Mark Rosenberg

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.

One-year outcomes after transcatheter insertion of an interatrial shunt device for the management of heart failure with preserved ejection fraction

Background—Heart failure with preserved ejection fraction has a complex pathophysiology and remains a therapeutic challenge. Elevated left atrial pressure, particularly during exercise, is a key contributor to morbidity and mortality. Preliminary analyses have demonstrated that a novel interatrial septal shunt device that allows shunting to reduce the left atrial pressure provides clinical and hemodynamic benefit at 6 months. Given the chronicity of heart failure with preserved ejection fraction, evidence of longer-term benefit is required. Methods and Results—Patients (n=64) with left ventricular ejection fraction ≥40%, New York Heart Association class II–IV, elevated pulmonary capillary wedge pressure (≥15 mm Hg at rest or ≥25 mm Hg during supine bicycle exercise) participated in the open-label study of the interatrial septal shunt device. One year after interatrial septal shunt device implantation, there were sustained improvements in New York Heart Association class (P<0.001), quality of life (Minnesota Living with Heart Failure score, P<0.001), and 6-minute walk distance (P<0.01). Echocardiography showed a small, stable reduction in left ventricular end-diastolic volume index (P<0.001), with a concomitant small stable increase in the right ventricular end-diastolic volume index (P<0.001). Invasive hemodynamic studies performed in a subset of patients demonstrated a sustained reduction in the workload corrected exercise pulmonary capillary wedge pressure (P<0.01). Survival at 1 year was 95%, and there was no evidence of device-related complications. Conclusions—These results provide evidence of safety and sustained clinical benefit in heart failure with preserved ejection fraction patients 1 year after interatrial septal shunt device implantation. Randomized, blinded studies are underway to confirm these observations. Clinical Trial Registration—URL: https://www.clinicaltrials.gov. Unique identifier: NCT01913613.

Triiodothyronine reverses depressed contractile performance after excessive catecholamine stimulation

BACKGROUND Conflicting results have been reported regarding the acute effects of triiodothyronine (T3) on myocardial contractile performance. The present study analyzes the role of T3 in reversing the depressant effect of excessive catecholamine stimulation in isolated porcine left ventricular myocardium. METHODS Thirty-six left ventricular trabeculae (0.4 x 6.0 mm) obtained from 6 pigs were used for measurements of isometric force development, isotonic shortening, and intracellular calcium in three experimental series (measurement conditions: 37 degrees C; optimal length; supramaximal electrical stimulation, 1 Hz; calcium measurement, fura-2 ratio method; frequency, 225 Hz). In series 1, isometric force development was measured before and after a 60-minute incubation with 10(-7) mol/L epinephrine in preparations with (n = 6) and without (n = 6) preceding fura-2 loading for calcium measurements. In series 2, the acute effects of a 30-minute administration of T3 (10(-9) mol/L) on isometric force and intracellular calcium were analyzed (n = 6). In series 3, after simultaneous fura-2 loading and a 6-hour 10(-7) mol/L epinephrine exposure the effects of T3 (10(-9) mol/L, 30 minutes) on force development, shortening, and intracellular calcium transient were analyzed. RESULTS Long-term and high-dose epinephrine exposure induced a severe contractile depression with a significant reduction of isometric force development (p < 0.05) and increased diastolic (p < 0.001) and systolic calcium (p < 0.001). In normal porcine myocardium T3 had no effect on the extent of isometric force generation but accelerated the time course of force development (p < 0.05) and increased the calcium transient (p < 0.001). After induction of myocardial depression by epinephrine exposure T3 accelerated the intracellular calcium transients and reduced diastolic calcium. Triiodothyronine increased the shortening amplitude and the force amplitude (p < 0.01). CONCLUSIONS Triiodothyronine reverses depressed contractile performance after preceding high-dose epinephrine exposure in isolated porcine myocardium. Increased force amplitudes and unaltered or even reduced intracellular calcium transients argue in favor of a resensitization of the contractile apparatus for calcium by T3. The study supports a potential role for T3 treatment in depressed myocardium after previous excessive catecholamine exposure (eg, brain death, catecholamine treatment, ischemia).

Rapid progressive eosinophilic cardiomyopathy in a patient with Churg–Strauss syndrome (CSS)

SummaryChurg–Strauss syndrome (CSS) is a rare necrotizing, systemic vasculitis that is almost invariably associated with bronchial asthma. Although overall prognosis is good and treatment with corticosteroids alone or in combination with other immunosuppressive agents is typically successful, there are reports of patients that do not show signs of clinical improvement under the usual pharmacotherapy. Small clinical studies suggested that cardiac or gastrointestinal involvement is associated with an adverse prognosis.We here report the case of a 38 year old male patient with a history of bronchial asthma who was admitted to our hospital for further evaluation of progressive dyspnea. Blood eosinophilia, infiltrates of both lungs, signs of necrosis and eosinophil deposits on myocardial biopsy combined with a history of bronchial asthma established the diagnosis of CSS with cardiac involvement. We initiated an immunosuppressive therapy with prednisone and methotrexate. Upon tapering of the dosage of prednisone, we noticed worsening of symptoms and further deterioration of cardiac function. Despite the addition of cyclophosphamide and adjustment of heart failure medication, we were not able to stabilize the cardiac situation. Due to rapid progressive eosinophilic cardiomyopathy associated with CSS refractory to medical therapy, our patient was placed on the urgent heart transplantation waiting list and, in the meantime, has undergone successful cardiac transplantation.

Real-time myocardial contrast echocardiography for the detection of stress-induced myocardial ischemia. Comparison with 99mTc-sestamibi single photon emission computed tomography.

Die Echtzeitkontrastechokardiographie (MCE) ist ein neues Verfahren zur Beurteilung der Myokardperfusion. Ziel der Studie war es zu testen, ob mittels Echtzeit MCE funktionell signifikante Koronarstenosen bei Patienten mit vermuteter oder bekannter koronarer Herzerkrankung erkannt werden können. Kontrastechokardiographische Untersuchungen wurden mit nahezu simultan durchgeführten 99mTc-sestamibi SPECT-Untersuchungen verglichen. Die SPECT-Szintigraphie diente als klinischer Goldstandard zum Nachweis regionaler myokardialer Perfusionsdefekte. Echtzeit-Kontrastechokardiographische Untersuchungen wurden unter Verwendung einer kontinuierlichen Infusion von Optison® (8–10 ml/h) durchgeführt. Eingeschlossen wurden 70 konsekutive Patienten, bei denen aus klinischer Indikation eine pharmakologische Stressuntersuchung (99mTc-SPECT, Dipyridamol 0,56 mg/kg×4 Minuten) durchgeführt wurde. Apikale Vier- und Zweikammerblicke wurden in jeweils 6 Segmente unterteilt. Traceranreicherung und Myokardkontrastierung wurden von zwei unabhängigen Untersuchern visuell beurteilt (als normal, gering reduziert, stark reduziert oder fehlend). Die Myokardkontrastierung konnte in 143 von 792 Wandsegemten (18%) nicht adäquat analysiert werden. Die Traceranreicherung war in 92 Segmenten (12%) nicht adäquat analysierbar. Die Untersucherübereinstimmung war akzeptabel (Konkordanzraten 83% (κ=0,72) für Ruhe- und 86% (κ=0,76) für stressechokardiographische Untersuchungen). Die Übereinstimmung zwischen MCE und SPECT-Befunden auf segmentaler Ebene war gut (83%, κ=0,63). Gute Übereinstimmungen wurden auch bei der Erfassung fixer und reversibler Perfusionsdefekte und normal perfundierter Segmente gefunden (65, 73 und 83%). Bei der Auswertung einzelner Koronarversorgungsgebiete lagen für alle drei Territorien gute Übereinstimmungen vor (LAD, 83%, κ=0,59; LCX, 86%, κ=0,64 und RCA, 80%, κ=0,68). Diese Daten zeigen, dass sich die Echtzeitkontrastechokardiographie zur Erfassung von Perfusionsdefekten eignet. Real-time contrast echocardiography (MCE) is a new promising technique for assessing myocardial perfusion. The purpose of this study was to test whether realtime MCE can be used to detect functionally significant coronary artery stenosis in patients with known or suspected coronary artery disease. Myocardial contrast echocardiographic studies were compared with nearly simultaneous 99mTc-sestamibi single photon emission computed tomography (SPECT) as a clinical standard reference to evaluate regional myocardial perfusion defects. Real-time MCE based on continuous infusion of Optison (8–10 ml/h) was performed in 66 patients during standard 99mTc-SPECT dipyridamole (0.56 mg/kg×4 min) stress testing. Images were obtained in apical 4- and 2-chamber views, each divided into 6 segments. Tracer uptake and myocardial opacification were visually analyzed for each segment by two pairs of blinded observers and graded as normal, mildly reduced, severely reduced, or absent. In 792 myocardial segments, myocardial opacification by MCE was uninterpretable in 143 (18%) segments and tracer uptake by SPECT was not clearly defined in 92 (12%) segments. Interobserver variability for MCE was good with concordance rates of 83% (κ=0.72) for rest- and 86% (κ=0.76) for stress images. Overall concordance between MCE and SPECT was good (83%, κ=0.63) at a segmental level. In the diagnosis of fixed and reversible defects, and of normal perfusion, concordance rates were 73, 65 and 83%, respectively. When analysis was performed at the regional level, we found comparable levels of concordance rates for LAD (83%, κ=0.59), LCX (86%, κ=0.64) and RCA (80%, κ=0.68) perfusion territories. These findings suggest that realtime MCE is a clinically acceptable method to evaluate myocardial perfusion defects during dipyridamole stress testing.

Die negativ inotrope Wirkung von Interleukin-1 und Interleukin-6 wird beim Menschen nicht auf der Ebene des kontraktilen Apparates vermittelt

ZusammenfassungEinführung: Verschiedene Arbeitsgruppen konnten den Nachweis einer negativ inotropen Wirkung der Zytokine Interleukin-1 und Interleukin-6 erbringen, allerdings ohne den genauen Wirkungsmechanismus aufschlüsseln zu können. Da niedermolekulare Peptide prinzipiell in der Lage sind, das Kontraktionsverhalten von Herzmuskelfasern auf Ebene des kontraktilen Apparates zu modulieren, beschäftigt sich die hier vorgelegte Studie mit der Frage, ob Interleukin-1 und/oder Interleukin-6 eine Wirkung auf Ebene des kontraktilen Apparates entfalten können.    Methoden: Im Rahmen von Bypass-Operationen wurden menschliche Myokardpräparate gewonnen (n=32), deren Zellmembran mittels lipophiler Detergenzien (Triton-X-100) permeabilisiert wurde. Somit wurde der kontraktile Apparat bei gleichzeitiger Ausschaltung sämtlicher membranabhängiger Prozesse frei zugänglich. Es wurden die Auswirkungen unterschielich hoher Interleukin-1 und Interleukin-6 Konzentrationen (pIL 10–11–10–5) auf das Kontraktions- bzw. Relaxationsverhalten demembranisierter Herzmuskelfasern bestimmt. Gemessen wurde die isometrische Kraftentwicklung, die Zeitkonstante, als maßgebliche Zahl der Kontraktionskinetik, sowie die T/2-Relaxationszeit (Meßbedingungen: Vordehnung 2mN, 26°C Badtemperatur, isometrische Bedingungen).    Ergebnisse: Nach Analyse der isometrischen Kraftentwicklung konnte weder für Interleukin-1 noch für Interleukin-6 ein von initial durchgeführten Kontrollmessungen (ohne Interleukin-Zusatz) abweichendes Ergebnis festgestellt werden. Auch die Auswertung der kinetischen Versuchsparameter (Zeitkonstante/T/2-Relaxationszeit) konnte kein statistisch signifikantes Abweichen von zuvor durchgeführten Kontrollen aufdecken. Selbst die Verwendung extrem hoher Interleukin-Konzentrationen (pIL-1/pIL-6 1–2×10–5) konnte keine Wirkung auf das Kontraktions- bzw Relaxationsverhalten demembranisierter Herzmuskelfasern hervorrufen.    Schlussfolgerungen: Die Ergebnisse der Studie zeigen, dass Interleukin-1 und Interleukin-6 keine Wirkung auf die kontraktilen Proteine entfalten können. Dementsprechend können einige auf Ebene des kontraktilen Apparates potenziell negativ inotropen Reaktionskaskaden als Wirkungsmechanismen der Zytokine ausgeschlossen werden. Klinische Interventionen, die eine Verbesserung des Kontraktionsverhalten bei Sepsis etc. auf der Ebene des kontraktilen Apparates anstreben, scheinen nach den hier vorgestellten Daten wenig erfolgversprechend zu sein.SummaryObjective: Elevated levels of interleukin-1 (IL-1) and Interleukin-6 (IL-6) have been reported after cardiac operation, during inflammatory process and cardiac allograft rejection. Although several groups proved the evidence of a negative inotropic effect, the actual mechanism is not completely understood. Speaking generally it is possible that low molecular weight proteins are capable of altering myocardial contractility on the level of the contractile apparatus. Therefore this study analyzes whether IL-1 and/or IL-6 influence myocardial contractility on the level of the contractile apparatus.    Methods: During aorto-coronary bypass operation, human muscle fibers were excised (n=32) and skinned using Triton-X-100. The experimental skinned fiber model excludes membrane-related factors such as receptor activation and provides direct examination of the contractile apparatus itself. Different concentrations of IL-1 and IL-6 were applied (pIL-1/IL-6 1–2×10–5–10–11M). Force generation, calcium sensitivity, and velocity of force generation and relaxation were measured. (Experiments were carried out at optimal length, bath temperature 23°C, and isometric conditions.)    Results: None of the skinned muscle preparations of the human myocardium showed under the given experimental setup a significant change in contractility and relaxation after exposure to IL-1 and IL-6. Despite using nonphysiologic concentrations of IL-1 and IL-6 (pIL-1/IL-6 10–5M) no significant effect occurred. Furthermore no difference in calcium-sensitivity of the contractile proteins following addition of IL-1 and IL-6 could be observed.    Conclusions: Thus, there is no experimental evidence for direct modulation of the contractile apparatus by IL-1 or IL-6. Given these results it is possible to exclude some potentially negative inotropic cascades that are mediated on the level of the contractile apparatus as the molecular mechanism. These data show that therapies which support myocardial contractility during sepsis by stimulation of the contractile proteins do not seem to be very promising.

Kontraktionsverhalten und intrazellulare Calciumtransienten bei ischamischer Kardiomyopathie: Der Einfluß der Vorlast, der Nachlast und der Frequenz

Zusammenfassung Bei dem Krankheitsbild der ischämischen Kardiomyopathie (ICM) kommt es zu Phänotypenveränderungen der Myozyten, die zu kritischen Veränderungen der intrazellulären Ca2+-Homöostase führen können. Diese Veränderungen können die Kontraktilität des Herzens maßgeblich beeinflussen und Rhythmusstörungen begünstigen. Am Modell des isolierten menschlichen Myokards prüft die vorliegende Untersuchung Kontraktionsverhalten, diastolischen Ca2+-Haushalt und Ruhekraft unter dem Einfluß der Vorlast, der Nachlast und der Frequenz.¶ Methoden: Muskelfaserpräparate (0,5×5,0mm) wurden aus der infarktfreien Zone linksventrikulären Myokards aus ICM-Empfängerherzen (n=8) und aus normalen Spenderherzen (n=11) exzidiert, mit dem Calciumindikator FURA-2 geladen, auf optimale Länge (Lmax) vorgedehnt und elektrisch stimuliert (1Hz, 37°C, oxygenierte Krebs-Henseleit-Lösung). In Abhängigkeit der Vorlast (0,8–1,05L/Lmax), der Nachlast (Verkürzung gegen eine definierte Kraft) und der Frequenz (0,5–3Hz) wurden die aktive Kraftentwicklung, die passive Ruhespannung und intrazelluläre Calciumtransienten unter isometrischen und isotonen Bedingungen gemessen.¶ Ergebnisse: 1) NSH entwickelt die maximale Kraftamplitude bei 2Hz, ICM hingegen bereits bei 1Hz. Höhere Frequenzen führen bei ICM zu einem signifikanten Abfall der Kraft (p<0,0001). 2) Diastolische Calciumkonzentrationen und Ruhespannungen sind bei Frequenzen >1,5Hz bei ICM signifikant erhöht (p<0,0001). 3) Die Erhöhung der Vorlast führt bei NSH und bei ICM zu ähnlichen Kraftanstiegen (n.s.). 4) Die passive Ruhedehnungskurve ist bei ICM signifikant steiler (p<0,0001). 5) Eine reduzierte Nachlast führt bei ICM zu einer massiven Calciumüberladung des Cytosols (p<0,0001).¶ Schlußfolgerung: Im Endstadium der ischämischen Kardiomyopathie bleibt in primär infarktfreien Myokardbezirken die Funktion des Frank-Starling-Mechanismus erhalten. Eine invertierte Kraft-Frequenz-Beziehung und Störungen der diastolischen Ca2+-Homöostase, die mit Veränderungen der passiven Ruhespannung verbunden sind, könnten jedoch nach den vorliegenden Befunden für das gestörte Kontraktionsverhalten des Herzens bei ICM von entscheidender Bedeutung sein.SummaryObjective: In ischemic cardiomyopathy (ICM) alterations of the phenotype of myocyte are responsible for critical changes in the intracellular Ca2+-handling. These changes can substantially influence myocardial performance and favor ventricular arrhythmia. Therefore, we investigated whether and how changes in preload, afterload and frequency effect contractility, diastolic Ca2+-handling and resting tension in isolated human myocardium from patients with ICM.¶ Methods: Small muscle strip preparations (0.5×5.0mm) were obtained from non-failing (NDH, n=11) and from non-infarcted areas of failing human hearts (ICM, n=8). Preparations were loaded with the Ca2+-indicator FURA-2 and mounted between a force transducer and servomotor (organ bath: 37°C, oxygenated KHS). The influence of stimulation frequency (0.5–3Hz), preload (0.8–1.5L/Lmax) and afterload on force, passive resting tension and diastolic Ca2+-handling was measured.¶ Results: 1) In NDH, peak isometric force was observed at 2Hz. In contrast, the ICM-myocardium developed maximum isometric force at 1Hz. At higher stimulation rates twitch tension was significantly reduced in ICM (p<0.0001). 2) Diastolic Ca2+-levels were elevated (p<0.0001) at higher stimulation frequencies (>1.5Hz), associated with parallel increase of diastolic resting tension in ICM (p<0.0001). 3) With increasing preload, force increased in NDH- and in ICM-myocardium. No significant difference in active force generation was observed (n.s.). 4) Passive resting tension was considerably elevated in ICM (p<0.0001). 5) During shortening, diastolic Ca2+-levels were significantly elevated in ICM (p<0.0001).¶ Conclusions: The function of the Frank-Starling-Mechanism is maintained in ICM, whereas a negative force-frequency relationship and a disturbed diastolic Ca2+-homeostasis, which is associated with alterations in resting tension, may contribute to the impairment of myocardial performance in end-stage ischemic cardiomyopathy.