Impact of sleep-disordered breathing on myocardial salvage and infarct size in patients with acute myocardial infarction.

AIMS: Sleep-disordered breathing (SDB) may be a risk factor for expansion of infarct size early after acute myocardial infarction (MI) by exposing the heart to repetitive oxygen desaturations and increased cardiac afterload. The objective of this study was to assess the impact of SDB on myocardial salvage and infarct size within 3 months after acute MI. METHODS AND RESULTS: Patients with acute MI and percutaneous coronary intervention were enrolled in this prospective observational study. All patients underwent cardiovascular magnetic resonance (CMR) to define salvaged myocardium and infarct size within three to five days and at 3 months after acute MI. Patients were stratified according to apnoea-hypopnoea index (AHI) assessed by polysomnography at baseline into those with (AHI ≥ 15/h) and without (AHI < 15/h) SDB. Of the 56 patients included, 29 (52%) had SDB. The area at risk between both groups was similar (40 ± 12% vs. 40 ± 14%, P = 0.925). Patients with SDB had significantly less salvaged myocardium (myocardial salvage index 52% vs. 77%, P < 0.001), smaller reduction in infarct size (0.3% vs. 6.5%, P < 0.001) within 3 months after acute MI, a larger final infarct size (23% vs. 12%, P < 0.001), and a lower final left ventricular ejection fraction (48% vs. 54%, P = 0.023). In a multivariate analysis, including established risk factors for large MI, AHI was independently associated with less myocardial salvage and a larger infarct size 3 months after acute MI. CONCLUSIONS: Sleep-disordered breathing was associated with less myocardial salvage and a smaller reduction in infarct size. These findings suggest a contribution of SDB to impaired healing of MI.

Emergency and prophylactic use of miniaturized veno-arterial extracorporeal membrane oxygenation in transcatheter aortic valve implantation.

OBJECTIVES: To report our center's experience using veno-arterial extracorporeal membrane oxygenation (vaECMO) in transcatheter aortic valve implantation (TAVI). BACKGROUND: In TAVI, short-term mortality closely relates to life threatening procedural complications. VaECMO can be used to stabilize the patient in emergency situations. However, for the prophylactic use of vaECMO in very high-risk patients undergoing TAVI there is no experience. METHODS: From January 2009 to August 2011, we performed 131 TAVI. Emergency vaECMO was required in 8 cases (7%): ventricular perforation (n = 3), hemodynamic instability/cardiogenic shock (n = 4), hemodynamic deterioration due to ventricular tachycardia (n = 1). Since August 2011, during 83 procedures, prophylactic vaECMO was systematically used in very high-risk patients (n = 9, 11%) and emergency ECMO in one case (1%) due to ventricular perforation. RESULTS: Median logistic EuroScore in prophylactic vaECMO patients was considerably higher as compared to the remaining TAVI population (30% vs. 15%, P = 0.0003) while in patients with emergency vaECMO it was comparable (18% vs. 15%, P = 0.08). Comparing prophylactic to emergency vaECMO, procedural success and 30-day mortality were 100% vs. 44% (P = 0.03) and 0% vs. 44% (P = 0.02), respectively. Major vascular complications and rate of life threatening bleeding did not differ between both groups (11% vs. 11%, P = 0.99 and 11% vs. 33%, P = 0.3) and were not vaECMO-related. CONCLUSIONS: Life-threatening complications during TAVI can be managed using emergency vaECMO but mortality remains high. The use of prophylactic vaECMO in very high-risk patients is safe and may be advocated in selected cases.

A comprehensive linkage analysis for myocardial infarction and its related risk factors.

Coronary artery disease and myocardial infarction (MI) are leading causes of death in the western world. Numerous studies have shown that risk factors such as diabetes mellitus, arterial hypertension and hypercholesterolemia contribute to the development of the disease. Although each risk factor by itself is partly under genetic control, a positive family history is an independent predictor, which suggests that there are additional susceptibility genes. We have scanned the whole genome in 513 families to identify chromosomal regions linked to myocardial infarction and related risk factors that are known to be under genetic control. Here we show, by using variance component analysis and incorporating risk factors, that risk of myocardial infarction maps to a single region on chromosome 14 with a significant lod score of 3.9 (pointwise P=0.00015, genome-wide P<0.05), providing evidence of a principal MI locus. To characterize this locus we analyzed each risk factor by itself. Serum concentrations of lipoprotein (a) show linkage to both the apolipoprotein (a) locus (lod score 26.99) and a new locus on chromosome 1 (lod score 3.8). There is suggestive linkage for diabetes mellitus on chromosome 6 (lod score 2.96), for hypertension on chromosomes 1 and 6, for high-density and low-density lipoprotein cholesterol on chromosomes 1 and 17, and for triglyceride concentrations on chromosome 9. Although some of these risk factors overlap with previously identified loci, none overlaps with the newly identified susceptibility locus for myocardial infarction and coronary artery disease.

Natural course of sleep-disordered breathing after acute myocardial infarction.

The aim of this study was to test whether an improvement of left ventricular ejection fraction (EF) in the early phase after acute myocardial infarction is associated with a reduction of the severity of central and obstructive sleep apnoea. 40 consecutive patients with acute myocardial infarction underwent polysomnography and cardiovascular magnetic resonance imaging within 5 days and 12 weeks after the event to assess sleep apnoea and cardiac function. We stratified the sample in patients who improved their left ventricular EF within 12 weeks by ≥ 5% (improved EF group, ΔEF 9 ± 1%, n=16) and in those who did not (unchanged EF group, ΔEF -1 ± 1%, n=24). Prevalence of sleep apnoea (≥ 15 apnoea and hypopnoea events·h(-1)) within ≤ 5 days after myocardial infarction was 55%. Apnoea and hypopnoea events·h(-1) were significantly more reduced in the improved EF group compared with the unchanged EF group (-10 ± 3 versus 1 ± 3 events·h(-1); p=0.036). This reduction was based on a significant alleviation of obstructive events (-7 ± 2 versus 4 ± 3 events·h(-1); p=0.009), while the reduction of central events was similar between groups (p=0.906). An improvement of cardiac function early after myocardial infarction is associated with an alleviation of sleep apnoea. This finding suggests that re-evaluation of treatment indication for sleep apnoea is needed when a change in cardiac function occurs.

Impact of three-dimensional transesophageal echocardiography on prosthesis sizing for transcatheter aortic valve implantation.

OBJECTIVES: To compare aortic annulus diameters obtained by 3D transesophageal echocardiography (TEE) with 2D-TEE and the impact on prosthesis size selection in transcatheter aortic valve implantation (TAVI). BACKGROUND: In TAVI the aortic annulus diameter determines prosthesis size. The ideal modality for annulus assessment has not been defined yet. METHODS: Annulus diameters in 2D-TEE (long-axis view) and in 3D-TEE (long-axis view in multiple-plane-reconstruction) were compared in consecutive patients with aortic stenosis screened for TAVI. Prosthesis size was selected according to industry guidelines, integrating data from 3D-TEE, angiography and computed tomography. The percentage of cases in which 2D-TEE and 3D-TEE correctly predicted final prosthesis size was calculated. RESULTS: Forty-nine patients were studied (Age 80 ± 5, 39% male, logistic EuroScore 17 ± 11%). Annulus diameters from 2D- and 3D-TEE correlated (r = 0.808, P < 0.0001). Mean diameters were significantly larger on 3D- vs. 2D-TEE (23.4 ± 2.2 vs. 22.1 ± 2.6 mm, P < 0.001) with a mean difference of 1.2 mm (limits of agreement: -1.8 to 4.3). The interobserver variability of 2D- and 3D-TEE was 3.5 ± 5.6% and 0.9 ± 5.1%, respectively. Thirty-nine patients underwent TAVI (27 CoreValve™, 12 Edwards Sapien™). The procedure was successful in 37 (95%) patients. Postprocedural regurgitation was none or mild in 89% of the cases with no severe insufficiency. Final prosthesis size was correctly predicted by 2D-TEE in 67% while in 80% by 3D-TEE. Overall, 3D-TEE suggested a different prosthesis size in 26% of all cases compared to 2D-TEE. CONCLUSIONS: Aortic annulus measurement by 3D-TEE yields significantly larger diameters than 2D-TEE. This impacts prosthesis size selection in a considerable percentage of cases.

Eplerenone prevents salt-induced vascular stiffness in Zucker diabetic fatty rats: a preliminary report.

BACKGROUND: Aldosterone levels are elevated in a rat model of type 2 diabetes mellitus, the Zucker Diabetic fatty rat (ZDF). Moreover blood pressure in ZDF rats is salt-sensitive. The aim of this study was to examine the effect of the aldosterone antagonist eplerenone on structural and mechanical properties of resistance arteries of ZDF-rats on normal and high-salt diet. METHODS: After the development of diabetes, ZDF animals were fed either a normal salt diet (0.28%) or a high-salt diet (5.5%) starting at an age of 15 weeks. ZDF rats on high-salt diet were randomly assigned to eplerenone (100 mg/kg per day, in food) (ZDF+S+E), hydralazine (25 mg/kg per day) (ZDF+S+H), or no treatment (ZDF+S). Rats on normal salt-diet were assigned to eplerenone (ZDF+E) or no treatment (ZDF). Normoglycemic Zucker lean rats were also divided into two groups receiving normal (ZL) or high-salt diet (ZL+S) serving as controls. Systolic blood pressure was measured by tail cuff method. The experiment was terminated at an age of 25 weeks. Mesenteric resistance arteries were studied on a pressurized myograph. Specifically, vascular hypertrophy (media-to-lumen ratio) and vascular stiffness (strain and stress) were analyzed. After pressurized fixation histological analysis of collagen and elastin content was performed. RESULTS: Blood pressure was significantly higher in salt-loaded ZDF compared to ZDF. Eplerenone and hydralazine prevented this rise similarily, however, significance niveau was missed. Media-to-lumen ratio of mesenteric resistance arteries was significantly increased in ZDF+S when compared to ZDF and ZL. Both, eplerenone and hydralazine prevented salt-induced vascular hypertrophy. The strain curve of arteries of salt-loaded ZDF rats was significantly lower when compared to ZL and when compared to ZDF+S+E, but was not different compared to ZDF+S+H. Eplerenone, but not hydralazine shifted the strain-stress curve to the right indicating a vascular wall composition with less resistant components. This indicates increased vascular stiffness in salt-loaded ZDF rats, which could be prevented by eplerenone but not by hydralazine. Collagen content was increased in ZL and ZDF rats on high-salt diet. Eplerenone and hydralazine prevented the increase of collagen content. There was no difference in elastin content. CONCLUSION: Eplerenone and hydralazine prevented increased media-to-lumen ratio in salt-loaded ZDF-rats, indicating a regression of vascular hypertrophy, which is likely mediated by the blood pressure lowering-effect. Eplerenone has additionally the potential to prevent increased vascular stiffness in salt-loaded ZDF-rats. This suggests an effect of the specific aldosterone antagonist on adverse vascular wall remodelling.

Association of early repolarization pattern on ECG with risk of cardiac and all-cause mortality: a population-based prospective cohort study (MONICA/KORA).

BACKGROUND: Early repolarization pattern (ERP) on electrocardiogram was associated with idiopathic ventricular fibrillation and sudden cardiac arrest in a case-control study and with cardiovascular mortality in a Finnish community-based sample. We sought to determine ERP prevalence and its association with cardiac and all-cause mortality in a large, prospective, population-based case-cohort study (Monitoring of Cardiovascular Diseases and Conditions [MONICA]/KORA [Cooperative Health Research in the Region of Augsburg]) comprised of individuals of Central-European descent. METHODS AND FINDINGS: Electrocardiograms of 1,945 participants aged 35-74 y, representing a source population of 6,213 individuals, were analyzed applying a case-cohort design. Mean follow-up was 18.9 y. Cause of death was ascertained by the 9th revision of the International Classification of Disease (ICD-9) codes as documented in death certificates. ERP-attributable effects on mortality were determined by a weighted Cox proportional hazard model adjusted for covariables. Prevalence of ERP was 13.1% in our study. ERP was associated with cardiac and all-cause mortality, most pronounced in those of younger age and male sex; a clear ERP-age interaction was detected (p = 0.005). Age-stratified analyses showed hazard ratios (HRs) for cardiac mortality of 1.96 (95% confidence interval [CI] 1.05-3.68, p = 0.035) for both sexes and 2.65 (95% CI 1.21-5.83, p = 0.015) for men between 35-54 y. An inferior localization of ERP further increased ERP-attributable cardiac mortality to HRs of 3.15 (95% CI 1.58-6.28, p = 0.001) for both sexes and to 4.27 (95% CI 1.90-9.61, p<0.001) for men between 35-54 y. HRs for all-cause mortality were weaker but reached significance. CONCLUSIONS: We found a high prevalence of ERP in our population-based cohort of middle-aged individuals. ERP was associated with about a 2- to 4-fold increased risk of cardiac mortality in individuals between 35 and 54 y. An inferior localization of ERP was associated with a particularly increased risk. Please see later in the article for the Editors' Summary.

Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.

BACKGROUND: Angiotensin-receptor blockers (ARBs) are effective treatments for patients with heart failure, but the relation between dose and clinical outcomes has not been explored. We compared the effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure. METHODS: This double-blind trial was undertaken in 255 sites in 30 countries. 3846 patients with heart failure of New York Heart Association class II-IV, left-ventricular ejection fraction 40% or less, and intolerance to angiotensin-converting-enzyme (ACE) inhibitors were randomly assigned to losartan 150 mg (n=1927) or 50 mg daily (n=1919). Allocation was by block randomisation stratified by centre and presence or absence of beta-blocker therapy, and all patients and investigators were masked to assignment. The primary endpoint was death or admission for heart failure. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00090259. FINDINGS: Six patients in each group were excluded because of poor data quality. With 4.7-year median follow-up in each group (IQR 3.7-5.5 for losartan 150 mg; 3.4-5.5 for losartan 50 mg), 828 (43%) patients in the 150 mg group versus 889 (46%) in the 50 mg group died or were admitted for heart failure (hazard ratio [HR] 0.90, 95% CI 0.82-0.99; p=0.027). For the two primary endpoint components, 635 patients in the 150 mg group versus 665 in the 50 mg group died (HR 0.94, 95% CI 0.84-1.04; p=0.24), and 450 versus 503 patients were admitted for heart failure (0.87, 0.76-0.98; p=0.025). Renal impairment (n=454 vs 317), hypotension (203 vs 145), and hyperkalaemia (195 vs 131) were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group. INTERPRETATION: Losartan 150 mg daily reduced the rate of death or admission for heart failure in patients with heart failure, reduced left-ventricular ejection fraction, and intolerance to ACE inhibitors compared with losartan 50 mg daily. These findings show the value of up-titrating ARB doses to confer clinical benefit. FUNDING: Merck (USA).

Contractile reserve and extent of transmural necrosis in the setting of myocardial stunning: comparison at cardiac MR imaging.

PURPOSE: To perform a comparison of cardiac magnetic resonance (MR) imaging-derived ejection fraction (EF) during low-dose dobutamine infusion (EF(D)) with the extent of segments with transmural necrosis in more than 50% of their wall thickness (ETN) for the prediction of major adverse cardiac events (MACEs) and late systolic recovery soon after a first ST-segment elevation myocardial infarction (STEMI). MATERIALS AND METHODS: Institutional ethics committee approval and written informed consent were obtained. One hundred nineteen consecutive patients with a first STEMI, a depressed left ventricular EF, and an open infarct-related artery underwent MR imaging at 1 week after infarction. EF(D) and ETN (by using a 17-segment model) were determined, and the prediction of MACEs and systolic recovery at follow-up was assessed by using area under the receiver operating characteristic curve (AUC) and multivariable regression analysis. RESULTS: During follow-up (median, 613 days; range, 312-1243 days), 18 MACEs (five cardiac deaths, six myocardial infarctions, seven readmissions for heart failure) occurred. MACEs were associated with a lower EF(D) (43% +/- 12 [standard deviation] vs 49% +/- 10, P = .02) and a larger ETN (seven segments +/- three vs four segments +/- three, P < .001). Patients with systolic recovery (increase in EF of >5% at follow-up compared with baseline EF, n = 44) displayed a higher EF(D) (51% +/- 10 vs 47% +/- 9, P = .04) and a smaller ETN (three segments +/- two vs five segments +/- three, P = .002) at 1 week. ETN and EF(D) both related to MACEs (AUC: 0.78 vs 0.67, respectively, P = .1) and systolic recovery (AUC: 0.68 vs 0.62, respectively, P = .3). According to multivariable analysis, ETN was the only MR variable associated with time to MACEs (hazard ratio, 1.38; 95% confidence interval: 1.19, 1.60; P < .001) and systolic recovery (odds ratio, 0.76; 95% confidence interval: 0.64, 0.92; P = .004) independent of baseline characteristics. CONCLUSION: ETN is as useful as EF(D) for the prediction of MACEs and systolic recovery soon after STEMI.

Dynamic changes in N-terminal pro-brain natriuretic peptide in acute coronary syndromes treated with percutaneous coronary intervention: a marker of ischemic burden, reperfusion and outcome.

BACKGROUND: Whereas N-terminal pro-brain natriuretic peptide (NT-proBNP) is approved for risk stratification of patients with acute coronary syndromes (ACS), short-term temporal changes in NT-proBNP concentrations and the optimal time points for sampling are not clear. The purpose of this study was to better define the short-term changes in NT-proBNP in relation to clinical presentation, reperfusion and prognostic value in patients with ACS, as well as to identify the optimum time points for sampling. METHODS: We studied daily plasma concentrations of NT-proBNP in 133 unselected patients with myocardial infarction (n=65), stable coronary artery disease (CAD, n=46) and no CAD (n=22) who underwent coronary angiography. RESULTS: Patients with non-ST-elevation myocardial infarction (NSTEMI) presented with markedly higher NT-proBNP than patients with ST-elevation myocardial infarction (STEMI) [1305 (741-3208) ng/L vs. 170 (70-424) ng/L, p<0.001]. Also, time to presentation from onset of pain was much longer in NSTEMI as compared to STEMI (>48 h vs. <6 h, p<0.001). Patients with NSTEMI also presented with higher NT-proBNP as compared with CAD [224 (98-732) ng/L] and no CAD [47 (26-102) ng/L; p<0.001, NSTEMI vs. both]. Following successful percutaneous coronary intervention [thrombolysis in myocardial infarction (TIMI) 3-flow established], NT-proBNP increased markedly within 24 h in patients with STEMI [718 (379-1338) ng/L, p<0.01 vs. 0 h], whereas no change in NT-proBNP was noted in patients with NSTEMI [1190 (1010-2024) ng/L, p=0.88 vs. 0 h]. In both STEMI and NSTEMI, NT-proBNP decreased significantly 96 h after successful reperfusion [STEMI -52%, 372 (189-610) ng/L, p<0.05; NSTEMI -52%, 613 (365-724) ng/L, p<0.05]. Unsuccessful reperfusion (TIMI<3) was associated with unchanged or increased NT-proBNP. NT-proBNP at 96 h and peak NT-proBNP further displayed a strong correlation with cardiac troponin T (r=0.64 and r=0.54, p<0.001), a marker of infarct size, and NT-proBNP at 96 h was a strong predictor of long-term prognosis (hazard ratio 7.29, p=0.025). CONCLUSIONS: In patients with NSTEMI, NT-proBNP may be increased as high as concentrations usually associated with acute congestive heart failure despite the absence of clinical signs. In contrast, patients with STEMI and short time to presentation may present with completely normal NT-proBNP, but dramatic short-term increases following reperfusion. NT-proBNP reflects ischemic burden, reperfusion success and prognosis, and the current data support repetitive sampling in patients with ACS.

Time course of continuous positive airway pressure effects on central sleep apnoea in patients with chronic heart failure.

Continuous positive airway pressure (CPAP) causes a variable immediate reduction in the frequency of central apnoeas and hypopnoeas in patients with congestive heart failure (CHF) and central sleep apnoea (CSA), but has beneficial mid-term effects on factors known to destabilize the ventilatory control system. We, therefore, tested whether CPAP therapy leads, in addition to its short-term effects on CSA, to a significant further alleviation of CSA after 12 weeks of treatment on the same CPAP level in such patients. CPAP therapy was initiated in 10 CHF patients with CSA. During the first night on CPAP, the pressure was stepwise increased to a target pressure of 8-12 cmH(2)O or the highest level the patients tolerated (<12 cmH(2)O). Throughout the second night (baseline CPAP), the achieved CPAP of the first night was applied. After 12 weeks of CPAP treatment, we performed a follow-up polysomnography (12 weeks CPAP) on the same CPAP level (8.6 +/- 1.1 cmH(2)0). We found a significant reduction of the apnoea-hypopnoea index (AHI) between the diagnostic polysomnography and baseline CPAP night (41.8 +/- 19.2 versus 22.2 +/- 12.6 events per hour; P = 0.005). The AHI further significantly decreased between the baseline CPAP night and the 12 weeks CPAP night on the same CPAP level (22.2 +/- 12.6 versus 12.8 +/- 11.0 events per hour; P = 0.028). We conclude that, in addition to its immediate effects, CPAP therapy leads to a time-dependent alleviation of CSA in some CHF patients, indicating that in such patients neither clinical nor scientific decisions should be based on a short-term trial of CPAP.

High osmolality induces the kidney-specific chloride channel CLC-K1 by a serum and glucocorticoid-inducible kinase 1 MAPK pathway.

The kidney-specific chloride channels CLC-K1/2 and their functionally important subunit barttin, by mediating solute transport in medulla, contribute to the osmotic gradient. We sought to determine whether they themselves are regulated by variations of osmolality. The expression of CLC-K1 and barttin mRNA and protein was significantly increased in a distal convoluted tubule cell line after a shift to high osmolar medium. This upregulation paralleled that of serum and glucocorticoid-inducible kinase 1 (SGK1), a gene known to be upregulated by cell shrinkage. Specific knockdown of SGK1 or addition of the p38 MAPK pathway inhibitor SB203580 abolished the induction of SGK1, CLC-K1 and barttin by high osmolarity suggesting that a functional MAPK pathway is required to mediate osmotic-driven induction of all three genes. The physiological relevance of our in vitro data was confirmed by water deprivation of male C57BL6 mice, which caused a significant increase in serum osmolality along with induction of CLC-K1, barttin and SGK1. Our study shows that change in intracellular volume, because of high osmolality, result in SGK1 upregulation and the subsequent increase of CLC-K1/barttin expression in distal renal tubular cells in vivo and in vitro.

Design of the heart failure endpoint evaluation of AII-antagonist losartan (HEAAL) study in patients intolerant to ACE-inhibitor.

BACKGROUND: In patients with heart failure and reduced left ventricular ejection fraction, angiotensin receptor blockers have been found to reduce mortality and morbidity and to prevent or reverse left ventricular remodelling, compared to optimized background treatment. In light of these data, The Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL) study was developed to determine whether losartan 150 mg is superior to losartan 50 mg (antihypertensive dose) in reducing morbidity and mortality among patients with symptomatic heart failure who are intolerant of angiotensin-converting enzyme (ACE)-inhibitors. AIMS/METHODS: To compare the effect of high and moderate doses of losartan on the primary endpoint of all-cause mortality and hospitalisation due to heart failure in patients (n = 3834) with symptomatic heart failure and an ejection fraction < or = 40% who are intolerant of ACE-inhibitor treatment. RESULTS: This paper presents the rationale, trial design, and baseline characteristics of the study population. The study, which completed recruitment on 31 March 2005, is event-driven and is estimated to accrue the target of 1710 adjudicated primary events during the latter half of 2008. CONCLUSIONS: The results of HEAAL should facilitate selection of an optimal dosing regimen for losartan in patients with symptomatic heart failure who are intolerant of ACE-inhibitors.

Association of polymorphisms of the apolipoprotein(a) gene with lipoprotein(a) levels and myocardial infarction.

BACKGROUND: Serum lipoprotein(a) [Lp(a)] concentration is largely determined by variability at the apolipoprotein(a) gene locus. Most prominent effects relate to polymorphisms in the promoter (a pentanucleotide [PN] repeat) and coding regions (a kringle IV [K4] repeat), the latter of which also affects Lp(a) particle size. The impact of these polymorphisms on cardiovascular risk is poorly understood. METHODS AND RESULTS: We studied both polymorphisms and Lp(a) levels in 834 registry-based myocardial infarction (MI) patients (38% women) and 1548 population-based controls. Lp(a) concentrations were inversely related with the numbers of K4 and PN repeats. However, the effect of the PN polymorphism was restricted to subjects producing small Lp(a) particles (8 PN 8.7 mg/dL; P<0.0001). The odds to present with MI were elevated in individuals producing small Lp(a) particles (

Enhanced ventilatory response to exercise in patients with chronic heart failure and central sleep apnea.

BACKGROUND: In patients with chronic heart failure (CHF), central sleep apnea (CSA) and enhanced ventilatory response (VE/VCO2 slope) to exercise are common. Both breathing disorders alone indicate poor prognosis in CHF. Although augmented chemosensitivity to CO2 is thought to be one important underlying mechanism for both breathing disorders, it is unclear whether both breathing disorders are related closely in patients with CHF. METHODS AND RESULTS: We investigated 20 CHF patients with clinically important CSA (apnea-hypopnea-index (AHI), number of episodes per hour >or=15) and 10 CHF patients without CSA. Patients with and without CSA did not differ with respect to exercise capacity (peak VO2, 63.4+/-3.4% versus 60.8+/-4.4% of predicted value; P=0.746) and left ventricular ejection fraction (LVEF, 31+/-2% versus 31+/-3%; P=0.948). The AHI was not correlated with exercise capacity (peak VO2, percent of predicted value; P=0.260) and LVEF (percent, P=0.886). In contrast, the positive correlation of the VE/VCO2 slope, determined by cardiopulmonary exercise testing, with the AHI was highly significant (P<0.001). The VE/VCO2 slope was significantly increased in patients with CSA compared with those without CSA (29.7 versus 24.9; P<0.001). CONCLUSIONS: The ventilatory response to exercise is significantly augmented in CHF patients with CSA compared with those without. In contrast to peak VO2 and LVEF, the VE/VCO2 slope is strongly related to the severity of CSA in patients with CHF, which underscores an augmented chemosensitivity to CO2 as a common underlying pathophysiological mechanism.

RANTES gene polymorphisms predict all-cause and cardiac mortality in type 2 diabetes mellitus hemodialysis patients.

INTRODUCTION: Patients with type 2 diabetes (DM2) and end stage renal disease (ESRD) have a dismal survival prognosis, mainly due to cardiovascular events. There is sparse data on genetic predictors. Chemokines and their receptors are important in regulating leukocyte influx and activation in atherosclerosis, and functional polymorphisms in the respective genes are associated with cardiovascular disease risk. METHODS: We enrolled 225 prevalent Caucasian DM2 patients receiving maintenance hemodialysis in 30 centres in Southern Germany (time from dialysis initiation <2.0 years) from August 1999 to January 2000 for prospective study until December 2003. The CX3CR1 T280M, and MCP-1 -2518 and RANTES -403 and -28 promoter and intronic In1.1T/C polymorphisms were assessed by real-time PCR. Primary end point was all-cause mortality (ACM). RESULTS: Patients carrying the RANTES -403A or In1.1C allele had a significantly higher ACM risk (multivariate hazard ratio for -403A, dominant model=1.81 [95% CI: 1.22-2.67], p=0.003), mainly due to cardiac events. Similar data were obtained by haplotype analysis. The other SNPs showed no effect on survival. DISCUSSION: In DM2 patients with ESRD, ACM due to cardiac events is associated with RANTES gene variants that are known to alter the expression of this chemokine important in atherosclerosis. Further study of the role of chemokine and chemokine receptor gene variation in determining vascular end points is needed.

Nocturnal continuous positive airway pressure improves ventilatory efficiency during exercise in patients with chronic heart failure.

OBJECTIVES: Chronic heart failure is closely related to impaired cardiorespiratory reflex control, including decreased ventilatory efficiency during exercise (Ve/Vco(2)-slope) and central sleep apnea (CSA). Continuous positive airway pressure (CPAP) and nocturnal oxygen therapy alleviate CSA. The aim of the present study was to compare the effects of nocturnal CPAP and oxygen therapy on Ve/Vco(2)-slope. DESIGN AND SETTING: Prospective controlled trial at a university hospital. PATIENTS: Twenty-six stable patients with chronic heart failure and CSA. INTERVENTION AND MEASUREMENTS: Ten patients received nocturnal oxygen, and 16 patients were assigned to CPAP treatment. At baseline and after 12 weeks of treatment, symptom-limited cardiopulmonary exercise testing was performed on a cycle ergometer. Expiratory gas was analyzed breath by breath for evaluation of ventilation and ventilatory efficiency in combination with arteriocapillary blood gas analysis during rest and exercise. RESULTS: CPAP treatment significantly reduced the Ve/Vco(2)-slope (31.2 +/- 1.6 vs 26.2 +/- 1.0, p = 0.005) and improved the left ventricular ejection fraction (LVEF) [31.7 +/- 2.6% vs 35.7 +/- 2.7%, p = 0.041]. CPAP treatment significantly reduced the apnea-hypopnea index (AHI) [35.9 +/- 4.0/h vs 12.2 +/- 3.6/h, p = 0.002]. Peak oxygen consumption (Vo(2)) [16.2 +/- 1.1 L/min/kg vs 16.3 +/- 1.2 L/min/kg, p = 0.755] remained similar after CPAP treatment. Oxygen therapy reduced the AHI (28.8 +/- 3.2/h vs 8.7 +/- 4.1/h, p = 0.019), but did not improve exercise capacity (peak Vo(2), 15.4 +/- 1.5 L/min/kg vs 15.6 +/- 1.9 L/min/kg, p = 0.760), LVEF (30.9 +/- 2.4% vs 32.5 +/- 2.3%, p = 0.231), or the Ve/Vco(2)-slope (30.0 +/- 1.5 vs 29.8 +/- 1.5, p = 0.646). CONCLUSION: Nocturnal CPAP and oxygen therapy alleviate CSA to a similar degree. Only CPAP therapy may improve ventilatory efficiency during exercise and may have favorable effects on LVEF. Therefore, our data suggest that CPAP is advantageous compared to oxygen in the treatment of CSA in patients with chronic heart failure.

Increased pulmonary prostacyclin synthesis in rats with chronic hypoxic pulmonary hypertension.

OBJECTIVE: The regulation of pulmonary prostacyclin synthesis is not completely understood. We tested the hypothesis that prostacyclin production is predominantly stimulated by hemodynamic factors, such as increased shear-stress, and is thus increased in rats with chronic hypoxic pulmonary hypertension. METHODS: To this end, we determined pulmonary prostacyclin synthase (PGIS) gene expression, circulating levels of the stable prostacyclin metabolite 6-keto prostaglandin F(1alpha) (6-keto-PGF(1alpha)), pulmonary endothelin (ET)-1 gene expression, and ET-1 plasma levels in rats exposed to 4 weeks of hypoxia (10% O(2)) in the presence or absence of either the nitric oxide (NO) donor molsidomine (MD, 15 mg/kg/day) or the ET-A receptor antagonist LU135252 (LU, 50 mg/kg/day). RESULTS: Right ventricular systolic pressure (RVSP), the cross-sectional medial vascular wall area of pulmonary arteries, and ET-1 production increased significantly during hypoxia. PGIS mRNA levels increased 1.7-fold, and 6-keto-PGF(1alpha) plasma levels rose from 8.2+/-0.8 to 12.2+/-2.2 ng/ml during hypoxia (each P<0.05 vs. normoxic controls). MD and LU reduced RVSP and pulmonary vascular remodeling similarly (each P<0.05 vs. hypoxia), but only MD inhibited pulmonary ET-1 formation (P<0.05 vs. hypoxia). Nevertheless, both drugs attenuated the increase in PGIS gene expression and plasma 6-keto-PGF(1alpha) levels (each P<0.05 vs. hypoxia). CONCLUSION: Our data suggest that prostacyclin production in hypertensive rat lungs is predominantly increased by hemodynamic factors while hypoxia, NO and ET-1 per are less important stimuli, and that this increase may serve as a compensatory mechanism to partially negate the hypoxia-induced elevation in pulmonary vascular tone.

Vascular gene delivery of anticoagulants by transplantation of retrovirally-transduced endothelial progenitor cells.

OBJECTIVE: Recent studies have documented the presence of bone marrow-derived endothelial progenitor cells (EPC) in the circulation of several species. This study was designed to evaluate the use of engineered EPC for vascular gene delivery into angioplasty-induced arterial lesions. METHODS AND RESULTS: EPC could easily be isolated from whole bone marrow and peripheral blood of adult rats. Differentiation was induced by culture on fibronectin in the presence of endothelial specific growth factors. Rat EPC shared several phenotypic and functional properties with mature endothelial cells. Recombinant retroviruses were generated encoding for the anticoagulants tissue-type plasminogen activator (tPA) and hirudin. Efficient (>90%) ex vivo gene transfer could be achieved resulting in high levels of transgene production. Engineered EPC were locally infused into freshly balloon-injured carotid arteries. Analysis of day 7 vessels showed 73+/-10% luminal coverage of the lesioned arterial bed with transduced EPC. Sustained secretion of both anticoagulants could be detected in organ cultures of explanted arteries. EPC seeding inhibited dilation of the injured arterial segment and prevented reduction of media thickness. However, rapid repopulation with EPC failed to attenuate neointima formation in this model. CONCLUSIONS: Peripheral blood and bone marrow can be used as source for endothelial lineage cells. Cultured EPC can be genetically engineered by retroviral gene transfer and serve as cellular vehicles for vascular gene and drug delivery of anticoagulants. Local transplantation of EPC attenuates reendothelialization of angioplasty-injured arteries but fails to inhibit neointima proliferation.

Gender-specific differences of cardiac remodeling in subjects with left ventricular dysfunction: a population-based study.

BACKGROUND: Recent studies suggest that female gender is associated with a lower prevalence and a more benign prognosis of heart failure. In the current population-based study, it was our objective to evaluate the implications of gender on the association between impaired left ventricular (LV) function and mass as well as neurohumoral activation. METHODS AND RESULTS: A total of 1883 subjects (992 female, 891 male) of two MONICA surveys in Augsburg, Germany, were analyzed. Participants of one of these surveys were additionally characterized with respect to neurohormonal activation. As compared to men, women were characterized by a slightly higher LV ejection fraction (EF, Teichholz-Method, 65.4 +/- 0.3% vs. 63.4 +/- 0.3, P<0.01) and a markedly lower LV mass index (LVMI 81 +/- 1 g/m(2) vs. 96 +/- 1, P<0.01). As compared to men with normal LV function, those with LV dysfunction (EF below mean minus two standard deviations, S.D.) were characterized by significantly increased LV mass (LVMI +48%, P<0.01), plasma BNP (+373%, P<0.01) and ANP (+57%, P<0.01), while no significant changes were observed in women (LVMI +3%, BNP +48%, ANP +27%, all P=n.s). Only a small subgroup of women with severe LVD (EF below mean - 3 S.D.) was characterized by significantly increased LV mass (LVMI +23%, P<0.05 vs. control and LVD), however, this increase was less pronounced as compared to men with severe LVD (LVMI +46%, P<0.01 vs. control). Gender-specific differences between LV function and structure were also confirmed by multivariate analysis. While LVMI was independently and significantly correlated with EF in male subjects in addition to systolic blood pressure, age, and body mass index (all P<0.01), these parameters displaced EF as a predictor of LVMI in female subjects. CONCLUSIONS: Men with moderate or severe LV dysfunction are characterized by an increase in both LV mass and cardiac natriuretic peptide plasma concentrations. In contrast, LV mass and natriuretic peptide concentrations increase to a lesser extent and only with severe LV dysfunction in women. These observational data suggest gender-specific control of myocardial adaptations to hemodynamic overload and a more rapid induction of LV hypertrophy during myocardial dysfunction in male subjects.