The Effect of LVAD Pressure Sensitivity on the Assisted Circulation Under Consideration of a Mitral Insufficiency: An In Vitro Study.

Current left ventricular assist devices (LVADs) differ with respect to their pump characteristics as described by the pump characteristic curve (also called HQ-curve). Pressure sensitive LVADs depict a flat characteristic curve while most available LVADs have a steep, less pressure sensitive characteristic curve. This in vitro study investigated the effect of LVAD pressure sensitivity with a focus on the afterload of the right ventricle (RV) which is one out of many factors influencing right heart failure (RHF). To this end, two laboratory pumps differing in pressure sensitivity were tested as LVAD in an established, active mock circulation loop (MCL). The MCL represented patients with left heart failure and mitral insufficiency as another contributing factor to RV afterload. The results show that the pressure-volume loop (PV-loop) of the left ventricle (LV) undergoes a leftward and thus somewhat of a downward-shift for highly pressure sensitive support. Consequently, the LV is unloaded to a higher degree at comparable arterial blood pressure and identical cardiac output, pulmonary and systemic vascular resistance and ventricular contractility. This causes a concomitant decrease of RV afterload. This effect seems to be due to increased unloading during systole. In case of a severe concomitant mitral insufficiency and looking at left atrial pressure, the difference is 18.5%. Without mitral insufficiency, the difference is reduced to 10.2%.

23S rDNA real-time polymerase chain reaction of heart valves: a decisive tool in the diagnosis of infective endocarditis.

AIMS: A new diagnostic strategy to improve the detection of pathogens in heart valves (HVs) from patients with infective endocarditis (IE) was evaluated. METHODS AND RESULTS: Three hundred and fifty seven HVs surgically removed from 326 patients with proven IE or suspicious intra-operative findings, examined by 16S rDNA polymerase chain reaction (PCR) and culture were retrospectively analysed according to the predictive value of various PCR methods. Patients were classified into four categories: active IE, IE with ambiguous infective status, healed IE, and valve diseases but no IE. Retained samples of 200 HVs were analysed by real-time PCR targeting bacterial 23S rDNA, fungal 28S rDNA, and mycoplasmal tuf gene. 16S rDNA PCR revealed 80.6% sensitivity, 100% specificity, 100% positive predictive value, and 71% negative predictive value (NPV), compared with cultivation with 33.4, 96.6, 95.5, and 40.9%, respectively. The use of real-time PCR increased diagnostic sensitivity to 96.4%, and NPV to 92.5%. Bacterial load, C-reactive protein, and white blood cell counts (WBCs) decreased during antibiotic treatment. Bacterial load showed no correlation to C-reactive protein or WBCs, whereas C-reactive protein and WBCs were significantly correlated. CONCLUSION: 23S rDNA real-time PCR of surgically removed HVs improves the diagnosis of IE. Polymerase chain reaction analysis of explanted HVs allow the optimization of the antimicrobial therapy, especially in patients with culture-negative IE.

Global gene expression analysis in nonfailing and failing myocardium pre- and postpulsatile and nonpulsatile ventricular assist device support.

Mechanical unloading by ventricular assist devices (VAD) leads to significant gene expression changes often summarized as reverse remodeling. However, little is known on individual transcriptome changes during VAD support and its relationship to nonfailing hearts (NF). In addition no data are available for the transcriptome regulation during nonpulsatile VAD support. Therefore we analyzed the gene expression patterns of 30 paired samples from VAD-supported (including 8 nonpulsatile VADs) and 8 nonfailing control hearts (NF) using the first total human genome array available. Transmural myocardial samples were collected for RNA isolation. RNA was isolated by commercial methods and processed according to chip-manufacturer recommendations. cRNA were hybridized on Affymetrix HG-U133 Plus 2.0 arrays, providing coverage of the whole human genome Array. Data were analyzed using Microarray Analysis Suite 5.0 (Affymetrix) and clustered by Expressionist software (Genedata). We found 352 transcripts were differentially regulated between samples from VAD implantation and NF, whereas 510 were significantly regulated between VAD transplantation and NF (paired t-test P < 0.001, fold change >or=1.6). Remarkably, only a minor fraction of 111 transcripts was regulated in heart failure (HF) and during VAD support. Unsupervised hierarchical clustering of paired VAD and NF samples revealed separation of HF and NF samples; however, individual differentiation of VAD implantation and VAD transplantation was not accomplished. Clustering of pulsatile and nonpulsatile VAD did not lead to robust separation of gene expression patterns. During VAD support myocardial gene expression changes do not indicate reversal of the HF phenotype but reveal a distinct HF-related pattern. Transcriptome analysis of pulsatile and nonpulsatile VAD-supported hearts did not provide evidence for a pump mode-specific transcriptome pattern.

K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2+ leak from the sarcoplasmic reticulum.

In heart failure, intracellular Ca2+ leak from cardiac ryanodine receptors (RyR2s) leads to a loss of Ca2+ from the sarcoplasmic reticulum (SR) potentially contributing to decreased function. Experimental data suggest that the 1,4-benzothiazepine K201 (JTV-519) may stabilise RyR2s and thereby reduce detrimental intracellular Ca2+ leak. Whether K201 exerts beneficial effects in human failing myocardium is unknown. Therefore, we have studied the effects of K201 on muscle preparations from failing human hearts. K201 (0.3 microM; extracellular [Ca2+]e 1.25 mM) showed no effects on contractile function and micromolar concentrations resulted in negative inotropic effects (K201 1 microM; developed tension -9.8 +/- 2.5% compared to control group; P < 0.05). Interestingly, K201 (0.3 microM) increased the post-rest potentiation (PRP) of failing myocardium after 120 s, indicating an increased SR Ca2+ load. At high [Ca2+]e concentrations (5 mmol/L), K201 increased PRP already at shorter rest intervals (30 s). Strikingly, treatment with K201 (0.3 microM) prevented diastolic dysfunction (diastolic tension at 5 mmol/L [Ca2+]e normalised to 1 mmol/L [Ca2+]e: control 1.26 +/- 0.06, K201 1.01 +/- 0.03, P < 0.01). In addition at high [Ca2+]e) K201 (0.3 microM) treatment significantly improved systolic function [developed tension +27 +/- 8% (K201 vs. control); P < 0.05]. The beneficial effects on diastolic and systolic functions occurred throughout the physiological frequency range of the human heart rate from 1 to 3 Hz. Upon elevated intracellular Ca2+ concentration, systolic and diastolic contractile functions of terminally failing human myocardium are improved by K201.

Genomic profiling of developing cardiomyocytes from recombinant murine embryonic stem cells reveals regulation of transcription factor clusters.

Cardiomyocytes derived from pluripotent embryonic stem cells (ESC) have the advantage of providing a source for standardized cell cultures. However, little is known on the regulation of the genome during differentiation of ESC to cardiomyocytes. Here, we characterize the transcriptome of the mouse ESC line CM7/1 during differentiation into beating cardiomyocytes and compare the gene expression profiles with those from primary adult murine cardiomyocytes and left ventricular myocardium. We observe that the cardiac gene expression pattern of fully differentiated CM7/1-ESC is highly similar to adult primary cardiomyocytes and murine myocardium, respectively. This finding is underlined by demonstrating pharmacological effects of catecholamines and endothelin-1 on ESC-derived cardiomyocytes. Furthermore, we monitor the temporal changes in gene expression pattern during ESC differentiation with a special focus on transcription factors involved in cardiomyocyte differentiation. Thus, CM7/1-ESC-derived cardiomyocytes are a promising new tool for functional studies of cardiomyocytes in vitro and for the analysis of the transcription factor network regulating pluripotency and differentiation to cardiomyocytes.

Valve replacement in octogenarians: arguments for an earlier surgical intervention.

BACKGROUND AND AIM OF THE STUDY: In octogenarians with symptomatic aortic valve stenosis (AS), aortic valve replacement (AVR) is frequently not performed in due time, because the prognostic benefit is underestimated, while perioperative morbidity and mortality are overestimated. The severely impaired prognosis and quality of life after myocardial decompensation then urges AVR with a significantly increased perioperative risk. METHODS: Between 2003 and 2006, all octogenarians with isolated symptomatic AS (indexed aortic valve opening area <0.5 cm2/m2) referred to the authors' unit were prospectively included in the survey. Among the 83 patients enrolled (51 women, 32 men; mean age 84 +/- 5.1 years), 38 patients (26 women, 12 men; mean age 84 +/- 2.3 years) had signs of chronic myocardial decompensation (dilated left ventricle and/or reduced left ventricular function; left ventricular ejection fraction (LVEF) 43 +/- 18% (range: 25-53%). These patients comprised group A. All other patients (group B) had normal left ventricular dimensions, a normal LVEF (>55%), and no clinical episodes of myocardial decompensation. All patients underwent AVR, while 23 (28%) underwent simultaneous coronary revascularization. RESULTS: In group A, the 30-day mortality rate was 5.3% (n = 2). Octogenarians without chronic myocardial decompensation had a lower 30-day mortality (1/45; 2.2%). The incidences of major postoperative complications (reversible acute renal failure, stroke, mechanical circulatory support) were significantly higher in group A (26.3% versus 8.9%, p < 0.05). During late follow up (mean 24.2 +/- 12.8 months), another four patients in group A (11.1%) and five in group B (11.4%) died. Octogenarians in group B had a significantly (p < 0.01) more favorable cumulative survival rate (87% versus 78% after 24 months; 81% versus 68% after 46 months). CONCLUSION: AVR can be performed in octogenarians with a low mortality and morbidity, but should not be postponed. The decision to perform for AVR may take into consideration any life-limiting comorbidities, but should be made independent of the patient's age.

Long-term results of heart transplantation for end-stage valvular heart disease.

BACKGROUND: In general, heart transplantation for patients with heart failure improves survival. However, the outcomes of heart transplantation for patients with end-stage valvular heart disease are less well reported. This is a substantial group of patients, many of whom have had previous cardiac surgery. They therefore may be considered a subgroup with a poor prognosis. This study reports on the outcomes of heart transplantation for patients with end-stage valvular heart disease. PATIENTS AND METHODS: From March 1989 to December 2004, 75 consecutive adult heart transplantations were performed for end-stage valvular heart disease. Clinical characteristics were retrieved from a computerized database. RESULTS: The early mortality risk in heart transplantation for end-stage valvular heart disease was 13%, compared to 8% for other indications (p = 0.12). The main causes of early death were rejection (20%) and right ventricular failure (20%). The total follow-up time was 415 patient-years. During the follow-up, another 23 patients died (55/1000 patient-years of late mortality rate), mostly due to infection (43%) and multiorgan failure (22%). Multivariable analysis demonstrated that increased waiting time to heart transplantation correlated with increased survival (HR = 0.998, p = 0.04). The survival at 1, 5, 10, and 15 years was 70%, 64%, 56%, and 46% compared to 78%, 68%, 53%, and 41% for other indications, respectively (p = 0.5). CONCLUSION: The outcomes of heart transplantation for patients with end-stage valvular heart disease are similar to those for other patients. Apparently, the longer the waiting time to heart transplantation the better the outcome becomes.

Influence of left ventricular assist device pressure-flow characteristic on exercise physiology: Assessment with a verified numerical model.

Current left ventricular assist devices are designed to reestablish patient's hemodynamics at rest but they lack the suitability to sustain the heart adequately during physical exercise. Aim of this work is to assess the performance during exercise of a left ventricular assist device with flatter pump pressure-flow characteristic and increased pressure sensitivity (left ventricular assist device 1) and to compare it to the performance of a left ventricular assist device with a steeper characteristic (left ventricular assist device 2). The two left ventricular assist devices were tested at constant rotational speed with a verified computational cardiorespiratory simulator reproducing an average left ventricular assist device patient response to exercise (EXE↑) and a left ventricular assist device patient with no chronotropic and inotropic response (EXE→). According to the results, left ventricular assist device 1 pumps a higher flow than left ventricular assist device 2 both at EXE↑ (6.3 vs 5.6 L/min) and at EXE→ (6.7 vs 6.1 L/min), thus it better unloads the left ventricle. Left ventricular assist device 1 increases the power delivered to the circulation from 0.63 W at rest to 0.67 W at EXE↑ and 0.82 W at EXE→, while left ventricular assist device 2 power shows even a minimal decrease. Left ventricular assist device 1 better sustains exercise hemodynamics and can provide benefits in terms of exercise performance, especially for patients with a poor residual left ventricular function, for whom the heart can hardly accommodate an increase of cardiac output.

Paxillin and ponsin interact in nascent costameres of muscle cells.

Muscle differentiation requires the transition from motile myoblasts to sessile myotubes and the assembly of a highly regular contractile apparatus. This striking cytoskeletal remodelling is coordinated with a transformation of focal adhesion-like cell-matrix contacts into costameres. To assess mechanisms underlying this differentiation process, we searched for muscle specific-binding partners of paxillin. We identified an interaction of paxillin with the vinexin adaptor protein family member ponsin in nascent costameres during muscle differentiation, which is mediated by an interaction of the second src homology domain 3 (SH3) domain of ponsin with the proline-rich region of paxillin. To understand the molecular basis of this interaction, we determined the structure of this SH3 domain at 0.83 A resolution, as well as its complex with the paxillin binding peptide at 1.63 A resolution. Upon binding, the paxillin peptide adopts a polyproline-II helix conformation in the complex. Contrary to the charged SH3 binding interface, the peptide contains only non-polar residues and for the first time such an interaction was observed structurally in SH3 domains. Fluorescence titration confirmed the ponsin/paxillin interaction, characterising it further by a weak binding affinity. Transfection experiments revealed further characteristics of ponsin functions in muscle cells: All three SH3 domains in the C terminus of ponsin appeared to synergise in targeting the protein to force-transducing structures. The overexpression of ponsin resulted in altered muscle cell-matrix contact morphology, suggesting its involvement in the establishment of mature costameres. Further evidence for the role of ponsin in the maintenance of mature mechanotransduction sites in cardiomyocytes comes from the observation that ponsin expression was down-regulated in end-stage failing hearts, and that this effect was reverted upon mechanical unloading. These results provide new insights in how low affinity protein-protein interactions may contribute to a fine tuning of cytoskeletal remodelling processes during muscle differentiation and in adult cardiomyocytes.

Culture-negative infectious endocarditis caused by Bartonella spp.: 2 case reports and a review of the literature.

Bartonella spp. are rare pathogens in humans and were recently recognized as important causative agents of culture-negative endocarditis. Here, we describe the 1st 2 documented cases of culture-negative endocarditis due to Bartonella henselae and Bartonella quintana encountered in a single hospital in Germany. Infection of the heart valve tissue was detected by broad-range polymerase chain reaction (PCR) and further confirmed by serologic testing. In particular, acute B. henselae infection with an impressive bacterial colonization of the infected cardiac valve was illustrated by transmission electron microscopy. B. henselae was further characterized by PCR assays targeting genotype-specific regions. Disease progression was initially monitored over the entire infection episode through inflammatory markers. In addition, a short overview of published detailed cases of Bartonella endocarditis in Europe within the last 7 years is given.

Significant obstruction of the right and left ventricular outflow tract in a patient with biventricular hypertrophic cardiomyopathy.

Echocardiography demonstrated pronounced asymmetric left ventricular (LV) hypertrophy and thickened right ventricular muscular components in a 54-year-old woman with a history of dyspnoea (NYHA III), and recurrent syncopes. Left ventricular outflow peak gradient was 80 mmHg at rest and 125 mmHg during Valsalva manoeuvre. Cardiac cine and gadolinium-enhanced T1 weighted magnetic resonance imaging (MRI) provided striking images of a right ventricular outflow tract obstruction and a markedly abnormal gadolinium uptake in the interventricular septum consistent with myocardial fibrosis. Right and left heart catherization, with simultaneous measurement of aortic and LV pressures revealed a 150 mmHg subaortic gradient and a 130 mmHg subpulmonic gradient at rest. Impediment to right ventricular (RV) outflow was due to massive hypertrophy of the crista supraventricularis with an 'hour-glass' deformity. A surgical intervention with LV septal myotomy-myectomy and RV ventriculotomy was performed successfully. Hypertrophic obstructive cardiomyopathy with significant RV and LV outflow tract obstruction is a very rare finding. Echocardiography and MRI can be used in combination for non-invasive evaluation of morphological and haemodynamic information because mechanisms of obstruction are different in each ventricle.

Prevalent platelet dysfunction in patients with aortic valve disease.

BACKGROUND AND AIM OF THE STUDY: In patients with heart valve disease, the valve leaflets display a gapped, rough endothelial lining often covered with calcified areas. As a consequence, blood flow is disturbed and a stimulation of components of the hemostasis system is assumed. The possible mechanisms of this process are, however, unclear at present. METHODS: Platelet function was studied in 660 patients considered for isolated coronary artery bypass graft (CABG) surgery, and in 421 patients considered for single aortic valve replacement (AVR). Platelet function was monitored preoperatively using the platelet function analyzer device (PFA-100). The test results were reported as closure time of the membrane hole at the end of a capillary tube. The von Willebrand factor antigen, and its collagen-binding activity, were also determined among subgroups of 40 AVR and 50 CABG candidates. RESULTS: Platelet dysfunction was displayed by only 22% of CAD patients, but by 83% of AVR candidates. The mean PFA closure time in AVR patients was considerably higher than in CAD patients (231 +/- 59 s versus 153 +/- 60 s, respectively; p < 0.01). The mean platelet volume, platelet distribution width and von Willebrand factor collagen binding and antigen levels did not differ between the patient groups. CONCLUSION: It is assumed that, due to disturbed flow and shear exposition, following an initial activation, the platelets are partially degranulated, shed microparticles, and might become involved in the pathogenesis of microvascular dysfunction and thrombotic events in patients with aortic valve disease.

Survival analysis in heart transplantation: results from an analysis of 1290 cases in a single center.

BACKGROUND: The clinical profiles of recipients and donors eligible for the procedure as well as the procedure itself have changed over time. We determined the impact of changes in baseline risk profiles at different transplant periods on outcome, and the time-specific distribution of causes of death. PATIENTS AND METHODS: Adult heart transplantations were performed consecutively on 1290 patients. Three transplant periods were defined: 1989-1993, 1994-1998, and 1999-2004. RESULTS: Recipient age and body mass index, previous cardiac surgery, high urgency status, need of ventricular assist device, waiting time (to transplantation and on ventricular assist device), donor age and body mass index, donor-recipient body mass index mismatch, and ischemic and cardiopulmonary bypass time were significantly different over the three transplant periods. There was, however, no significant difference in mortality risk. The major causes of deaths were: acute rejection, multiorgan failure, and right heart failure (1-5 years); cardiac allograft vasculopathy and malignancy (>5-10 years); and malignancy and infection (>10 years). The overall 1-, 5-, 10- and 15-year survival was respectively 77%, 67%, 53% and 42%. There was no difference in survival by different transplant periods (p=0.68). CONCLUSION: Despite clearly increased baseline risk profiles over time, the outcome of adult heart transplantation remains stable and encouraging. Cardiac allograft vasculopathy, malignancy, and infection threaten the long-term survival.

Relevance of brain natriuretic peptide in preload-dependent regulation of cardiac sarcoplasmic reticulum Ca2+ ATPase expression.

BACKGROUND: In heart failure (HF), ventricular myocardium expresses brain natriuretic peptide (BNP). Despite the association of elevated serum levels with poor prognosis, BNP release is considered beneficial because of its antihypertrophic, vasodilating, and diuretic properties. However, there is evidence that BNP-mediated signaling may adversely influence cardiac remodeling, with further impairment of calcium homeostasis. METHODS AND RESULTS: We studied the effects of BNP on preload-dependent myocardial sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) expression. In rabbit isolated muscle strips stretched to high preload and shortening isotonically over 6 hours, the SERCA/glyceraldehyde phosphate dehydrogenase mRNA ratio was enhanced by 168% (n=8) compared with unloaded preparations (n=8; P<0.001). Recombinant human BNP at a concentration typically found in end-stage HF patients (350 pg/mL) abolished SERCA upregulation by stretch (n=9; P<0.0001 versus BNP free). Inhibition of cyclic guanosine 3',5' monophosphate (cGMP)-phosphodiesterase-5 mimicked this effect, whereas inhibition of cGMP-dependent protein kinase restored preload-dependent SERCA upregulation in the presence of recombinant human BNP. Furthermore, in myocardium from human end-stage HF patients undergoing cardiac transplantation (n=15), BNP expression was inversely correlated with SERCA levels. Moreover, among 23 patients treated with left ventricular assist devices, significant SERCA2a recovery occurred in those downregulating BNP. CONCLUSIONS: Our data indicate that preload stimulates SERCA expression. BNP antagonizes this mechanism via guanylyl cyclase-A, cGMP, and cGMP-dependent protein kinase. This novel action of BNP to uncouple preload-dependent SERCA expression may adversely affect contractility in patients with HF.

Long-term experiences on cardiac retransplantation in adults.

BACKGROUND: It remains disputed whether cardiac retransplantation should be performed. This study aimed to evaluate our long-term experiences on cardiac retransplantation in adults. PATIENTS AND METHODS: Between March 1989 and December 2004, 2% (28/1290) of cardiac retransplantations were performed. RESULTS: The reasons for cardiac retransplantation were cardiac allograft vasculopathy (n=13; 47%), primary graft failure (n=11; 39%), and refractory acute rejection (n=4; 14%). The 30-day mortality risk was 29% (acute rejection: 50%; primary graft failure: 36%; cardiac allograft vasculopathy: 15%, p=0.324), compared to 8.5% for primary cardiac transplantation (p<0.001). The causes of early death were acute rejection (n=3; 37%), multiorgan failure (n=3; 37%), primary graft failure (n=1; 13%), and right ventricular failure (n=1; 13%). The late mortality rate was 96/1000 patient-years. The causes of late death were acute rejection (n=4; 50%), cardiac allograft vasculopathy (n=2; 25%), multiorgan failure (n=1; 13%), and infection (n=1; 13%). The 1-, 5-, 10-, and 15-year survival was respectively 78, 68, 54, and 38% (primary cardiac transplantation), and 46, 41, 32, and 32% (cardiac retransplantation) (p=0.003). The short-term survival for cardiac retransplantation due to cardiac allograft vasculopathy was likely better than primary graft failure and refractory acute rejection (p=0.09). CONCLUSION: The overall outcomes of cardiac retransplantation are significantly inferior to primary cardiac transplantation. Cardiac retransplantation should be only performed for selected patients.

Predictors of mortality after aortic valve replacement.

Aortic valve replacement (AVR) is recommended as a standard surgical procedure for aortic valve disease. Still the evidence for commonly claimed predictors of post-AVR prognosis, in particular mortality, appears scant. This systematic review reports on the evidence for predictors of post-AVR mortality, and may be helpful in pre-surgical risk-stratification. In PubMed, we searched for original reports of post-AVR follow-up studies. We assessed the quality of study design and methods with a standardized checklist. Data of the reported predictors of mortality and outcomes were extracted. Twenty-eight studies met our inclusion criteria. Sixteen studies were considered of high quality. There is strong evidence that the risk of early mortality is increased by emergency surgery, while the risk of late mortality is increased with older age and preoperative atrial fibrillation. There is moderate evidence that the risk of early mortality is increased by older age, aortic insufficiency, coronary artery disease, longer cardiopulmonary bypass time, reduced left ventricular ejection fraction (LV-EF), infective endocarditis, hypertension, mechanical valves, preoperative pacing, dialysis-dependent renal failure and valve size; and that the risk for late mortality is increased by emergency surgery and urgency of the operation. There is little evidence for high New York Heart Association class, concomitant coronary artery bypass graft and many other commonly claimed risk factors for post-AVR mortality. The reported evidence on predictors of post-AVR mortality will help for pre-surgical risk-stratification, i.e. to discern patients at high or low risk for early and late post-AVR mortality. Future prognostic studies should take the evidence from this review into account and should focus on derivation of a predictive model for post-AVR survival.

Composite polymorphisms in the ryanodine receptor 2 gene associated with arrhythmogenic right ventricular cardiomyopathy.

OBJECTIVE: Mutations in the cardiac ryanodine receptor (RYR2) gene have been reported to cause arrhythmogenic right ventricular cardiomyopathy (ARVC). The molecular mechanisms by which genetic modifications lead to ARVC are still not well understood. METHODS: ARVC patients were screened for mutations in the RYR2 gene by denaturing HPLC and DNA sequencing. Single channel measurements were carried out with RyR2 channels purified from explanted hearts of ARVC patients. RESULTS: None of the published RYR2 mutations were found in our ARVC-cohort. However, we identified two single nucleotide polymorphisms (SNPs) in exon 37 of the human RYR2 gene which lead to the amino acid exchanges G1885E and G1886S, respectively. Both SNPs together were found exclusively in 3 out of 85 ARVC patients in a composite heterozygous fashion (genotype T4). This genotype was associated with ARVC (p<0.05) but not with dilated cardiomyopathy (DCM, 79 patients) or none-failing controls (463 blood donors). However, either one of the two SNPs were identified in further 7 ARVC patients, in 11 DCM patients, and in 64 blood donors. The SNP leading to G1886S may create a protein kinase C phosphorylation site in the human RyR2. Single channel recordings at pCa4.3 revealed four conductance states for the RyR2 of genotype T4 and a single open state for the wild type RyR2. At pCa7.7, the lowest subconductance state of the RyR2 channel of genotype T4 persisted with a greatly enhanced open probability indicating a leaky channel. CONCLUSION: The RyR2 channel leak under diastolic conditions could cause SR-Ca2+ depletion, concomitantly arrhythmogenesis and heart failure in a subgroup of ARVC patients of genotype T4. A change in the RyR2 subunit composition due to the combined expression of both SNPs alters the behaviour of the tetrameric channel complex.

Influence of ACE-inhibition and mechanical unloading on the regulation of extracellular matrix proteins in the myocardium of heart transplantation candidates bridged by ventricular assist devices.

BACKGROUND: Whether adverse structural changes in the myocardium due to remodelling can be reversed by ventricular assist device (VAD) support in patients with end-stage heart failure is controversial. AIMS: To investigate the effect of VAD support on the extra-cellular matrix. METHODS: We analysed the collagen content in terminal failing ventricles of VAD-patients and donor hearts using 4-hydroxyproline for total collagen and real time RT-PCR for fibronectin (FN), collagen I alpha 1 (Col1A1), III alpha 1 (Col3A1) and TGF beta 1 analysis. RESULTS: Compared to donor hearts we found similar increases in Col1A1 and TGF beta1 but not Col3A1 and FN mRNAs, which were similar in the myocardium from patients receiving a VAD or heart transplant. However, patients receiving ACE-I during VAD-support had lower Col1A1 mRNA content at transplantation. The total collagen content was not influenced by mechanical unloading or by ACE-I medication. CONCLUSION: Mechanical unloading by VAD does not reduce the collagen content of the terminal failing ventricle possibly due to increased TGF beta1 levels. However, Col1A1 production may be reduced by ACE-I medication during VAD support.

The worldwide mid-term experience with the Medtronic ADVANTAGE bileaflet mechanical heart valve.

BACKGROUND AND AIM OF THE STUDY: A total of 639 patients (479 men, 160 women; mean age 60 +/- 10 years) underwent isolated aortic valve replacement (AVR) between 25 November 1999 and 20 October 2003, using the Medtronic ADVANTAGE bileaflet mechanical heart valve. The study aim was to quantify the clinical performance of a valve with two design modifications: (i) an enlarged central orifice intended to improve blood flow characteristics; and (ii) an asymmetric butterfly pivot recess with expanded outflow component designed to enhance the washing of blood flow through the pivot region. METHODS: Patients were enrolled at 21 centers located in Europe, Canada, Australia, and the USA. The study was conducted under the authority of regional ethics committees, as well as the respective national regulatory agencies. All centers adhered to a common protocol. RESULTS: The total follow up was 1,215.9 patient-years. The average systolic mean pressure gradient across the prosthesis was < 10 mmHg. The mean left ventricular mass index decreased by 22.87 g/m2 (13% reduction) over 12 months. The numbers of valve-related intraoperative, early (< or = 30 days or prior to discharge) and late (> or = 31 days) deaths were 0, 10 and 19, respectively. After one year and four years of follow up, 99.3% (n = 560) and 100% of patients (n = 37), respectively, were in NYHA class I or II. CONCLUSION: The evolutionary bileaflet design of the ADVANTAGE valve achieved the desired clinical functionality and performance.

Introduction of a new oxygenator including a tight fiber for long-term ECMO in infants.

Plasma leakage is a known complication in the use of a microporous membrane oxygenator in extracorporeal membrane oxygenation cases. An oxygenator with a tight fiber offers an alternative whereby plasma leakage can be prevented. We report the use of such an oxygenator in 13 extracorporeal membrane oxygenation cases in which no problems were encountered regarding blood trauma and plasma leakage.