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Aims Life-threatening arrhythmias are a major problem in chronic heart failure (CHF). The aim of the present study was to investigate the mechanism underlying the low proarrhythmic potential of amiodarone in a model of pacing-induced heart failure. Methods and results Heart failure was induced in 35 female rabbits by rapid ventricular pacing, resulting in a significant decrease of ejection fraction. Thirty-four rabbits were sham-operated. In 17 of 35 CHF-rabbits and 20 of 34 ‘sham’-rabbits, amiodarone (50 mg/kg/day) was fed for 6 weeks. Eight monophasic action potentials and a simultaneously recorded 12-lead electrocardiogram showed prolongation of QT-interval and action potential duration (APD90) in all failing hearts (P< 0.05). Amiodarone pre-treatment led to a prolongation of APD90 (+19 ms) as compared with sham-controlled hearts but showed only a marginal effect on APD90 in failing hearts. Infusion of sotalol (50–100 µM) led to a significant prolongation of APD90 in sham and a further prolongation of APD90 in failing hearts [+55 ms (50 µM); +70 ms (100 µM); P< 0.01 as compared with sham hearts]. Sotalol led to a triangular action potential configuration in sham and failing hearts, whereas amiodarone did not cause triangularization but caused a rapid phase-III repolarization. Moreover, amiodarone did not increase dispersion of repolarization either in sham or in failing hearts. Infusion of sotalol led to a significant increase in dispersion of repolarization in sham (+29 ms) and a further increase in failing hearts (+67 ms; P< 0.05). Conclusion Chronic amiodarone results in a rapid phase-III-repolarization and does not increase dispersion of repolarization. These electrophysiological findings are present in healthy hearts and are preserved in heart failure. This contributes to the low proarrhythmic potential of amiodarone in heart failure.

G-CSF (granulocyte colony-stimulating factor) treatment has been shown to cause beneficial effects including a reduction of inducible arrhythmias in rodent models of ischemic cardiomyopathy. The aim of the present study was to test whether these effects do also apply to pacing-induced non-ischemic heart failure. In 24 female rabbits, heart failure was induced by rapid ventricular pacing. 24 rabbits were sham operated. The paced rabbits developed a significant decrease of ejection fraction. 11 heart failure rabbits (CHF) and 11 sham-operated (S) rabbits served as controls, whereas 13 sham (S-G-CSF) and 13 heart failure rabbits (CHF-G-CSF) were treated with 10 μg/kg G-CSF s.c. over 17 ± 4 days. G-CSF treatment caused a ~25% increased arterial and capillary density and a ~60% increased connexin 43 expression in failing hearts. In isolated, Langendorff-perfused rabbit hearts eight monophasic action potential recordings showed prolongation of repolarization in CHF as compared with controls in the presence of the QT prolonging agent erythromycin (+33 ± 12 ms; p

Aims Myocardial infarction (MI) results in acute impairment of left ventricular (LV) function through the initial development of cardiomyocyte death and subsequent progression of LV remodelling. The expression of syndecan-4 (Sdc4), a transmembrane proteoglycan, is up-regulated after MI, but its function in the heart remains unknown. Here, we characterize the effects of Sdc4 deficiency in murine myocardial ischaemia and permanent infarction. Methods and results Targeted deletion of Sdc4 (Sdc4–/–) leads to increased myocardial damage after ischaemic–reperfusion injury due to enhanced cardiomyocyte apoptosis associated with reduced activation of extracellular signal-regulated kinase in cardiomyocytes in vitro and in vivo . After ischaemic–reperfusion injury and permanent infarction, we observed an increase in cardiomyocyte area, nuclear translocation of nuclear factor of activated T cells (NFAT), and transcription of the NFAT target rcan1.4 in wild-type mice. NFAT pathway activation was enhanced in Sdc4–/– mice. In line with the in vivo data, NFAT activation and hypertrophy occurs in isolated cardiomyocytes with reduced Sdc4 expression during phenylephrine stimulation in vitro . Despite the initially increased myocardial damage, echocardiography revealed improved LV geometry and function in Sdc4–/– mice 7 days after MI. Conclusion Interception of the Sdc4 pathway enhances infarct expansion and hypertrophic remodelling during early infarct healing in ischaemic–reperfusion injury and permanent infarction mouse models and exerts net beneficial effects on LV function.

Cellular cardiomyoplasty (CMP) is a novel therapeutic approach to myocardial injury (MI). Post-MI remodeling of the left ventricle (LV) comprises dilatation and impairment of systolic function and gives rise to progressive hemodynamic deterioration. We aimed to investigate: a) the impact of CMP on global and regional parameters of LV remodeling (LVR) as well as contractile reserve and b) the suitability and validity of different echocardiographic methods in this scenario. Murine ventricular cardiomyocytes (E13.5–E16.5) were transplanted into cryolesioned hearts of male HIM-OF1 mice. Echocardiography was performed at rest 4 and 14 days postoperatively. For quantification of akinetic myocardial mass and contractile reserve 2 weeks postoperatively additionally low-dose dobutamine stress echocardiography was conducted. Reconstructive 3D-echocardiography (r3D-echo) was compared to “plain” echocardiographic investigations and was compared to invasive measurements with conduction catheter. CMP significantly attenuated LV dilatation and reduced LV function decline on day 14, as obtained with all echocardiographic modalities and confirmed with conduction catheter measurements. In contrast to plain echocardiography and invasive testing, r3D-echo allowed noninvasive quantification of scar size and assessment of regional contractile reserve. Cell transplanted hearts demonstrated a significant decrease of akinetic myocardial mass (-CMP: 13 ± 2%; +CMP 7 ± 1%; p < 0.001) and increased regional contractile reserve, an indirect sign of myocardial viability. The present study demonstrates beneficial effects of CMP on global and regional parameters of LVR and contractile reserve after MI. In contrast to “simple” 2D echocardiography, r3D-echo allowed the assessment of regional contractile reserve and quantification of akinetic myocardial mass as additive functional and morphological measures of LVR.

The aim of the present study was to assess the feasibility and safety of target-directed sampling of right ventricular (RV) endomyocardial biopsies (EMB) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC).EMB is an integral part of the diagnostic evaluation of ARVC. Due to safety concerns, EMB are often obtained from the RV septum, which is usually spared from characteristic alterations. At our institution, EMB in ARVC patients were sampled target-directed from predilection areas and areas with abnormal contraction.Under fluoroscopic guidance, 3,777 EMB samples from 6 different RV sites were obtained in 482 patients who were evaluated for unclear cardiomyopathy (n = 280; 58%), assumed myocarditis (n = 59; 12%), or unexplained ventricular tachyarrhythmias (n = 143; 30%). Complication rates were compared with those from exclusively septal EMB procedures (n = 2,321) in 271 patients after heart transplantation (HTx).Overall, no procedure-related deaths or sustained ventricular tachyarrhythmias occurred. A pericardial effusion was reported in 6 of 161 patients with the final diagnosis of ARVC (3.7%) needing no further intervention in all but 1 patient (0.6%) who required pericardiocentesis. Among the non-ARVC patients (n = 321), the incidence of a minor pericardial effusion (3.9%) and cardiac tamponade (2.2%) was comparable to that in ARVC (p = NS) but was higher when compared with HTx (p0.001). A transient complete atrioventricular block occurred in 1 of 321 non-ARVC (0.3%) and 2 of 271 HTx patients (0.1%).Multisite target-directed EMB sampling in ARVC is a safe procedure when performed by experienced interventionalists. The procedure-related complication rates were low and comparable to those in other cardiomyopathies.

Lipomatous hypertrophy of the right atrium is a rare lesion that is usually limited to the interatrial septum. The authors report on a patient that suffered from an extensive lipomatous hypertrophy, which protruded into the right and left atrium as well as the superior vena cava and caused inflow obstruction. Therapeutic management is discussed.

Address: 1Institute of Physiology, University of Wurzburg, Germany, 2Institute of Experimental and Clinical Pharmacology and Toxicology, University of Heidelberg, Mannheim, Germany, 3Department of Cardiovascular Physiology, Heinrich-Heine-University of Dusseldorf, Germany, 4Department of Cardiology and Angiology, University Hospital Munster, Germany, 5Institute of Physiology II, Rheinische Friedrich-WilhelmsUniversity of Bonn, Germany, 6Institute of Clinical Biochemistry and Pathobiochemistry, University of Wurzburg, Germany and 7Institute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany

Cardiac atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) modulate blood pressure and volume by activation of the receptor guanylyl cyclase-A (GC-A) and subsequent intracellular cGMP formation. Here we report what we believe to be a novel function of these peptides as paracrine regulators of vascular regeneration. In mice with systemic deletion of the GC-A gene, vascular regeneration in response to critical hind limb ischemia was severely impaired. Similar attenuation of ischemic angiogenesis was observed in mice with conditional, endothelial cell-restricted GC-A deletion (here termed EC GC-A KO mice). In contrast, smooth muscle cell-restricted GC-A ablation did not affect ischemic neovascularization. Immunohistochemistry and RT-PCR revealed BNP expression in activated satellite cells within the ischemic muscle, suggesting that local BNP elicits protective endothelial effects. Since within the heart, BNP is mainly induced in cardiomyocytes by mechanical load, we investigated whether the natriuretic peptide/GC-A system also regulates angiogenesis accompanying load-induced cardiac hypertrophy. EC GC-A KO hearts showed diminished angiogenesis, mild fibrosis, and diastolic dysfunction. In vitro BNP/GC-A stimulated proliferation and migration of cultured microvascular endothelia by activating cGMP-dependent protein kinase I and phosphorylating vasodilator-stimulated phosphoprotein and p38 MAPK. We therefore conclude that BNP, produced by activated satellite cells within ischemic skeletal muscle or by cardiomyocytes in response to pressure load, regulates the regeneration of neighboring endothelia via GC-A. This paracrine communication might be critically involved in coordinating muscle regeneration/hypertrophy and angiogenesis.

Background Cyclin D1, the retinoblastoma (Rb) protein, and the E2F transcription factors are involved in the pathogenesis of cardiac hypertrophy. Cyclin D1/cdk4 complexes, by phosphorylation, inactivate Rb, thereby abrogating its growth-inhibitory effect. Ventricular unloading is associated with reversible regulation of numerous cardiomyocyte molecular systems and decreased hypertrophy. Accordingly, the hypothesis whether the Rb/E2F-1 pathway is altered by ventricular unloading was tested, and correlations with the cyclin D1 protein expression and cardiomyocyte diameters were explored. Methods In 21 paired myocardial samples (before and after unloading) from patients with congestive heart failure (CHF), cyclin D1, phosphorylated Rb (pRb), its homologues p107 and p130 (pocket proteins), and E2F-1 were immunohistochemically investigated and morphometrically quantified. Cardiomyocyte diameters were morphometrically determined. Results Cyclin D1 and the proteins of the Rb/E2F-1 pathway were significantly increased during CHF compared with controls and were significantly decreased after unloading. Cyclin D1, pRb, and p130 protein expression correlated significantly with cardiomyocyte diameters. A significant positive correlation was noted between the pocket proteins, E2F-1, and cyclin D1. Conclusion Increased protein expression of phosphorylated (inactivated) Rb and the pocket proteins is associated with cardiomyocyte hypertrophy in CHF. Rb inactivation might be explained by phosphorylation by increased numbers of cyclin D1/cdk4 complexes associated with cardiomyocyte hypertrophy. However, ventricular unloading can reversibly regulate this process. These data underscore the importance of cell cycle regulatory proteins in the pathogenesis of CHF-associated (maladaptive) cardiomyocyte hypertrophy and might offer novel clues for pharmacologic approaches of congestive heart failure.

Doppler-echocardiographic assessment of cardiovascular structure and function in murine models has developed into one of the most commonly used non-invasive techniques during the last decades. Recent technical improvements even expanded the possibilities. In this review, we summarize the current options to assess global left ventricular (LV) function in mice using echocardiographic techniques. In detail, standard techniques as structural and functional assessment of the cardiovascular phenotype using one-dimensional M-mode echocardiography, two-dimensional B-mode echocardiography and spectral Doppler signals from mitral inflow respective aortal outflow are presented. Further pros and contras of recently implemented techniques as three-dimensional echocardiography and strain and strain rate measurements are discussed. Deduced measures of LV function as the myocardial performance index according to Tei, estimation of the mean velocity of circumferential fibre shortening, LV wall stress and different algorithms to estimate the LV mass are described in detail. Last but not least, specific features and limitations of murine echocardiography are presented. Future perspectives in respect to new examination techniques like targeted molecular imaging with advanced ultrasound contrast bubbles or improvement of equipment like new generation matrix transducers for murine echocardiography are discussed.

Udgivelsesdato: 2008-Jul The myocytes comprising the ventricular mass are arranged so as to function in antagonistic fashion, the walls having the capacity to generate both constrictive and dilatory forces. This dualistic activity is organized on the basis of a site-specific morphologic pattern, permitting marked regional specificity for mural motion and providing a target for regional therapy. Diseased regions can be removed surgically without danger of jeopardizing the remaining healthy mural segments. The sensitivity of the intruding population of myocytes to positive and negative inotropic medication is markedly more pronounced than that of the prevailing tangentially aligned myocytes. This asymmetrical action of inotropes in the setting of global ventricular imbalance promotes the potential to restore constrictive as opposed to dilatory actions.

Deficiency of the lysosomal cysteine protease cathepsin L (Ctsl) in mice results in a phenotype affecting multiple tissues, including thymus, epidermis, and hair follicles, and in the heart develops as a progressive dilated cardiomyopathy (DCM). To understand the role of Ctsl in the maintenance of regular heart morphology and function, it is critical to determine whether the DCM in Ctsl-/- mice is primarily because of the lack of Ctsl expression and activity in the cardiomyocytes or is caused by the additional extracardiac pathologies. Cardiomyocyte-specific expression of Ctsl in Ctsl-/- mice, using an alpha-myosin heavy chain promoter-Ctsl transgene, results in improved cardiac contraction, normal mRNA expression of atrionatriuretic peptide, normal heart weight, and regular ultrastructure of cardiomyocytes. Epithelial expression of cathepsin L2 (CTSL2) by a K14 promoter-CTSL2-transgene resulted in rescue of the Ctsl-/- hair loss phenotype. In these mice, cardiac atrionatriuretic peptide expression and end systolic heart dimensions were also significantly attenuated. However, cardiac contraction was not improved, and increased heart weight as well as the typical changes in lysosomal ultrastructure of Ctsl-/- hearts persisted. Myocardial fibrosis was detected in all Ctsl-/- mice irrespective of transgene-mediated cardiac Ctsl expression or extracardiac CTSL2 expression. Expression of collagen 1 was not enhanced in Ctsl-/- hearts, but a reduced collagenolytic activity suggests a role for Ctsl in collagen turnover by cardiac fibroblasts. We conclude that the DCM of Ctsl-/- mice is primarily caused by absence of the protease in cardiomyocytes, whereas the complex gross phenotype of Ctsl-deficient mice, i.e. the fur defect, results in additional stress to the heart.

The question raised by Dr Xia is based on the hypothesis that plasma proteins “buffer” the large amounts of sphingosine 1-phosphate (S1P) present in plasma to prevent it from erroneously activating S1P receptors.1 Although reconstituted high-density lipoprotein (HDL) that does not contain S1P has numerous biological effects when administered in vivo, it is unknown whether and how rapidly it may actually acquire S1P from the plasma once it enters the circulation. Subsequently, such “S1P-charged” HDL may be partially responsible for the effects attributed to …

Assessment of replenishment kinetics (RK) following ultrasound-induced destruction of contrast microbubbles allows quantification of myocardial blood flow reserve (MBFR) applying the model f (t) = A (1 - e(-betat)), with parameter beta describing mean flow velocity and parameter A representing blood volume. However, few data on the variability and reproducibility of RK in a clinical setting are available. Therefore, we examined 30 patients in a rest-adenosine protocol in one center. Off-line quantification of real-time perfusion imaging (RTPI) and triggered replenishment imaging (TRI) was performed at two sites and compared with coronary angiography and flow reserve measurements. Parameter A was found to be robust in all investigated segments (coefficient of variation (CV) < 7.2%+/- 5.1). Variability was lowest for parameter beta using TRI in apical segments (CV 6.5%+/- 5.2, P < 0.01). Highest CV was found with RTPI in lateral segments (CV : 39.8%+/- 40.6). Concerning day-to-day reproducibility both methods revealed similar results within range of heterogeneity of myocardial blood flow. Both sites obtained significantly lower MBFR in patients with flow-limiting CAD, compared to subjects without (P < 0.01). Correlation of both sites showed close relationship (y = 0.88x + 0.45, r = 0.83, P < 0.0001), without systematic bias. TRI significantly reduces variability of RK in quantitative MCE. Assessment of MBFR allows investigator-independent evaluation of CAD.

Color, power, spectral, and tissue Doppler have been applied to mice. Due to the noninvasive nature of the technique, serial intraindividual Doppler measurements of cardiovascular function are feasible in wild-type and genetically altered mice before and after microsurgical procedures or to follow age-related changes. Fifty-megahertz ultrasound biomicroscopy allows to record the first beats of the embryonic mouse heart at somite stage 5, and the first Doppler-flow signals can be recorded after the onset of intrauterine cardiovascular function at somite stage 7. Using 10- to 20-MHz ultrasound transducers in the mouse embryo, cardiac, and circulatory function can be studied as early as 7.5 days after postcoital mucous plug. Postnatal Doppler ultrasound examinations in mice are possible from birth to senescent age. Several strain-, age-, and gender-related differences of Doppler ultrasound findings have been reported in mice. Results of Doppler examinations are influenced by the experimental settings as stress testing or different forms of anesthesia. This review summarizes the present status of Doppler ultrasound examinations in mice and animal handling in the framework of a comprehensive phenotype characterization of cardiac contractile and circulatory function.

s S115 additional serial samples were obtained from each pt (82 samples total). 21 pts were treated for the rejection event, with 17 having consecutive samples available from both the treatment and post-treatment visits required to determine the change in dd-cfDNA following treatment for rejection. Results: For these 17 cases, dd-cfDNA increased more than 2-fold in 3 cases, decreased more than 2-fold in 6 cases, and changed modestly (less than a 2-fold increase or decrease) in 8 cases. In 5 cases where the post-treatment biopsy was graded 0R, suggesting the pt responded favorably to treatment, dd-cfDNA decreased by more than 1.8-fold in 3 cases. Of the 11 samples that did not decrease by at least 2-fold, 6 cases experienced a subsequent 1R or 2R grade rejection event within 30 days of the post-treatment visit, suggesting that the initial treatment may not have been sufficient. Two samples with relatively large (1.9and 3.6-fold) increases in dd-cfDNA following treatment did not show any clinical signs of rejection. Conclusion: Consistent with previously observed rapid-clearance of ddcfDNA from peripheral blood, dd-cfDNA is a quantitative indicator of allograft health. Preliminary data suggest that levels of dd-cfDNA immediately following treatment of a rejection event often decrease when the rejection resolves, but may stay elevated or increase if signs of rejection persist. ddcfDNA may be a useful, non-invasive biomarker to ascertain clinical response to rejection treatment. (Study sponsored by CareDx, Inc.)

Background Transmitral flow patterns derived from Doppler echocardiography carry prognostic information in patients with chronic heart failure and systolic dysfunction. In such patients, chronic kidney disease (CKD) defined as a reduction in estimated glomerular filtration rate less than 60 mL/min/1.73 m 2 is frequent, but its prognostic impact relative to that of transmitral flow patterns is unknown. Methods This prospective study enrolled 292 patients with stable chronic heart failure and systolic dysfunction (mean ejection fraction 30 ± 10), of whom 148 had CKD. Echocardiographic measurements comprised left ventricular dimensions/volumes, ejection fraction, the ratio of early (E) to late (A) transmitral flow velocity, deceleration time, and tissue Doppler mitral annular velocities. The mitral filling pattern (FP) was classified as either restrictive FP (RFP) or non-RFP. A cardiac event (cardiac death or urgent cardiac transplantation) was defined as combined study end point. Results During a follow-up of 497 ± 373 days, 45 patients had a cardiac event (cardiac death, n=42; urgent cardiac transplantation, n=3). On multivariate Cox analysis including clinical and echocardiographic variables, independent prognostic predictors were RFP (hazard ratio: 2.77, 95% confidence interval 1.28-6.09), CKD (hazard ratio: 2.79, 95% confidence interval 1.24-6.28), and left atrial diameter. In patients with RFP, the prognosis was markedly worse in the presence of CKD as compared with the absence (event-free survival of 23% vs 83%, P = .03). Similarly, in patients with non-RFP, outcome was worse in the presence of CKD (event-free survival of 71% vs 88%, P = .003). Conclusions In patients with chronic heart failure and systolic dysfunction, the presence of CKD adds incremental value to transmitral flow patterns in determining the prognosis.

Objectives Cyclooxygenase-2 is associated with cardiac hypertrophy during chronic heart failure and is regulated through the PI3K/Akt pathway. Cyclooxygenase-2-induced cell growth through Akt phosphorylation was demonstrated in vitro. In chronic heart failure, left ventricular assist devices lead to hypertrophy regression and molecular changes. Therefore, the expression of cyclooxygenase-2, phosphorylated Akt (p-Akt), and p-Erk 1/2, as well as cardiac hypertrophy before and after left ventricular assist device insertion, was investigated. Methods In myocardial tissue before and after left ventricular assist device insertion, the expression of cyclooxygenase-2, p-Akt (Thr308) , p-Akt (Ser473) , and p-Erk 1/2 was demonstrated by immunohistochemistry and quantified by morphometry. Colocalization of cyclooxygenase-2 and p-Akt (Thr308) was investigated by immuno-doublestaining. Results A significant decrease of cyclooxygenase-2, p-Akt (Thr308) , p-Akt (Ser473) , and p-Erk 1/2 protein expression and hypertrophy regression was observed after left ventricular assist device insertion. A significant correlation between cyclooxygenase-2 and p-Akt (Thr308) expression, as well as between cyclooxygenase-2 expression and cardiomyocyte diameter, was observed before, but not after, left ventricular assist device insertion. Only cyclooxygenase-2-positive cardiomyocytes showed significant hypertrophy regression on unloading. Sarcoplasmic colocalization of cyclooxygenase-2 and p-Akt (Thr308) is present before left ventricular assist device insertion and is decreased after unloading, whereas the normal myocardium is completely devoid of it. Conclusions Left ventricular assist device treatment is associated with a significant decrease of cyclooxygenase-2, p-Akt (Thr308) , p-Akt (Ser473) , and p-Erk 1/2, and cardiac hypertrophy regression of cyclooxygenase-2-positive cardiomyocytes. The significant correlation and colocalization in cardiomyocytes of cyclooxygenase-2 and p-Akt (Thr308) before left ventricular assist device insertion suggests a cross-talk between the 2 molecules in the progression of cardiac hypertrophy, which is reversibly regulated by the left ventricular assist device.

Although lysosomal proteases are expressed in the heart at considerable levels, their specific functions in this organ remain elusive. Mice deficient for the lysosomal cysteine protease cathepsin L (CTSL) develop a late onset dilated cardiomyopathy (DCM) that is characterized by cardiac chamber dilation, fibrosis, and impaired cardiac contraction at 12 month of age. Investigation of the pathogenic sequence of DCM in ctsl-/- mice revealed numerous dysmorphic lysosome-like structures in heart muscle as early as 3 days after birth, whereas skeletal muscle was not affected. Labeling of the acidic cell compartment of neonatal cardiomyocytes and detection of lysosomal markers after subcellular fractionation confirmed increased lysosome content in CTSL deficient myocardium; however, specific storage materials were not detected. The myocardium of ctsl+/+ and ctsl-/- mice revealed no differences in incidence of cell death, proliferation, and capillary density during DCM progression. However, an observed increase in mRNA expression of natriuretic peptides in young adult mice indicates the activation of the adaptive "fetal" gene program, while proteome analysis revealed decreased levels of the sarcomere-associated proteins alpha-tropomyosin, desmin, and calsarcin 1, as well as considerable changes of metabolic enzymes. Bioinformatic pathway analysis suggested a switch to anaerobic catabolism and impairment of mitochondrial respiration. This interpretation was supported by a 50% reduction in resting state oxygen consumption and impaired respiration capacity in ctsl-/- myocardial homogenates. In summary, the data indicate an essential role of CTSL in maintaining the structure of the endosomal/lysosomal compartment in cardiomyocytes. Lysosomal impairment in ctsl-/- hearts results in metabolic and sarcomeric alterations that promote DCM development.

In patients with chronic heart failure (CHF), N-terminal pro-brain natriuretic peptide (NT-proBNP) provides relevant prognostic information, but its usefulness in the presence of kidney disease has been questioned.We prospectively enrolled 142 patients with stable CHF and a wide spectrum of renal function (estimated glomerular filtration rates [eGFRs] ranging from 17.1 to 100.3 ml/min/1.73 m2). Chronic kidney disease, defined as eGFR60 ml/min/1.73 m2, was present in 63 patients (44%). NT-proBNP measurements were carried out on a bench-top analyzer (Elecsys 2010). Cardiac death or urgent cardiac transplantation were considered as a combined study end-point.During a follow-up of 383 +/- 237 days, 19 patients underwent a cardiac event (cardiac death, n = 17; urgent cardiac transplantation, n = 2). By multivariate Cox analysis, including clinical and laboratory variables, NT-proBNP and serum hemoglobin were independent prognostic predictors. In patients with NT-proBNP1,129 pg/ml, outcome was significantly worse compared to patients with NT-proBNP1,129 pg/ml (event-free survival rate 67% vs 94% in those with NT-proBNP1,129 pg/ml, p = 0.001). By linear regression analysis, NT-proBNP levels were related to New York Heart Association (NYHA) functional class (R = 0.41, p0.001), and inversely related to eGFR (R = -0.29, p = 0.001) and to left ventricular ejection fraction (R = -0.43, p0.001).In CHF patients with and without kidney disease, NT-proBNP provides independent prognostic information. In such patients, NT-proBNP levels are not only reflective of a reduced clearance (i.e., a lower eGFR) but also of the severity of the underlying structural heart disease.

Background A utosomal d ominant p olycystic k idney d isease (ADPKD) is caused by mutations in PKD1 or PKD2. Patients with ADPKD have an increased incidence of cardiac valve abnormalities and left ventricular hypertrophy. Systematic analyses of cardiovascular involvement have so far been performed only on genetically unclassified patients or on ADPKD1 patients, but not on genetically defined ADPKD2 patients. Even existing Pkd1 or Pkd2 mouse models were not thoroughly analyzed in this respect. Therefore, the aim of this project was the noninvasive functional cardiovascular characterization of a mouse model for ADPKD2. Methods Pkd2 +/LacZ mice and wildtype controls were classified into 8 groups with respect to gender, age and genotype. In addition, two subgroups of female mice were analyzed for cardiac function before and during advanced pregnancy. Doppler-echocardiographic as well as histological studies were performed. Results Doppler-echocardiography did not reveal significant cardiovascular changes. Heart rate and left ventricular (LV) length, LV mass, LV enddiastolic and LV endsystolic diameters did not differ significantly among the various groups when comparing wildtype and knockout mice. There were no significant differences except for a tendency towards higher maximal early and late flow velocities over the mitral valve in old wildtype mice. Conclusions Non-invasive phenotyping using ultrasound did not reveal significant cardiovascular difference between adult Pkd2 +/LacZ and WT mice. Due to the lack of an obvious renal phenotype in heterozygous mice, it is likely that in conventional ADPKD knock out mouse models severe cardiac problems appear too late to be identified during the reduced lifespan of the animals.

Doppler-echocardiography of the mouse has evolved to a commonly used technique in the past years as recent advances in imaging quality have substantially improved spatial and temporal resolution allowing the adaptation of this technique to murine models. Although mouse echocardiography is widely used, there is only little information on reference data for wild-type animals available, particularly in older mice.We therefore established a database with echocardiographic reference-values in a large set of young (8 weeks) and older adult (52 weeks) Swiss type CD1-mice of either sex. We performed a complete Doppler-echocardiographic examination under light Ketamine-Xylazine-anesthesia. LV-mass was calculated and compared with necropsy heart weights to validate the LV-mass calculation.Doppler-echocardiographic measurements in mice were feasible to assess cardiac morphology and function. Sonomorphological and functional parameters hardly changed between the age of 12 and 52 weeks. Wall thickness, LV-mass and cardiac output were stable with aging. There was a good relative correlation between echocardiographically estimated LV-mass and necropsy heart weight although absolute values differed. There were no significant echocardiographic differences between male and female mice.The reference values established in this study can be useful in recording and quantifying pathological changes in murine models of cardiovascular diseases. There is hardly any change of cardiac function between the age of 12 and 52 weeks.

Aminoterminal B-type pro-natriuretic peptide (NT-proBNP) is a reliable indicator of heart failure severity. Levels of NT-proBNP are markedly increased in patients with coronary artery disease (CAD) and severely impaired left ventricular (LV) function. The aim of our study was to assess the impact of NT-proBNP levels after high-risk coronary artery bypass grafting (CABG) with regard to recovery potential.Between 1998 and 2004, 121 patients with CAD and severely impaired LV function, who were undergoing CABG, were investigated. Their mean age was 64 +/- 11 years. All patients were in New York Heart Association (NYHA) Class III/IV status; LV ejection fraction (EF) was 20 +/- 6%. All survivors underwent follow-up (59 +/- 34 months) spiroergometric, electrocardiographic (ECG) and echocardiographic assessment and were tested for routine blood controls and NT-proBNP levels (Roche, Mannheim, Germany).The survival rate after 8 years was 70%. All survivors received follow-up assessment. Among survivors the median NT-proBNP level at follow-up was 896 (521 to 1,687) pg/ml. The maximum oxygen uptake was 14.6 +/- 4.9 ml/min/kg, and EF increased to 42% at follow-up among all survivors. On dichotomizing survivors into two groups with NT-proBNP levels above and below the median, the post-operative body mass index was significantly higher in the high NT-proBNP group (p = 0.036). EF (p = 0.028) and NYHA classification (p0.05) improved significantly in both groups, with a tendency toward higher EF in the low NT-proBNP group.Patients undergoing a high-risk CABG procedure have a survival rate comparable to heart transplantation patients and show a potential for clinical and myocardial recovery. NT-proBNP use a useful marker for recovery after a high-risk CABG procedure, with significant correlation with clinical parameters.

Mitral annular velocities derived from pulsed tissue Doppler imaging (TDI) were recently demonstrated to complement the analysis of systolic and diastolic left ventricular (LV) performance in different clinical settings.1,2 The early diastolic mitral annular velocity (E′) was found to behave as a preload independent index of relaxation.3 The mitral E/E′ ratio (that is, the mitral E velocity corrected for the influence of relaxation) has been suggested as an estimate of LV filling pressures.3 We hypothesised that LV stroke volume (SV) impacts on mitral annular velocities derived from TDI. Thus, mitral annular velocities should be altered in the presence of either increased or reduced SV. LV stroke volume index (SVI) was derived from biplane two dimensional images by subtracting LV end systolic volume from LV end diastolic volume, calculated by using Simpson’s rule. According to previously published normal values,4 expressed as mean (SEM), an SVI of 35.0 (6.8) ml/m2 (range 22–48 ml/m2) was considered normal for female subjects, and an SVI of 39.9 (6.0) ml/m2 (range 28–52 ml/m2) was considered normal for male subjects. Following these definitions, three study groups were separated. Group 1 comprised 19 patients with increased SVI (mean 62 (18) ml/m2), mean age …

In long QT syndrome (LQTS), prolongation of the QT-interval is associated with sudden cardiac death resulting from potentially life-threatening polymorphic tachycardia of the torsade de pointes (TdP) type. Experimental as well as clinical reports support the hypothesis that calcium channel blockers such as verapamil may be an appropriate therapeutic approach in LQTS. We investigated the electrophysiologic mechanism by which verapamil suppresses TdP, in a recently developed intact heart model of LQT3.In 8 Langendorff-perfused rabbit hearts, veratridine (0.1 microM), an inhibitor of sodium channel inactivation, led to a marked increase in QT-interval and simultaneously recorded monophasic ventricular action potentials (MAPs) (p0.05) thereby mimicking LQT3. In bradycardic (AV-blocked) hearts, simultaneous recording of up to eight epi- and endocardial MAPs demonstrated a significant increase in total dispersion of repolarization (56%, p0.05) and reverse frequency-dependence. After lowering potassium concentration, veratridine reproducibly led to early afterdepolarizations (EADs) and TdP in 6 of 8 (75%) hearts. Additional infusion of verapamil (0.75 microM) suppressed EADs and consecutively TdP in all hearts. Verapamil significantly shortened endocardial but not epicardial MAPs which resulted in significant reduction of ventricular transmural dispersion of repolarization.Verapamil is highly effective in preventing TdP via shortening of endocardial MAPs, reduction of left ventricular transmural dispersion of repolarization and suppression of EADs in an intact heart model of LQT3. These data suggest a possible therapeutic role of verapamil in the treatment of LQT3 patients.

Introduction: The present study was designed to gain experience with rapamycin-based immunosuppression in thoracic organ transplant recipients with severely compromised kidney function. Material and Methods: 38 heart transplant patients were included into the study (serum creatinine >2.5mg/dL), with an average time after transplantation of more than 2 years. The calcineurin inhibitor (cyclosporine A=29, tacrolimus=9) was reduced by 50%, and rapamycin added (target level of 6–10 ng/dL). Azathioprine, MMF and corticosteroid treatment remained unchanged. Kidney function was monitored by serum creatinine levels and graft function was surveyed by echocardiography and scintigraphy. Results: During the 3 year follow up 2 patients died from cancer. After implementing the rapamycin-based immunosuppression kidney function improved in 95% of the patients. Serum creatinine dropped from 3.21mg/dL to 1.9 within 4 weeks after conversion. This improvement continued up to 1 year. Thereafter, no statistically significant changes were noted. There were no statistically significant differences between the patients who had cyclosporin A and tacrolimus. The improvement of kidney function was slightly better when MMF was used instead of azatioprin (serum creatinine 1.84mg/dl vs. 2.01 at 4 weeks). Graft function remained stable in all patients. Side-effects occurred in 6 patients and were all related to a rapamycin level exceeding 12 ng/mL. Conclusions: Transplant patients with impaired kidney function have an immediate benefit from partially replacing calcineurin inhibitors by rapamycin. Addition of MMF seems to be superior to azathioprine. Partially replacing calcineurin inhibitors by rapamycin is save as far as graft function is concerned.

Purpose GEP (AlloMap) score instability has been shown to predict of events of graft dysfunction or death in an analysis of the IMAGE data set by Deng et al. Our goal is to test this hypothesis in the independent CARGO 2 patient data set. Methods and Materials In a case-cohort design, patients with >2 serial GEP tests were studied in multivariate Cox regression models to predict future clinical events. Intra-patient GEP score instability was defined as the standard deviation of an individual’s cumulative test scores. GEP score (range 0-39), GEP score ≥34, and GEP score stability were studied. Results GEP scores tend to rise and become more stable in the whole population during the first year post-transplantation than after 1 year. After 12 months, GEP score instability (p=0.001) and GEP ≥34 (p=0.06) predict future events. [ figure 1 ]

Phytanic Acid Causes Cardiac Conduction Block. Introduction: The sterol carrier protein-2 gene encodes two functionally distinct proteins: sterol carrier protein-2 (SCP2, a peroxisomal lipid carrier) and sterol carrier protein-x (SCPx, a peroxisomal thiolase known as peroxisomal thiolase-2), which is involved in peroxisomal metabolism of bile acids and branched-chain fatty acids. We show in this study that mice deficient in SCP2 and SCPx (SCP2 null )d evelop a cardiac phenotype leading to a high sudden cardiac death rate if mice are maintained on diets enriched for phytol (a metabolic precursor of branched-chain fatty acids). Methods and Results: In 210 surface and 305 telemetric ECGs recorded in wild-type (C57BL/6; wt; n = 40) and SCP2 null mice (n = 40), no difference was observed at baseline. However, on diet, cycle lengths were prolonged in SCP2 null mice (262.9 ± 190 vs 146.3 ± 43 msec), AV conduction was prolonged (58.3 ± 17 vs 42.6 ± 4 ms), and QRS complexes were wider (19.1 ± 5v s14.0 ± 4 ms). In 11 gene-targeted Langendorff-perfused hearts isolated from SCP2 null mice after dietary challenge, complete AV blocks (n = 5/11) or impaired AV conduction (Wenckebach point 132 ± 27 vs 92 ± 10 msec; P < 0.05) could be confirmed. Monophasic action potentials were not different between the two genotypes. Left ventricular function studied by echocardiography was similar in both strains. Phytanic acid but not pristanic acid accumulated in the phospholipid fraction of myocardial membranes isolated from SCP2 null mice. Conclusion: Accumulation of phytanic acid in myocardial phospholipid membranes is associated with bradycardia and impaired AV nodal and intraventricular impulse conduction, which could provide an explanation for sudden cardiac death in this model. (J Cardiovasc Electrophysiol, Vol. 15, pp. 1310-1316

This prospective study tested whether Doppler echocardiographic variables add incremental value to QRS duration in determining the prognosis of patients with chronic heart failure (CHF) and systolic dysfunction.Diastolic dysfunction frequently is observed in patients with CHF, but its prognostic impact relative to that of QRS duration is unknown.A total of 193 patients with CHF and an ejection fraction45% were enrolled prospectively. Echo measurements included left ventricular dimensions/volumes, ejection fraction, mitral early/late diastolic velocity ratio, deceleration time, and tissue Doppler mitral annular velocities. The mitral filling pattern was classified as either restrictive (RFP) or nonrestrictive. A cardiac event (cardiac death or urgent cardiac transplantation) was defined as combined study end point.During a follow-up of 385 +/- 270 days, 24 patients suffered an event (cardiac death, n = 21; urgent transplantation, n = 3). The RFP, QRS duration, left ventricular systolic diameter, and mitral annular early diastolic velocity were independent predictors of an event. In patients with QRS duration144 ms, the outcome was markedly poorer in the presence of RFPs as compared with their absence. Similarly, despite a QRS durationor =144 ms, the outcome was worse in the presence of a RFP. A risk-stratification model based on the three strongest independent predictors separated groups into those with good prognosis and those with high, intermediate, and low event-free survival rates.In subjects with CHF and systolic dysfunction, transmitral flow patterns add incremental value to QRS duration in determining the prognosis.

A myocardial remodeling in dilated cardiomyopathy (DCM) after partial left ventriculectomy (PLV) has been previously discussed. The aim of this study was to investigate the functional changes in the follow-up of patients with DCM undergoing PLV using electrocardiographically triggered perfusion SPECT (gated SPECT).Twelve DCM patients (10 men, 2 women; 56 +/- 9 y [mean +/- SD]), after successful PLV and mitral valve repair (PLV-MVR), were monitored by gated SPECT and echocardiography. Gated SPECT quantified end-diastolic volumes (EDV), end-systolic volumes (ESV), myocardial and scar volumes, as well as ejection fraction (EF) preoperatively, early (38 +/- 28 d), and late (296 +/- 130 d) after PLV-MVR.EDV and ESV showed an immediate reduction after PLV-MVR (EDV from 542 +/- 90 mL to 350 +/- 81 mL, P0.001; ESV from 452 +/- 91 mL to 254 +/- 79 mL, P0.001) with no significant change in the late follow-up (EDV late, 316 +/- 63 mL; ESV late, 207 +/- 63 mL; both P = not significant vs. early follow-up). PLV-MVR immediately improved EF (preoperative, 16.8% +/- 5.5%; early, 28.8% +/- 7.6%; P = 0.003) with no significant change in the late follow-up (36.0% +/- 9.4%; P = not significant vs. early follow-up).In this highly selected DCM patient group, gated perfusion SPECT assessed early responses in volumes and EF after PLV-MVR. However, although statistically nonsignificant in the small patient group, ESV and EDV were further decreased, whereas EF improved toward 1 y, coinciding with the improvement of clinical symptoms (New York Heart Association), potentially indicating a functional remodeling after PLV-MVR. Further studies in larger patient cohorts and longer follow-up are warranted.

Background: Congenital and acquired long QT syndrome (LQTS) are caused by abnormalities of ionic currents underlying ventricular repolarization. For a better understanding of the mechanisms by which functional electrical instability at the level of the whole heart leads to torsade de pointes (TdP), a novel model of LQT3 was developed and the role of transmural dispersion of repolarization for the development of proarrhythmia was evaluated. Methods and results: In 11 Langendorff-perfused rabbit hearts, veratridine (0.1–0.5 MM), an inhibitor of sodium channel inactivation, led to a concentration-dependent increase in QT-interval and simultaneously recorded monophasic ventricular action potentials (MAPs) (pb0.05) and thereby mimicked LQT3. Veratridine reproducibly induced early afterdepolarizations (EADs) and TdP after lowering potassium concentration. In bradycardic (AV-blocked) hearts, the increase in MAP duration showed marked regional differences. It was significantly more pronounced on the left endocardium as compared to left or right epicardium. This resulted in a significant increase in dispersion of repolarization (24% at 0.1 AM, 92% at 0.25 AM, 208% at 0.5 AM; pb0.01). Left ventricular transmural dispersion of repolarization increased significantly more than interventricular dispersion (104 to 33 ms at 0.5 AM veratridine; pb0.05). Conclusion: By inhibition of sodium channel inactivation, veratridine mimics LQT3 in this intact heart model. In bradycardic, hypokalemic hearts, it reproducibly induced EADs and TdP in the setting of significantly increased left ventricular transmural dispersion of repolarization. Based on these experimental data, reduction of transmural dispersion of repolarization may be considered an important target for the prevention of TdP in patients with LQT3.

Objective: Pulsatile left ventricular assist devices serving as mechanical circulatory support for patients with end-stage heart failure are associated with complications, including bleeding, thromboembolism, and infection. Axial-flow pumps might overcome some of these shortcomings. Here we report our experience with long-term application of the DeBakey VAD (MicroMed Technology, Inc, Houston, Tex). Methods: Nine male transplant candidates (37 ± 14 years) with severe hemodynamic compromise (cardiac index, 1.6 ± 0.5 L·min⁻¹·m⁻²; pulmonary capillary wedge pressure, 27 ± 6 mm Hg) and beginning end-organ failure despite inotropic and intra-aortic balloon pump support received the DeBakey VAD. Clinical outcome was evaluated. Results: Cumulative support was 7.8 years, and the mean duration of support was 314 ± 75 days (range, 229-438 days). Eight patients were transplanted, and one died from intracerebral bleeding. Peripheral circulation and end-organ function recovered rapidly after implantation. Continuous flow was able to maintain adequate organ perfusion over the long term. Eight patients were discharged during support, with good quality of life. There were no early bleedings, but there were late bleedings in 3 patients caused by excessive anticoagulation and platelet inhibition. Neurologic events occurred in 4 patients. Three patients recovered completely from symptoms, and one had lethal intracerebral bleeding. Because of thrombus formation, the device was exchanged in 4 patients. With increasing experience, thrombolysis was performed in similar situations. All such patients underwent successful transplantation. Hemolysis occurred, with events indicating thrombus formation. Device-related infection was found in one patient. Conclusions: The DeBakey VAD demonstrated its potential for long-term bridge to transplantation. The risk for thrombus formation needs to be addressed by improvement of pump technology and new strategies for platelet inhibition. Copyright © 2005 by The American Association for Thoracic Surgery.

Atrial (ANP) and B-type natriuretics peptides (BNP) via their guanylyl cyclase-A (GC-A) receptor not only regulate arterial blood pressure and volume but also exert local antihypertrophic, antifibrotic and lusitropic effects in the heart. To elucidate whether cardiac hypertrophy/insufficiency and reversal is associated with changes in the local responsiveness to NPs, we compared the mRNA expression of ANP, BNP and receptors and the responsiveness of GC-A to ANP in left ventricular tissue obtained from 10 patients with congestive heart failure (CHF) before and after hemodynamic unloading by left ventricular assist device (LVAD) support. Quantitative "real time" RT-PCR demonstrated that the mRNA expression levels of ANP, BNP and the NP-metabolizing NPR-C receptor were both markedly increased in human failing hearts. GC-A mRNA expression levels were not different from nonfailing hearts, but cGMP production by GC-A in response to ANP was nearly abolished. Reversal of cardiomyocyte hypertrophy during LVAD support was accompanied by normalization of ANP, BNP and NPR-C mRNA levels and a significant recovery of GC-A responsiveness to ANP. In CHF patients, increased local clearance by NPR-C receptors and diminished responsiveness of cardiac GC-A might impair the local antihypertrophic effects of natriuretic peptides and contribute to the progression of cardiac hypertrophy and insufficiency. Reverse remodeling during LVAD support reverses these changes and can thereby recuperate the local protective effects of ANP and BNP. © 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Background: B-type natriuretic peptide (BNP) is released from the cardiac ventricles in response to increased wall tension. We studied the relation of NT-proBNP to Heart Failure Survival Score (HFSS) and New York Heart Association (NYHA) class in patients with chronic heart failure (CHF). We also studied the impact for recipient selection for cardiac transplant and assessed it as a predictive and prognostic marker of CHF. Methods: A total of 550 patients with dilative cardiomyopathy (n 323), and coronary artery disease (n 227) were prospectively examined. All patients underwent spiroergometry, echocardiography, right heart catheterization, and electrocardiogram. Routine blood levels and NT-proBNP were measured. The clinical selection for cardiac transplant candidates was adjudicated by 2 independent cardiologists who were blinded to the results of NT-proBNP assays. Clinical outcome and predictive power of NT-proBNP were analyzed. Results: NT-proBNP levels in patients clinically considered for cardiac transplantation were significantly higher (2293 ng/ml vs 493 ng/ml; p 0.001). The receiver operating characteristic (ROC) analysis regarding transplant candidacy showed an area under the ROC curve (AUC) of 0.84 0.01 for HFSS, 0.86 0.001 for NYHA, and 0.96 0.01 for NT-proBNP. Patients with increasing NT-proBNP levels or remaining elevated levels despite adequate heart insufficiency treatment were maintained with left ventricular assist device implantation (n 10) or urgent heart transplantation (n 2). Patients with NT-proBNP levels above 5000 pg/ml had a mortality rate of 28.4% per year. Twenty-eight patients died during the observation period; all these patients were within NYHA Classes 3 and 4 (NT-proBNP 5423 423 ng/ml). Conclusions: NT-proBNP discriminates patients at high likelihood of being a candidate for transplantation and provides prognostic informations in patients with CHF. NT-proBNP levels above 5000 pg/ml at admission were associated with death, and these levels markedly discriminated candidates for left ventricular assist devices or urgent transplantation. J Heart Lung Transplant.

Because of the scarcity of donor hearts, surgical alternatives to heart transplantation, such as partial left ventriculectomy (PLV), were introduced for treatment of advanced heart failure. Here, we report our experience with this procedure performed in combination with mitral valve repair.Twelve patients with dilated cardiomyopathy (DCM), New York Heart Association (NYHA) class exceeding III on maximal medical therapy, cardiac index of 2.5 liter/min/m2 or less, VO2max of 14 ml/kg/min or less, left ventricular end-diastolic diameter (LVEDD) of 7.0 cm or more, and grade II or greater mitral incompetence, were selected for PLV and mitral valve reconstruction (MVR). Echocardiography, hemodynamics, spiroergometry, and clinical assessment were performed before and 1 year after the operation.One-year survival was 83.3%. All 10 surviving patients were free from failure of the procedure 1 year post-operatively. From pre-operatively to 1 year post-operatively, NYHA functional class improved from 3.3 +/- 0.3 to 1.9 +/- 0.2 (p0.001), cardiac index increased from 2.0 +/- 0.2 liter/min/m2 to 2.9 +/- 0.2 liter/min/m2 (p0.001), stroke volume index from 25.9 +/- 4.8 ml/m2 to 40.3 +/- 7.3 ml/m2 (p = 0.008), and VO2max from 10.9 +/- 2.4 ml/kg/min to 16.0 +/- 3.6 ml/kg/min (p = 0.016), whereas LVEDD decreased from 8.4 +/- 0.6 cm to 6.6 +/- 0.3 cm (p0.001), left ventricular end-systolic diameter from 6.8 +/- 0.8 cm to 5.3 +/- 0.5 cm (p0.001), and mitral incompetence from 2.4 +/- 0.6 to 0.9 +/- 0.6 (p0.001). Pulmonary pressures and fractional shortening did not change significantly (p0.05). Four patients received an implantable cardioverter/defibrillator as a result of their pathologic electrophysiologic examination.In carefully selected patients, PLV combined with MVR achieves short-term results comparable to that after heart transplantation. However, long-term results and multicenter evaluation will be needed to define its place in the treatment of advanced heart failure.

Aims This study investigated the hypothesis that direct epicardial bipolar mapping is able to predict the recovery of left ventricular (LV) dysfunction in ischaemic myocardium. Methods and results In 34 patients with CAD, a maximum of 102 bipolar epicardial electrograms per patient ( n =3468 electrograms) were simultaneously recorded with a ventricular jacket array intraoperatively immediately prior to revascularization. Only LV electrograms with good myocardial contact ( n =1813, 52±14 per patient, mean±SD) were analyzed. In accordance to the position of each electrode, segmental myocardial function was assessed by transthoracic echocardiography before and 7±2 months (mean±SD; range 3–10 months) after CABG using a wall motion score. Preoperatively dysfunctional segments ( n =700) were classified as viable (improvement in wall motion score of at least 20% following CABG, n =424) or non-viable (no improvement, n =276). Bipolar voltage was significantly lower in non-viable when compared to viable myocardium ( P

The aim of this study was to assess the impact of stroke volume (SV) on mitral annular velocities derived from tissue Doppler imaging (TDI). To this end, conventional echocardiographic variables and TDI derived mitral annular velocities (S', E', A') were obtained in 14 patients (pts) with increased SV (due to primary mitral (n=12) (ISV group)), in 41 pts with reduced SV (due to ischemic (n=27) or dilated cardiomyopathy (n=9) or hypertensive heart disease (n=5) (RSV group)) and 29 asymptomatic controls with normal SV (CON group). Systolic (S') and early diastolic (E') mitral annular velocities were elevated in the ISV group in the comparison to the CON group, but were significantly reduced in the RSV group. Late diastolic annular velocities (A') did not differ between the ISV and the CON group, but were lowest in the RSV group. On simple linear regression analysis, SV was significantly related to S' (r=0.74, p

Mutations in the highly glycosylated lysosome associated membrane protein-2 (LAMP-2) cause, as recently shown, familial Danon disease with mental retardation, mild myopathy and fatal cardiomyopathy. Extent and basis of the contractile dysfunction is not completely understood.In LAMP-2 deficient mice, we investigated cardiac function in vivo using Doppler-echocardiography and contractile function in vitro in isolated myocardial trabeculae.LAMP-2 deficient mice displayed reduced ejection fraction (EF) (58.9+/-3.4 vs. 80.7+/-5.1%, P0.05) and reduced cardiac output (8.3+/-3.1 vs. 14.7+/-3.6 ml/min, P0.05) as compared to wild-type controls. Isolated multicellular muscle preparations from LAMP-2 deficient mice confirmed depressed force development (3.2+/-0.6 vs. 8.4+/-0.9 mN/mm2, P0.01). All groups showed similar force-frequency behaviour when normalised to baseline force. Post-rest potentiation was significantly depressed at intervals15 s in LAMP-2 deficient mice (P0.05). Although attenuated in absolute force development, the normalised inotropic response to increased calcium and beta-adrenoreceptor stimulation was unaltered. Electron microscopic analysis revealed autophagic vacuoles in LAMP-2 deficient cardiomyocytes. Protein analysis showed unaltered levels of SERCA2a, calsequestrin and phospholamban.Cardiac contractile function in LAMP-2 deficient mice as a model for Danon disease is significantly attenuated. The occurrence of autophagic vacuoles in LAMP-2 deficient myocytes is likely to be causal for the depressed contractile function resulting in an attenuated cardiac pump reserve.

Cardiovascular diseases are associated with multiple changes in gene expression. In general, cardiac tissue is not accessible to expression analysis. This study was designed to investigate expression of cardiac significant genes in white blood cells of heart failure patients and to identify differentially expressed genes. The quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) method was used for quantification of messenger RNA (mRNA) transcripts in blood samples of 20 patients (NYHA III-IV) with severe heart failure and of 20 healthy controls (NYHA I). Total RNA was extracted from leukocytes, reverse transcribed into cDNA, amplified and quantitated by SYBR Green detection. Relative mRNA expression was calculated using phosphoglycerate kinase-1 ( PGK-1) gene expression as an endogenous reference. Identified were 14 genes relevant to cardiomyocyte excitability or contractility. Most of them had not been previously reported to be expressed in blood cells. Data was based on 0.5 micro g total RNA applied to RT-PCR and on leukocyte number. In both, an increased transcription level of the Na/Ca exchanger ( NCX) was found in blood of heart failure patients as compared to controls (p0.02), in line with an upregulated NCX expression known from myocardial tissue of heart failure patients. This pilot study demonstrates that NCX transcription increased in potential relation to heart failure disease.

Objective: Ca2+ release from the cardiac junctional sarcoplasmic reticulum (SR) is regulated by a complex of proteins, including the ryanodine receptor (RyR), calsequestrin (CSQ), junctin (JCN), and triadin 1 (TRD). Moreover, triadin 1 appears to anchor calsequestrin to the ryanodine receptor. Methods: To determine whether triadin 1 overexpression alters excitation–contraction coupling, we examined the effects of cardiac-specific overexpression of triadin 1 on SR Ca2+ handling and contractility in transgenic (TG) compared to wild-type (WT) mice. Results: The overexpression of triadin 1 was associated with an enhanced SR Ca2+ load, reflected by a 22% higher amplitude of caffeine-induced Ca2+ transients. The decline of Ca2+ transients during caffeine exposure was prolonged by 57%. The detection of resting spontaneous SR Ca2+ release events (Ca2+ sparks) revealed an increased amplitude (by 16%), decline (by 47%), and width (by 47%) in TG. This was associated with a redistribution of Ca2+ spark amplitudes from one population to two populations. Measurement of cardiac function by echocardiography and left ventricular (LV) catheterization revealed a decreased cardiac contractility in vivo. The impaired response to β-adrenergic receptor (β-AR) stimulation in TG hearts was associated with an increased protein expression of β-AR kinase 1. In addition, the increase of the L-type Ca2+ peak current and the increase of phospholamban (PLB) phosphorylation at Thr17 were reduced under β-AR stimulation. Conclusion: Taken together, our data suggest that triadin 1 overexpression results in a complex modulation of SR Ca2+ handling, which may contribute, at least in part, to the depressed basal contractility and the blunted response to β-adrenergic agonists in TG mice.

Background: Transesophageal echocardiography (TEE) and transcranial Doppler sonography (TCD) can identify right-to-left-shunts that predispose to paradoxical embolism. In a large cohort we compared the results of both techniques. Methods: 222 patients were investigated by both techniques using the contrast agent Echovist®-300 and performing each test once without and once with the Valsalva maneuver (VM). Results: TEE-proven right-to-left-shunts were detected by TCD with a high sensitivity of 94%. In addition, TCD revealed shunts not noted during TEE in about 20% of all patients studied. These shunts are in general smaller than those concordantly identified; however, 9% of the patients without a TEE-proven shunt presented with a shunt that allows a considerable amount of contrast medium to pass. There were 12% more microbubbles detected in the right middle cerebral artery than in the left middle cerebral artery during the TCD test performed with VM, but not during the TCD test performed without VM. Conclusions: Contrast-enhanced TEE and TCD are complementary methods in the assessment of stroke and stroke-prone patients. The side difference of microbubbles may indicate a selective streaming of cardiac emboli during VM.