Manfred Nelles

Remote preconditioning by infrarenal occlusion of the aorta protects the heart from infarction: a newly identified non-neuronal but PKC-dependent pathway

BACKGROUND Ischemic preconditioning is a powerful mechanism in reducing infarct size of the heart. Protection can be performed either by an ischemic stimulus of the heart itself or by ischemia of an organ distant to the heart. To address the question whether this remote preconditioning is transduced by neuronal or humoral factors an in situ model of infrarenal occlusion of the aorta (IOA) in the rat was developed. Furthermore, the signal transduction pathways of classical and remote preconditioning regarding protein kinase C, which is one of the key enzymes in classical preconditioning, were compared. METHODS AND RESULTS Controls (30 min regional ischemia followed by 2 h of reperfusion) had an infarct size of 62+/-5% whereas classical preconditioning reduced it to 10+/-3% of the risk zone (P< or =0.001). Fifteen minutes IOA without reperfusion of the aorta had no influence on infarct size (52+/-4%). When, however, IOA was performed for 15, 10, or 5 min, respectively, followed by a 10-min reperfusion period the size of myocardial infarction decreased significantly. This decrease was dependent on the duration of IOA (18+/-3%, 37+/-8%, 42+/-2%, respectively; P< or =0.001 for the time-dependent linear trend in decrease of infarct size). Fifteen minutes IOA showed the strongest protection which was comparable to classical preconditioning (18+/-3%, P< or =0.001 vs. control). Blockade of the nervous pathway by 20 mg/kg hexamethonium could not inhibit the protection afforded by IOA (14+/-4%). Using chelerythrine, a selective protein kinase C-inhibitor, at a dose of 5 mg/kg body weight, protection from remote (68+/-4%, P< or =0.001 vs. 15 min IOA followed by 10 min of reperfusion without chelerythrine) as well as from classical preconditioning (56+/-5%, P< or =0.001) was completely blocked. CONCLUSION Protection of the heart by remote preconditioning using IOA is as powerful as classical preconditioning. Both protection methods share protein kinase C as a common element in their signal transduction pathways. Since hexamethonium could not block the protection from IOA and a reperfusion period has to be necessarily interspaced between the IOA and the infarct inducing ischemia of the heart, a neuronal signal transmission from the remote area to the heart can be excluded with certainty. A humoral factor must be responsible for the remote protection. Interestingly the production of the protecting factor is dependent on the duration of the ischemia of the lower limb. The protecting substance, which must be upstream of protein kinase C, remains to be identified.

Osteopontin, a New Prognostic Biomarker in Patients With Chronic Heart Failure

Background—Osteopontin, a glycoprotein that can be detected in plasma, was found to be upregulated in several animal models of cardiac failure and may thus represent a new biomarker that facilitates risk stratification in patients with heart failure. We therefore tested whether osteopontin plasma levels are elevated in patients with chronic heart failure and whether they provide independent prognostic information. Methods and Results—We analyzed osteopontin plasma levels in 420 patients with chronic heart failure due to significantly impaired left ventricular systolic function and correlated the results with disease stage and prognostic information (median follow-up of 43 months). We found that osteopontin plasma levels were significantly elevated in patients with heart failure as compared with healthy control subjects (532 versus 382 ng/mL, P=0.008), irrespective of heart failure origin (ischemic versus dilated cardiomyopathy). Furthermore, osteopontin levels were higher in patients with moderate to severe heart failure than in patients with no or mild symptoms (672 ng/mL for New York Heart Association class III/IV versus 479 ng/mL for class I/II, P<0.0001). Estimated 4-year death rates in patients with osteopontin levels above or below a cutoff value derived from receiver operating characteristic analyses were 56.5% and 28.4%, respectively (hazard ratio 3.4, 95% confidence interval 2.2 to 5.3, P<0.0001). In a multivariable model that included demographic, clinical, and biochemical parameters such as N-terminal prohormone brain natriuretic peptide, osteopontin emerged as an independent predictor of death (hazard ratio 2.3, 95% confidence interval 1.4 to 3.5, P<0.001). Conclusion—Our findings suggest that osteopontin might be useful as a novel prognostic biomarker in patients with chronic heart failure.

The obesity paradox in stable chronic heart failure does not persist after matching for indicators of disease severity and confounders

To verify whether controlling for indicators of disease severity and confounders represents a solution to the obesity paradox in chronic heart failure (CHF).

Exploring potential associations of suicidal ideation and ideas of self-harm in patients with congestive heart failure.

Objective: To determine the factors, which are associated with suicidal ideation and ideas of self‐harm in patients with congestive heart failure (CHF). Methods: We examined 294 patients with documented CHF, New York Heart Association (NYHA) functional class II‐IV, in a cross sectional study at three cardiac outpatient departments. Measures included self‐reports of suicidal ideation and self‐harm (PHQ‐9), depression (SCID), health‐related quality of life (SF‐36), multimorbidity (CIRS‐G), consumption of alcoholic beverages, as well as comprehensive clinical status. Data were analyzed using logistic regression analyses. Results: 50 patients (17.1%) reported experiencing suicidal ideation and/or ideas of self‐harm on at least several days over the past two weeks. The final regression model revealed significant associations with health‐related quality of life, physical component (odds ratio [OR] 0.56; 95% confidence interval [CI]: 0.35–0.91), and mental component (OR 0.50; 95% CI: 0.31–0.82), consumption of alcoholic beverages (OR 1.27; 95% CI: 1.05–1.54), first‐episode depression (OR 3.92; 95% CI: 1.16–13.22), and lifetime depression (OR 10.89; 95% CI: 2.49–47.72). Age was only significant in the univariable (P=.03) regression analysis. NYHA functional class, left ventricular ejection fraction (LVEF), etiology of CHF, medication, cardiovascular interventions, multimorbidity, gender, and living situation were not significantly associated with suicidal ideation or ideas of self‐harm. Conclusions: Lifetime depression, in particular, increases the risk of suicidal ideation and ideas of self‐harm in CHF patients. Furthermore, the findings of our study underline the necessity of differentiating between first‐episode and lifetime depression in CHF‐patients in future research and clinical practice. Depression and Anxiety, 2009.

Panic disorder in patients with chronic heart failure

OBJECTIVE Our objective was to assess the prevalence of panic disorder, its influence on quality of life (QoL), and the presence of further anxiety and depressive comorbid disorders in outpatients with chronic heart failure (CHF). METHODS In a cross-sectional study, anxiety and depressive disorders were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnostic criteria in patients with CHF who were aged > or =18 years and had New York Heart Association (NYHA) Functional Classes I-IV, using the Patient Health Questionnaire. Health-related QoL was evaluated using the Short-Form 36 Health Survey (SF-36). RESULTS Of the 258 participating patients, 24 (9.3%) fulfilled diagnostic criteria for panic disorder. Seven of these (29.2%) were diagnosed with comorbid anxiety disorders, 11 (47.3%) were diagnosed with comorbid depressive disorder, and 5 (20.8%) were diagnosed with other anxiety disorders and any depressive disorder. Female gender [odds ratio (OR)=3.1; 95% confidence interval (95% CI)=1.2-7.8; P=.02] and a lower level of education (OR=0.3; 95% CI=0.1-0.9; P=.04) were associated with the presence of panic disorder. In patients with panic disorder, QoL was significantly more restricted on all subscales of the SF-36 as compared to those without panic disorder, even when age, gender, and NYHA functional class were controlled for (P=.05 to <.01). CONCLUSION Approximately 1 of 10 patients with CHF suffers from panic disorder, many of whom also have additional anxiety or depressive comorbid disorders. Female gender and a low level of education are positively associated with the presence of panic disorder. QoL is severely limited by the presence of panic disorder. Diagnosis of mental disorders and treatment offers for affected patients should be available in patient care.

Relation of N-terminal pro-brain natriuretic peptide levels and their prognostic power in chronic stable heart failure to obesity status

AIMS To investigate the relationship between body mass index (BMI) and N-terminal pro-brain natriuretic peptide (NTproBNP) level and resultant prognostic capacity in chronic heart failure (CHF) controlled for known confounders. METHODS AND RESULTS We formed 206 triplets of patients (n = 618) with stable systolic CHF matched with respect to age, sex, renal function (MDRD, modification of diet in renal disease formula), and NYHA class, each with a BMI >30 kg/m(2) (group 3), 20-24.9 kg/m(2) (group 1), and 25-29.9 kg/m(2) (group 2). BMI conveys a 4% drop in NTproBNP per unit increase. This influence remained significant after correction for age, sex, MDRD, NYHA, heart rate, rhythm, and ejection fraction. NTproBNP remained an independent predictor of adverse outcome after correction for age, sex, BMI, NYHA, MDRD, and ejection fraction. Despite numerical differences, prognostic power was comparable between BMI groups (log-transformed NTproBNP; group 1: hazard ratio (HR) 1.435, 95% CI 1.046-1.967, chi(2) 5.02, P = 0.03; group 2: HR 1.604, 95% CI 1.203-2.138, chi(2) 10.36, P = 0.001; group 3: HR 1.735, 95% CI 1.302-2.313, chi(2) 14.12, P = 0.0002) (P = NS, all). An NTproBNP correction factor was calculated. CONCLUSION Even matched for NYHA, age, sex, and renal function, BMI exerts a significant and independent inverse influence on NTproBNP in patients with stable CHF. NTproBNP retained equal statistical power in all three BMI groups.

Multicentre evaluation of a new point-of-care test for the determination of NT-proBNP in whole blood

Abstract Background: The Roche CARDIAC proBNP point-of-care (POC) test is the first test intended for the quantitative determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) in whole blood as an aid in the diagnosis of suspected congestive heart failure, in the monitoring of patients with compensated left-ventricular dysfunction and in the risk stratification of patients with acute coronary syndromes. Methods: A multicentre evaluation was carried out to assess the analytical performance of the POC NT-proBNP test at seven different sites. Results: The majority of all coefficients of variation (CVs) obtained for within-series imprecision using native blood samples was below 10% for both 52 samples measured ten times and for 674 samples measured in duplicate. Using quality control material, the majority of CV values for day-to-day imprecision were below 14% for the low control level and below 13% for the high control level. In method comparisons for four lots of the POC NT-proBNP test with the laboratory reference method (Elecsys proBNP), the slope ranged from 0.93 to 1.10 and the intercept ranged from 1.8 to 6.9. The bias found between venous and arterial blood with the POC NT-proBNP method was ≤5%. All four lots of the POC NT-proBNP test investigated showed excellent agreement, with mean differences of between −5% and +4%. No significant interference was observed with lipaemic blood (triglyceride concentrations up to 6.3mmol/L), icteric blood (bilirubin concentrations up to 582μmol/L), haemolytic blood (haemoglobin concentrations up to 62mg/L), biotin (up to 10mg/L), rheumatoid factor (up to 42IU/mL), or with 50 out of 52 standard or cardiological drugs in therapeutic concentrations. With bisoprolol and BNP, somewhat higher bias in the low NT-proBNP concentration range (<175ng/L) was found. Haematocrit values between 28% and 58% had no influence on the test result. Interference may be caused by human anti-mouse antibodies (HAMA) types 1 and 2. No significant influence on the results with POC NT-proBNP was found using volumes of 140–165μL. High NT-proBNP concentrations above the measuring range of the POC NT-proBNP test did not lead to false low results due to a potential high-dose hook effect. Conclusions: The POC NT-proBNP test showed good analytical performance and excellent agreement with the laboratory method. The POC NT-proBNP assay is therefore suitable in the POC setting. Clin Chem Lab Med 2006;44:1269–77.

Telemedizinisches Monitoring bei herzinsuffizienten Patienten

SummaryHeart failure exhibits a significant clinical and health economic problem. The implementation of new therapeutic strategies favorably affecting the course of disease is still insufficient in day-to-day practice. Thus, the usage of telemedicine offers a central instrument for service and information, so that an optimized therapy can be achieved by consequent surveillance of the patient with chronic heart disease. Predefined vital parameters are automatically transmitted to the telemedicine center; if individually predefined limits are exceeded, therapeutic means are immediately initiated. For the patient, the center is attainable 24 h throughout the year in case he experiences cardio-pulmonary symptoms. This patient-oriented usage of technology should not replace the physician-patient relationship, but improves and supports the participation and self-management of patients. Furthermore, the results show that this technology can significantly reduce the amount of emergency physician services, hospital admissions and primary care physician visits, and displays for health economics purposes a clearly more cost-effective treatment strategy, while allowing for additional costs inherent to the system. The usage of telemonitoring in chronic heart failure patients may be a trendsetting form of care, which can be used to drastically optimize the information and data flow between patient, hospital and primary care physician individually and at any time.ZusammenfassungDie Herzinsuffizienz stellt ein bedeutendes klinisches und gesundheitsökonomisches Problem dar. Die Umsetzung neuer, den Krankheitsverlauf günstig beeinflussender Therapiestrategien und der hieraus resultierenden Therapieleitlinien in der chronischen Herzinsuffizienz sind im Praxisalltag nach wie vor unzureichend. Der Einsatz der Telemedizin bietet sich daher als zentrales Service- und Informationsinstrument an, so dass durch eine konsequente Überwachung des chronisch herzkranken Patienten eine optimierte Therapieführung ermöglicht wird. Vorgegebene Vitalparameter werden automatisch an das telemedizinische Zentrum übermittelt, bei Überschreitung individuell festgelegter Grenzwerte werden umgehend therapeutische Maßnahmen eingeleitet. Bei kardiopulmonalen Symptomen ist das Zentrum an 24 h für 365 Tagen im Jahr für den Patienten erreichbar. Dieser patientenorientierte Technologieeinsatz sollte dabei die Arzt-Patientenbeziehung nicht ersetzen, sondern verbessert und fördert die Partizipation sowie das Selbstmanagement der Patientinnen und Patienten. Außerdem zeigen die Ergebnisse, dass durch diese Technologie die Zahl der Notarzteinsätze, Klinikeinweisungen und Arztbesuche hochsignifikant reduziert werden kann und aus gesundheitsökonomischer Sicht, auch unter Berücksichtigung der systemimmanenten Mehrkosten, die eindeutig kosteneffektivere Behandlungsstrategie darstellt. Der Einsatz der Telemedizin bei chronisch herzinsuffizienten Patienten könnte somit eine zukunftsweisende Betreuungsform darstellen, durch die der Informations- und Datenfluss zwischen Patient, Krankenhaus und niedergelassenem Arzt entscheidend individuell und zu jeder Zeit optimiert werden kann.

The prognostic value of individual NT-proBNP values in chronic heart failure does not change with advancing age

Background: It is unclear whether age-related increases in N-terminal pro-brain natriuretic peptide (NT-proBNP) represent a normal physiological process—possibly affecting the prognostic power—of NT-proBNP—or reflect age-related subclinical pathological changes. Objective: To determine the effect of age on the short-term prognostic value of NT-proBNP in patients with chronic heart failure (CHF). Design: Prospective observational study with inclusion and matching of consecutive patients aged >65 years (mean (SD) 73.1 (6.0) years) to patients <65 years (53.7 (8.6) years) with respect to NT-proBNP, New York Heart Association stage, sex and aetiology of CHF (final n = 443). Setting: University hospital outpatient departments in the UK and Germany. Patients: Chronic stable heart failure due to systolic left ventricular dysfunction. Intervention: None. Outcome measure: All-cause mortality. Results: In both age groups, NT-proBNP was a significant univariate predictor of mortality, and independent of age, sex and other established risk markers. The prognostic information given by NT-proBNP was comparable between the two groups, as reflected by the 1-year mortality of 9% in both groups. The prognostic accuracy of NT-proBNP as judged by the area under the receiver operating characteristics curve for the prediction of 1-year mortality was comparable for elderly and younger patients (0.67 vs 0.71; p = 0.09). Conclusion: NT-proBNP reflects disease severity in elderly and younger patients alike. In patients with chronic stable heart failure, the NT-proBNP value carries the same 1-year prognostic information regardless of the age of the patient.

Validity, prognostic value and optimal cutoff of respiratory muscle strength in patients with chronic heart failure changes with beta-blocker treatment

Background Training studies frequently use maximum inspiratory mouth occlusion pressure (PImax) as a therapeutic target and surrogate marker. For patients on β-blocker (BBL), prognostic data allowing this extrapolation do not exist. Furthermore, the effects of BBL, mainstay of modern chronic heart failure therapy, on respiratory muscle function remain controversial. Finally, no proper separate cutoff according to treatment exists. Design Prospective, observational inclusion of patients with stable systolic chronic heart failure and recording of 1 year and all-time mortality for endpoint analysis. Methods In 686 patients, 81% men, 494 patients on BBL, PImax was measured along with clinical evaluation. The median follow-up was 50 months (interquartile range: 26–75 months). Results Patients with or without BBL did not differ significantly for PImax, percentage of predicted PImax or other marker of disease severity. PImax was a significant (hazard ratio: 0.925; 95% confidence interval: 0.879–0.975; χ2: 8.62) marker of adverse outcome, independent of BBL-status or aetiology. Percentage of predicted PImax was not independent of PImax. The cutoff identified through receiver-operated characteristics for 1-year mortality was 4.14 kPa for patients on BBL and 7.29 kPa for patients not on BBL. When separated accordingly, 1-year mortality was 8.5 versus 21.4%, P = 0.02, for patients not on BBL and 4.3 versus 16.2%, P < 0.001, for patients on BBL. Conclusion This study fills the gap between trials targeting respiratory muscle on a functional basis and the resultant prognostic information with regard to BBL. BBL lowered the optimal PImax cutoff values for risk stratification without changing the measured values of PImax. This should be considered at inclusion and evaluation of trials and interpretation of exercise parameters.