF). The present study evaluates the efficacy and safety of a single oral dose of amiodarone in patients with recent-onset AF (<48 hours). Seventy-two patients were randomized to receive 30 mg/kg of either amiodarone or placebo. Conversion to SR was verified by 24-hour Holter monitoring. Ten patients were excluded because of SR in the beginning of monitoring or technical failure during Holter monitoring. The remaining study groups were comparable (n = 31 for each), except that in the placebo group beta blockers were more common. The patients receiving amiodarone converted to SR more effectively than those receiving placebo (p<0.0001). At 8 hours, approximately 50% of patients in the amiodarone group and 20% in the placebo group (Holter successful) had converted to SR, whereas after 24 hours the corresponding figures were 87% and 35%, respectively. The median time for conversion (8.7 hours for amiodarone and 7.9 hours for placebo) did not differ in the groups. Amiodarone was hemodynamically well tolerated, and the number of adverse events in the study groups was similar. Amiodarone as a single oral dose of 30 mg/kg appears to be effective and safe in patients with recent-onset AF.

Vasoactive peptide release in relation to hemodynamic and metabolic changes during rapid ventricular pacing.

Plasma atrial natriuretic peptide (ANP) concentration increases during ventricular arrhythmias and rapid ventricular pacing but less is known about plasma brain natriuretic peptide (BNP) and endothelin (ET-1). In the present study concentrations of ANP, the amino terminal part of the proANP (NT-proANP), BNP, and ET-1 were measured in the coronary sinus and femoral artery before and at the end of rapid ventricular pacing in 15 patients with coronary arterial disease. The changes were compared with the changes in mean arterial blood pressure, pulmonary capillary wedge pressure (PCWP), transcardiac differences in pH, pCO2, lactate, and norepinephrine. There was an increase in PCWP and a transient decrease in blood pressure after initiation of pacing. Pacing caused a decrease in ST-segment, transcardiac difference of norepinephrine, lactate extraction, pCO2 difference, and an increase in pH difference. Concentration of ANP in the coronary sinus and femoral artery and its transcardiac difference increased during pacing (P < 0.001), whereas changes in NT-proANP were small and BNP and ET-1 levels remained unchanged. The change in transcardiac ANP difference correlated with the change in lactate (r = 0.53, P < 0.05) but not that of norepinephrine, PCWP, or blood pressure. The results show that the plasma concentration of ANP increases more than that of NT-proANP during rapid ventricular pacing. Ischemia-induced release of ANP and its diminished elimination may contribute to the increased plasma ANP level.