Markus Haass

Health related quality of life in patients with congestive heart failure: comparison with other chronic diseases and relation to functional variables.

Objective: To assess health related quality of life of patients with congestive heart failure; to compare their quality of life with the previously characterised general population and in those with other chronic diseases; and to correlate the different aspects of quality of life with relevant somatic variables. Setting: University hospital. Patients and design: A German version of the generic quality of life measure (SF-36) containing eight dimensions was administered to 205 patients with congestive heart failure and systolic dysfunction. Cardiopulmonary evaluation included assessment of New York Heart Association (NYHA) functional class, left ventricular ejection fraction, peak oxygen uptake, and the distance covered during a standardised six minute walk test. Results: Quality of life significantly decreased with NYHA functional class (linear trend: p < 0.0001). In NYHA class III, the scores of five of the eight quality of life domains were reduced to around one third of those in the general population. The pattern of reduction was different in patients with chronic hepatitis C and major depression, and similar in patients on chronic haemodialysis. Multiple regression analysis showed that only the NYHA functional class was consistently and closely associated with all quality of life scales. The six minute walk test and peak oxygen uptake added to the explanation of the variance in only one of the eight quality of life domains (physical functioning). Left ventricular ejection fraction, duration of disease, and age showed no clear association with quality of life. Conclusions: In congestive heart failure, quality of life decreases as NYHA functional class worsens. Though NYHA functional class was the most dominant predictor among the somatic variables studied, the major determinants of reduced quality of life remain unknown.

Mode of Death in Patients With Heart Failure and a Preserved Ejection Fraction Results From the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) Trial

Background— The mode of death has been well characterized in patients with heart failure and a reduced ejection fraction; however, less is known about the mode of death in patients with heart failure and a preserved ejection fraction (HFPEF). The purpose of this study was to examine the mode of death in patients with HFPEF enrolled in the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) trial and to determine whether irbesartan altered the distribution of mode of death in HFPEF. Methods and Results— All deaths were reviewed by a clinical end-point committee, and the mode of death was assigned by consensus of the members. The annual mortality rate was 5.2% in the I-Preserve trial. There were no significant differences in mortality rate between the placebo and irbesartan groups. The mode of death was cardiovascular in 60% (including 26% sudden, 14% heart failure, 5% myocardial infarction, and 9% stroke), noncardiovascular in 30%, and unknown in 10%. There were no differences in the distribution of mode-specific mortality rates between placebo and irbesartan. Conclusions— Sixty percent of the deaths in patients with HFPEF were cardiovascular, with sudden death and heart failure death being the most common. Treatment with irbesartan did not affect overall mortality or the distribution of mode-specific mortality rates. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Transcatheter closure of patent foramen ovale in patients with cerebral ischemia

OBJECTIVES The present study was conducted to determine the safety of the transcatheter closure of a patent foramen ovale (PFO) in patients with cryptogenic cerebral ischemia and the midterm follow-up of recurrent thromboembolic events after interventional PFO closure. BACKGROUND Current therapeutic options for stroke prevention in patients with PFO and a history of thromboembolic events include chronic antithrombotics and more invasive treatments such as surgical closure or minor invasive transcatheter permanent closure of the PFO. Promising preliminary and pilot data with the Amplatzer Septal Occluder or the PFO-Star Occluder have been reported. Systematic and long-term data are still missing. METHODS A total of 276 consecutive patients with a PFO and a history of at least one thromboembolic event were recruited in four medical centers and underwent percutaneous PFO closure with the PFO-Star device. Follow-up data were analyzed over an average of 15.1 months, equivalent to 345 patient-years. RESULTS The implantation was successful in all 276 patients. Peri-interventional reversible complications included transient ST-segment elevations (1.8%) and transient ischemic attack (TIA) (0.8%). Two devices have been removed surgically. During follow-up the annual recurrence rate of thromboembolic events was 1.7% for TIA, 0% for stroke and 0% for peripheral emboli. CONCLUSIONS Interventional PFO closure with the PFO-Star device appears to be a reliable and promising technique resulting in a low recurrence rate of thromboembolic events, especially stroke in patients with a history of cryptogenic ischemia presumably due to paradoxical embolization. To our knowledge, this is the largest coherent and prospective study for interventional PFO closure.

Respiratory Muscle Dysfunction in Congestive Heart Failure Clinical Correlation and Prognostic Significance

BackgroundIn congestive heart failure (CHF), the prognostic significance of impaired respiratory muscle strength has not been established. Methods and ResultsMaximal inspiratory pressure (Pimax) was prospectively determined in 244 consecutive patients (207 men) with CHF (ischemic, n=75; idiopathic dilated cardiomyopathy, n=169; age, 54±11 years; left ventricular ejection fraction [LVEF], 22±10%). Pimax was lower in the 244 patients with CHF than in 25 control subjects (7.6±3.3 versus 10.5±3.7 kPa;P =0.001). The 57 patients (23%) who died during follow-up (23±16 months; range, 1 to 48 months) had an even more reduced Pimax (6.3±3.2 versus 8.1±3.2 kPa in survivors;P =0.001). Kaplan-Meier survival curves differentiated between patients subdivided according to quartiles for Pimax (P =0.014). Pimax was a strong risk predictor in both univariate (P =0.001) and multivariate Cox proportional hazard analyses (P =0.03); multivariate analyses also included NYHA functional class, LVEF, peak oxygen consumption (peak ˙Vo2), and norepinephrine plasma concentration. The areas under the receiver-operating characteristic curves for prediction of 1-year survival were comparable for Pimax and peak ˙Vo2 (area under the curve [AUC], 0.68 versus 0.73;P =0.28), and they improved with the triple combination of Pimax, peak ˙Vo2, and LVEF (AUC, 0.82;P =0.004 compared with AUC of Pimax). ConclusionsIn patients with CHF, inspiratory muscle strength is reduced and emerges as a novel, independent predictor of prognosis. Because testing for Pimax is simple in clinical practice, it might serve as an additional factor to improve risk stratification and patient selection for cardiac transplantation.

Depression increasingly predicts mortality in the course of congestive heart failure.

Congestive heart failure (CHF) is frequently associated with depression. However, the impact of depression on prognosis has not yet been sufficiently established.

Nicotine and sympathetic neurotransmission.

SummaryNicotine increases heart rate, myocardial contractility, and blood pressure. These nicotine-induced cardiovascular effects are mainly due to stimulation of sympathetic neurotransmission, as nicotine stimulates catecholamine release by an activation of nicotinic acetylcholine receptors localized on peripheral postganglionic sympathetic nerve endings and the adrenal medulla. The nicotinic acetylcholine receptor is a ligand-gated cation channel with a pentameric structure and a central pore with a cation gate, which is essential for ion selectivity and permeability. Binding of nicotine to its extracellular binding site leads to a conformational change of the central pore, which results in the influx of sodium and calcium ions. The resulting depolarization of the sympathetic nerve ending stimulates calcium influx through voltage-dependent N-type calcium channels, which triggers the nicotine-evoked exocytotic catecholamine release. In the isolated perfused guinea-pig heart, cardiac energy depletion sensitizes cardiac sympathetic nerves to the norepinephrine-releasing effect of nicotine, as indicated by a leftward shift of the concentration-response curve, a potentiation of maximum transmitter release, and a delay of the tachyphylaxis of nicotine-evoked catecholamine release. This sensitization was also shown to occur in the human heart under in vitro conditions. Through the intracardiac release of norepinephrine, nicotine induces a beta-adrenoceptormediated increase in heart rate and contractility, and an alpha-adrenoceptor-mediated increase in coronary vasomotor tone. The resulting simultaneous increase in oxygen demand and coronary resistance has a detrimental effect on the oxygen balance of the heart, especially in patients with coronary artery disease. Sensitization of the ischemic heart to the norepinephrine-releasing effect of nicotine may be a trigger for acute cardiovascular events in humans, such as acute myocardial infarction and/or life-threatening ventricular tachyarrhythmias.

Prognostic value of Doppler echocardiographic mitral inflow patterns: implications for risk stratification in patients with chronic congestive heart failure

OBJECTIVES This prospective study tested whether transmitral flow patterns add incremental value to peak oxygen consumption (VO2) in determining the prognosis of patients with chronic congestive heart failure (CHF) and systolic dysfunction. BACKGROUND Peak VO2 is an objective marker of functional capacity and is routinely used as a criterion to identify heart transplant candidates. Diastolic dysfunction limits functional capacity, but its prognostic importance relative to that of peak VO2 is unknown. METHODS Peak VO2 and mitral inflow velocities were prospectively measured in 311 consecutive patients (mean age 54 years, 84% male) with impaired left ventricular function (ejection fraction <40%; 88 patients with ischemic and 223 with dilated cardiomyopathy) who were evaluated for heart transplant candidacy. RESULTS During a mean follow-up period of 512 +/- 314 days, 65 patients died and 43 patients underwent heart transplantation. Diastolic filling patterns, peak VO2 and left ventricular end-diastolic diameters were independent predictors of cardiac mortality. In patients with peak VO2 < or = 14 ml/min per kg body weight, the outcome was markedly poorer in the presence of restrictive filling patterns as compared with their absence (two-year survival rate 52% vs. 80%). Similarly, despite peak VO2 levels >14 ml/min per kg, the outcome was less favorable in the presence of restrictive filling patterns (two-year survival rate 80% vs. 94%). A risk-stratification model based on the identified independent noninvasive predictors separated groups into those with high (93%), intermediate (65%) and low (39%) two-year survival rates. CONCLUSIONS Transmitral flow patterns add incremental value to peak VO2 in determining the prognosis of patients with CHF and impaired systolic function.

Intracellular compartmentation of troponin T: Release kinetics after global ischemia and calcium paradox in the isolated perfused rat heart

The marked differences in troponin T serum concentrations observed in patients with reperfused and non-reperfused myocardial infarction may be due to a perfusion dependent wash-out of an unbound fraction of cardiac troponin T. To test the release kinetics of troponin T experimentally, the isolated rat heart (Langendorff preparation) was damaged either by the calcium paradox or by no-flow ischemia. Following membrane damage by the calcium paradox troponin T (TNT) showed the same release kinetics in the coronary effluent as the cytosolic markers creatine kinase (CK) or lactate dehydrogenase (LDH). Peak levels of troponin T (282 +/- 58 micrograms/l), CK (6754 +/- 1642 U/l), and LDH (5817 +/- 1730 U/l) occurred 5 min after onset of reperfusion with calcium containing buffers and returned to 9.9%, 1.3%, and 1% of their respective peak levels within 55 min of reperfusion. During reperfusion after no-flow ischemia different release kinetics were found for cytosolic enzymes and troponin T. After 60 min of ischemia, troponin T levels in the coronary effluent increased over the entire reperfusion period of 55 min, almost doubling the 5 min value (191%). In contrast, cardiac enzymes rapidly declined to 18% (CK) and 23% (LDH) of their respective 5 min values at the end of reperfusion. Light microscopy after reperfusion with carbon black revealed a complete and homogeneous reperfusion of Langendorff hearts after no-flow ischemia. Immunoblot analysis confirmed the release of an undegraded 39 kDa troponin T molecule, both after global ischemia and the calcium paradox. These data indicate that prolonged ischemia induces a continuous liberation of cardiac troponin T, most probably from disintegrating myofibres, whereas membrane damage leads almost exclusively to leakage of a functionally unbound troponin T pool. These findings may explain the biphasic serum concentration changes of cardiac troponin T in patients with reperfused myocardial infarction.

Body Mass Index and Adverse Cardiovascular Outcomes in Heart Failure Patients With Preserved Ejection Fraction Results From the Irbesartan in Heart Failure With Preserved Ejection Fraction (I-PRESERVE) Trial

Background— Obesity is a major risk factor for incident heart failure (HF). Paradoxically, in HF with reduced left ventricular ejection fraction (HFREF), a high body mass index (BMI) appears to be beneficial. Approximately 50% of HF patients have a preserved left ventricular ejection fraction (HFPEF). However, there are few data regarding the relationship between BMI and outcomes in HFPEF. Methods and Results— Baseline characteristics and cardiovascular outcomes were assessed in the 4109 patients (mean age, 72 years; mean follow-up, 49.5 months) in the Irbesartan in HF with Preserved Ejection Fraction (I-PRESERVE) trial. Based on the BMI distribution, 5 BMI categories were defined: <23.5, 23.5 to 26.4, 26.5 to 30.9, 31 to 34.9, and ≥35 kg/m2. Most patients (71%) had a BMI ≥26.5, 21% had a BMI between 23.5 and 26.4, and 8% had a BMI <23.5 kg/m2. Patients with higher BMI were younger, more often women, and more likely to have hypertension and diabetes and higher left ventricular ejection fraction. Patients with BMI of 26.5 to 30.9 kg/m2 had the lowest rate for the primary composite outcome (death or cardiovascular hospitalization) and were used as reference group. After adjustment for 21 risk variables including age, sex, and N-terminal pro-brain natriuretic peptide, the hazard ratio for the primary outcome was increased in patients with BMI <23.5 (hazard ratio, 1.27; 95% confidence interval, 1.04 to 1.56; P=0.019) and in those with BMI ≥35 kg/m2 (hazard ratio, 1.27; 95% confidence interval, 1.06 to 1.52; P=0.011) compared with the referent group. A similar relationship was found for all-cause mortality and for HF hospitalization. Conclusions— Obesity is common in HFPEF patients and is accompanied by multiple differences in clinical characteristics. Independent of other key prognostic variables, there was a U-shaped relationship, with the greatest rate of adverse outcomes in the lowest and highest BMI categories. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT000095238.Background— Obesity is a major risk factor for incident heart failure (HF). Paradoxically, in HF with reduced left ventricular ejection fraction (HFREF), a high body mass index (BMI) appears to be beneficial. Approximately 50% of HF patients have a preserved left ventricular ejection fraction (HFPEF). However, there are few data regarding the relationship between BMI and outcomes in HFPEF. Methods and Results— Baseline characteristics and cardiovascular outcomes were assessed in the 4109 patients (mean age, 72 years; mean follow-up, 49.5 months) in the Irbesartan in HF with Preserved Ejection Fraction (I-PRESERVE) trial. Based on the BMI distribution, 5 BMI categories were defined: <23.5, 23.5 to 26.4, 26.5 to 30.9, 31 to 34.9, and ≥35 kg/m2. Most patients (71%) had a BMI ≥26.5, 21% had a BMI between 23.5 and 26.4, and 8% had a BMI <23.5 kg/m2. Patients with higher BMI were younger, more often women, and more likely to have hypertension and diabetes and higher left ventricular ejection fraction. Patients with BMI of 26.5 to 30.9 kg/m2 had the lowest rate for the primary composite outcome (death or cardiovascular hospitalization) and were used as reference group. After adjustment for 21 risk variables including age, sex, and N-terminal pro-brain natriuretic peptide, the hazard ratio for the primary outcome was increased in patients with BMI <23.5 (hazard ratio, 1.27; 95% confidence interval, 1.04 to 1.56; P =0.019) and in those with BMI ≥35 kg/m2 (hazard ratio, 1.27; 95% confidence interval, 1.06 to 1.52; P =0.011) compared with the referent group. A similar relationship was found for all-cause mortality and for HF hospitalization. Conclusions— Obesity is common in HFPEF patients and is accompanied by multiple differences in clinical characteristics. Independent of other key prognostic variables, there was a U-shaped relationship, with the greatest rate of adverse outcomes in the lowest and highest BMI categories. Clinical Trial Registration— URL: . Unique identifier: NCT000095238.

Characterization and presynaptic modulation of stimulation-evoked exocytotic co-release of noradrenaline and neuropeptide Y in guinea pig heart.

SummaryThe relationship between noradrenaline and neuropeptide Y (NPY) release was investigated in the in situ perfused guinea pig heart with intact sympathetic innervation. For determination of NPY concentrations in the perfusate, a specific radioimmunoassay was employed and further characterized. Electrical stimulation of the left stellate ganglion (4, 8, 12, and 50 Hz; for 10 min) evoked a calcium-dependent and frequency-related overflow of noradrenaline and NPY, which was positively correlated (r = 0.83; p < 0.001; n = 25). When two subsequent stimulations (12 Hz; each for 1 min) were performed in the same heart, addition of noradrenaline (10 μM) 5 min prior to the second stimulation reduced NPY overflow by 43 ± 10%. The stimulated release of noradrenaline and NPY was increased by the alpha2-adrenoceptor antagonist yohimbine (1 μM) to 170 ± 10% and 199 ± 26%, and attenuated by the alpha2-adrenoceptor agonist B-HT 920 (1 μM) to 70 ± 9% and 68 ± 9%, respectively. The adenosine analogue cyclohexyladenosine (1 μM) significantly reduced the stimulated overflow of both noradrenaline (to 57 ± 5%) and NPY (to 73 ± 8%). Exogenous NPY (100 nM) attenuated the stimulated overflow of noradrenaline by 30 ± 6%. Uptake1 blockade with desipramine (100 nM) or nisoxetine (100 nM) prior to the second stimulation significantly increased noradrenaline overflow and attenuated that of NPY; the attenuation of the stimulation-evoked overflow of NPY was abolished by yohimbine (1 μM).Our results indicate that electrical stimulation induces a calcium-dependent, exocytotic co-release of noradrenaline and NPY. The co-release of both transmitters is regulated by presynaptic receptors in a parallel manner; furthermore, both transmitters, noradrenaline and possibly NPY, modulate their own release by a presynaptic negative feedback mechanism via presynaptic alpha2-adrenoceptors and NPY-receptors.