Interventional Treatment of Severe Tricuspid Regurgitation: Early Clinical Experience in a Multicenter, Observational, First-in-Man Study.

BACKGROUND: Transcatheter caval valve implantation is under evaluation as a treatment option for inoperable patients with severe tricuspid regurgitation (TR). The procedure involves the catheter-based implantation of bioprosthetic valves in the inferior vena cava and superior vena cava to treat symptoms associated with TR. This study is the first to evaluate the feasibility, safety, and efficacy of this interventional concept. METHODS AND RESULTS: Twenty-five patients (mean age, 73.9±7.6 years; women, 52.0%) with severe symptomatic TR despite optimal medical treatment deemed unsuitable for surgery were treated with caval valve implantation under a compassionate clinical use program. Technical feasibility defined as procedural success, hemodynamic effect defined as venous pressure reduction, and safety defined as periprocedural adverse events were evaluated, with clinical follow-up at discharge and up to 12 months. The functional impact was evaluated by assessment of New York Heart Association class at the time of hospital discharge. The total number of valves implanted in the caval position was 31. Patients were treated with single (inferior vena cava-only; n=19; 76.0%) or bicaval valve implantation (inferior vena cava+superior vena cava; n=6; 24.0%). Either balloon-expandable valves (Sapien XT/3: n=18; 72.0%) or self-expandable valves (TricValve: n=6; 24.0%; Directflow: n=1; 4.0%) were used. Procedural success was achieved in 96% (n=24). Early and late valve migration requiring surgical intervention occurred in 1 patient each. Thirty-day and in-hospital mortality were 8% (2 of 25) and 16% (4 of 25). Causes of in-hospital mortality included respiratory (n=1) or multiple organ failure (n=3) and were not linked to the procedure. Mean overall survival in the study cohort was 316±453 days (14-1540 days). CONCLUSIONS: Caval valve implantation for the treatment of severe TR and advanced right ventricular failure is associated with a high procedural success rate and seems safe and feasible in an excessive-risk cohort. The study demonstrates hemodynamic efficacy with consistent elimination of TR-associated venous backflow and initial clinical improvement. These results encourage further trials to determine which patients benefit most from this interventional approach.

Time course of vascular response after an a priori strategy of bare metal stent implantation post-dilated with a paclitaxel-coated balloon: Implementation of a three-dimensional analysis algorithm with optical coherence tomography.

BACKGROUND: An a priori combined therapy of a bare metal stent post-dilated with a paclitaxel- -coated balloon (PCB) was investigated with optical coherence tomography (OCT) at 2 and 6 months regarding vessel response. Previous studies have shown inconsistent results and the time course of vessel healing after such an interventional strategy is unknown. METHODS: Thirty-three de novo lesions in 32 patients were electively treated. Six-month OCT analysis was available in 24 lesions. Two-month OCT follow-up was obtained in 16 lesions. Sequential OCT at 2 and 6 months was available in 7 patients. A novel 3-dimensional picture of vessel segments as spread outs was implemented. RESULTS: Severe incomplete stent apposition (ISA) accompanied by significantly lower strut coverage were found at 2-month compared with 6-month follow-up (ISA struts: 11.4 ± 11.8% vs. 1.8 ± 4.8%, p = 0.001; uncovered struts: 14.5 ± 14.8% vs. 2.0 ± 5.3%, p = 0.001). ISA size diminished over time and the possibly observed phenomenon of positive vessel remodeling (remodeling volume: 4.9 ± 5.9 mm3 at 2-months vs. 2.0 ± 2.6 mm3 at 6-months; p = 0.042) was largely reversible in most lesions. CONCLUSIONS: Bare metal stenting with adjunctive application of paclitaxel by a coated bal-loon shows transient severe incomplete strut apposition, most likely due to focal positive ves-sel remodeling. Thus, caution is needed in bailout situations following a PCB angioplasty. A novel illustration of OCT parameters as "carpet views" enables a comprehensive analysis of investigated stents.

Decrease in circulating plasmacytoid dendritic cells during short-term systemic normobaric hypoxia.

BACKGROUND: During exposure to high altitude, the immune system is altered. During hypoxia, an increase in interleukin (IL)-6 and high sensitivity C-reactive protein (hs-CRP), and an increase in natural killer cells and decrease in T cells in blood was shown. However, the impact of hypoxia on dendritic cells has not been investigated yet. MATERIAL AND METHODS: Twelve healthy volunteers were subjected to a transient normobaric hypoxia for 6·5 h simulating an oxygen concentration at 5500 m. During exposure to hypoxia, blood samples were collected and analysed by flow cytometrical cell sorting (FACS) for circulating myeloid (mDCs) and plasmacytoid (pDCs) DCs. Serum levels of IL-6 and tumour necrosis factor (TNF)-α were analysed. In a cell culture hypoxia chamber, blood samples were subjected to the same hypoxia and analysed regarding DCs. RESULTS: Exposure to normobaric hypoxia induced a significant decrease in circulating pDCs about 45% (P = 0·001) but not of mDC compared to baseline normoxia. Furthermore, we observed a significant increase of TNF-α about 340% (P = 0·03) and of IL-6 about 286% (P = 0·002). In cell culture experiments exposure of blood to hypoxia led to no significant changes in DCs, so that a direct cytotoxic effect was excluded. During hypoxia, we observed a transient increase in stromal-derived factor 1 (SDF-1) which is important for pDC tissue recruitment. CONCLUSIONS: We show a significant decrease in circulating pDCs during hypoxia in parallel to a pro-inflammatory response. Further studies are necessary to evaluate whether the decrease in circulating pDCs might be the result of an enhanced tissue recruitment.

Decrease in circulating dendritic cell precursors in patients with peripheral artery disease.

Peripheral artery disease (PAD) is a common manifestation of atherosclerosis. Inflammation is important for initiation and progression of the disease. Dendritic cells (DCs) as antigen-presenting cells play an important role in the immune system. Therefore, we hypothesize that, in patients with PAD, DCPs might be reduced in blood due to their recruitment into the vascular wall and induce a proinflammatory response. The numbers of myeloid DCPs, plasmacytoid DCPs, and total DCPs were analyzed by flow cytometry in blood of patients with PAD (n = 52) compared to controls (n = 60). Femoralis plaques (n = 12) of patients who underwent surgery were immunostained for CD209 and CD83 (mDCs) as well as CD304, CD123 (pDCs), and HLA-DR. In patients with PAD, a significant decrease in mDCPs, pDCPs, and tDCPs was observed. In immunostaining, markers indicative for mDCs (CD209: 16 versus 8 cells/0.1 mm(2), P = 0.02; CD83: 19 versus 5 cells/0.1 mm(2), P = 0.03) were significantly elevated in femoralis plaques compared to control vessels. We show for the first time that mDCPs, pDCPs, and tDCPs are significantly reduced in patients with PAD. Immunohistochemical analysis unraveled that the decrease in DCPs might be due to their recruitment into atherosclerotic plaques.

Valve-in-valve transcatheter aortic valve implantation: the new playground for prosthesis-patient mismatch.

Transcatheter aortic valve implantation (TAVI) has become an established procedure for patients with aortic valve stenosis and significant comorbidities. One option offered by this technique is the implantation of a transcatheter valve inside a surgically implanted bioprosthesis. Many reports address the feasibility but also the pitfalls of these valve-in-valve (VIV) procedures. Review articles provide tables listing which valve sizes are appropriate based on the size of the initially implanted bioprosthesis. However, we previously argued that the hemodynamic performance of a prosthetic tissue valve is in large part a result of the dimensions of the bioprosthesis in relation to the patient's aortic outflow dimensions. Thus, the decision if a VIV TAVI procedure is likely to be associated with a favorable hemodynamic result cannot safely be made by looking at premade sizing tables that do not include patient dimensions and do not inquire about the primary cause for bioprosthetic valve stenosis. Prosthesis-patient mismatch (PPM) may therefore be more frequent than expected after conventional aortic valve replacement. Importantly, it may be masked by a potentially flawed method assessing its relevance. Such PPM may therefore impact significantly on hemodynamic outcome after VIV TAVI. Fifteen percent of currently published VIV procedures show only a minimal reduction of pressure gradients. We will address potential pitfalls in the current determination of PPM, outline the missing links for reliable determination of PPM, and present a simplified algorithm to guide decision making for VIV TAVI.

Increased levels of circulating arginase I in overweight compared to normal weight adolescents.

BACKGROUND AND AIMS: Overweight and the metabolic syndrome have become major problems, especially in children and adolescents. Obesity at a young age increases the risk for cardiovascular diseases and diabetes mellitus later in life. An early event in the development of cardiovascular disease is endothelial dysfunction which is found in obese young individuals. Increased activity of the enzyme arginase has been described as a central mechanism for endothelial dysfunction, especially in patients with diabetes mellitus. The aim of the study was to determine plasma levels of arginase in overweight adolescents. METHODS: Sixty-six male German adolescents (age: 15.2 ± 1.1 years old) were included. Thirty-one of them were overweight (>90th age-specific weight percentile). Plasma arginase I and tumor necrosis factor alpha (TNFα) were determined. In addition, clinical data were recorded and anthropometrical measurements of obesity were performed. RESULTS: Overweight adolescents had a higher systolic blood pressure, lower high-density lipoprotein and increased levels of high-sensitive C-reactive protein (CRP). Circulating arginase I was elevated in overweight adolescents (95.8 ± 68.2 ng/ml) compared to normal weight adolescents (39.3 ± 26.9 ng/ml, p < 0.001) and correlated with markers of obesity. There was no difference between the two groups regarding TNFα. CONCLUSIONS: We demonstrate that arginase I levels are increased in obese adolescents. Knowing the important role for arginase in endothelial dysfunction, elevated levels of arginase I may represent a link between obesity, endothelial dysfunction and related comorbidities.

Antibacterial capacity of differentiated murine embryonic stem cells during defined in vitro inflammatory conditions.

Embryonic stem (ES) cells are a powerful model for the development of cells responsible for the cellular immune response. Therefore, we analyzed the defense and phagocytic capacity of embryoid bodies (EBs) derived from ES cells using in the vitro inflammatory conditions caused by Escherichia coli. Further, we used this phagocytic activity to purify activated immune cells. Our data show that spontaneously differentiated 18-day-old EBs of the cell line CGR8 contained immune cells, which were positive for CD45, CD68, CD11b, F4/80, and CD19. Exposure of these EBs to E. coli with defined infection doses of bacterial colony-forming units (CFUs) led to a significant time-dependent reduction of CFUs, indicating the immune responses exerted by EBs. This was paralleled by an upregulation of inflammatory cytokines, that is, IL-1ß and TNF-α. Western blot analysis of infected EBs indicated an upregulation of CD14 and cytochrome b-245 heavy chain (NOX2). Silencing of NOX2 significantly reduced the antibacterial capacity of EBs, which was partially explained by reduction of F4/80-positive cells. To identify, isolate, and further cultivate phagocytic active cells from differentiated EBs, a cocultivation assay of differentiated ES cells with green fluorescent protein (GFP)-labeled E. coli was established. Colocalization of GFP-labeled E. coli with cells positive for CD45, CD68, and F4/80 revealed time-dependent phagocytotic uptake, which was underlined by colocalization with the LysoTracker-Red(®) dye as well as preincubation with cytochalasin D. In conclusion, a primitive immune response with efficient phagocytosis was responsible for the antibacterial capacity of differentiated EBs.

Immunomodulatory effects of cardiotrophin-1 on in vitro cytokine production of monocytes & CD4 + T-lymphocytes.

BACKGROUND & OBJECTIVES: In congestive heart failure (CHF), increased concentrations of several cytokines including cardiotrophin-1 (CT-1) and immunactivation are found. This study was performed to evaluate whether CT-1 can induce in vitro cytokines in monocytes and CD4 + T-lymphocytes of healthy volunteers. METHODS: The study was performed in vitro to see whether CT-1 can modulate monocyte or CD4 + T-lymphocyte interleukin (IL)-1ß, -2, -4, -5, -10, interferon γ (IFNγ), and tumour necrosis factor α (TNFα) expression by flow cytometry following stimulation with CT-1 alone or together with lipopolysaccharide (LPS) or phorbol myristate acetate (PMA)/ionomycine (iono). RESULTS: CT-1 increased the number of TNFα and IL-1ß positive monocytes. LPS induced IL-10, TNFα, and IL-1ß in monocytes but only IL-2 in CD4+ T-lymphocytes, whereas PMA/iono induced all cytokines besides IL-5 in monocytes and IL-1ß in CD4+ T-lymphocytes. In LPS activated monocytes, CT-1 induced a concentration-dependent reduction in the number of TNFα positive monocytes. After LPS activation, CT-1 decreased the number of CD4+ lymphocytes positive for IL-2, IL-4, and IL-5. In addition, following PMA/iono stimulation, CT-1 initiated a concentration-dependent decrease of CD4 + T-lymphocytes positive for TNFα, IL-4, IL-5, and IL-10. INTERPRETATION & CONCLUSIONS: The present data show that in vitro CT-1 can activate monocytes and modulate cytokine production of activated CD4 + T-lymphocytes. We speculate that CT-1 may at least be partly responsible for immunactivation in CHF.

Prognostic relevance of heart rate at rest for survival and the quality of life in patients with dilated cardiomyopathy.

OBJECTIVES: Reduction of resting heart rate (HR) has been suggested as a novel therapeutic approach in patients with chronic heart failure because it has been shown to prolong survival and also to improve health-related quality of life (Hr-QoL). The purpose of this analysis was to assess the prognostic impact of resting HR in patients with dilated cardiomyopathy (DCM). METHODS: 217 patients with DCM confirmed by endomyocardial biopsy were investigated (age 49 ± 11 years, 20.7 % were female). The study population was divided into two groups according to the median of the resting HR. After a median follow-up time of 7.4 years overall survival and health-related quality of life (Hr-QoL) were compared in both groups. Survival was compared using Kaplan-Meier method and Hr-QoL was assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ). RESULTS: Elevated resting HR was associated with poor 1-year survival (p = 0.03). In contrast, long-term survival was not affected by HR (p = 0.20). Patients with lower HR at rest scored significantly lower on the MLHFQ (20 vs. 36, p = 0.03), indicating that higher resting HR is associated with an impairment of Hr-QoL. CONCLUSIONS: Increased HR might be used as a diagnostic tool to identify patients at risk. Reduction of resting HR in patients with DCM might be a therapeutic option to improve Hr-QoL and therefore merits further investigation in future studies.

Cardiac magnetic resonance imaging as a tool to link cardiac conduction disease to myocarditis with minimal left ventricular impairment.

Myocarditis is an injury of the myocardium caused by a variety of agents. Conduction disturbances such as complete atrioventricular block (AV block) may occur as an infrequent but serious complication of myocarditis. Early detection and accurate diagnosis of myocarditis are still unresolved challenges. We present 2 cases of otherwise mild myocarditis complicated by high-degree AV block in combination with isolated delayed uptake of contrast at the septal regions in the cardiac magnetic resonance imaging. Because the AV block was persistent in both cases, permanent pacemaker implantation was necessary. Delayed enhancement in the septal area in myocarditis might be predictive of infra-Hisian AV block.

Human cytomegalovirus induces MMP-1 and MMP-3 expression in aortic smooth muscle cells.

Human cytomegalovirus (HCMV) infection may be involved in the pathogenesis of atherosclerosis by modulating functions of smooth muscle cells (SMC). In this study, we performed an oligonucleotide microarray screening of 780 inflammation-associated genes in HCMV-infected aortic SMC (AoSMC). The expression of 31 genes was stimulated and 24 genes were down-regulated following infection with HCMV strain DC-134. Following infection with HCMV strain AD-169 infection, we found 24 genes to be stimulated and 32 genes to be down-regulated. Among these were primarily genes encoding for CC and CXC chemokines, adhesion molecules, and tumor necrosis factor (TNF) receptor superfamily members, apoptosis-related factors, signal transduction molecules and transcription regulators. The up-regulated genes included matrix metalloproteinase (MMP)-1 and MMP-3 in HCMV infected cells. Using RT-PCR and enzyme immunoassay we found stimulated expression of MMP-1 (3.2-fold expression) and MMP-3 (334-fold expression) in HCMV strain DC-134-infected AoSMC at 72 h following infection.The findings of our study suggest that HCMV infection of AoSMC cause an activation of atherosclerosis-relevant factors in SMC. The increased expression of MMPs which have been shown to be involved in atherosclerotic plaque rupture and myocardial infarction is in agreement with the hypothesis that this pathogen might contribute to plaque inflammation in atherosclerotic disease.

Impact of short-term systemic hypoxia on phagocytosis, cytokine production, and transcription factor activation in peripheral blood cells.

Hypoxia frequently associated with certain physiologic and pathologic conditions influences numerous cellular functions. Because the effects of short-term hypoxia are incompletely understood, we examined phagocytosis and cytokine production as well as the activation of the transcription factors HIF-1 and NFκB in peripheral blood cells of healthy volunteers exposed to an oxygen concentration equivalent to that found at a height of 5500 m. Furthermore, we analysed plasma HIF-1 and serum concentrations of various HIF-1-dependent genes. Results showed that short-term hypoxia increased phagocytosis in neutrophils without affecting monocyte phagocytosis. Hypoxia decreased basal TNFα concentration in monocytes and basal interferon γ concentration in CD4(+) T lymphocytes. In contrast, plasma HIF and serum VEGF concentrations were not affected by hypoxia, although serum EPO concentration was raised. In PBMC, hypoxia increased cytosolic HIF-1 concentration without affecting nuclear HIF-1 concentration and led to a rise in the nuclear NFκB in PBMC. Our results show that short-term hypoxia affects immune functions in healthy individuals. Furthermore, we speculate that the effects of hypoxia are not due to HIF-1, but are caused by the activation of NFκB .

Echocardiographic evaluation of left ventricular filling pressures validated against an implantable left ventricular pressure monitoring system.

BACKGROUND: Aim of this study was to assess the ability of different echocardiographic indices to evaluate left ventricular (LV) filling pressures in patients with reduced LV function. METHODS: In 5 patients scheduled for aortocoronary bypass surgery, a telemetric intraventricular pressure sensor was implanted. Over 6 months, these patients underwent a total of 21 echocardiographic examinations with a simultaneous recording of left ventricular mean (LVMDP) and end-diastolic pressure (LVEDP). The following echocardiographic parameters were extracted from the transmitral flow profile: early (E) and late (A) diastolic flow velocity, deceleration time of the E-wave (DT) and the isovolumic relaxation time (IVRT). Early diastolic velocity of the mitral ring (E') was recorded using pulsed-wave tissue Doppler echocardiography. RESULTS: All patients were in NYHA class III and mean ejection fraction was 30%. E correlated only moderately with LVMDP (r =-0.60, P = 0.003), but revealed the highest area under the receiver operating characteristic curve for the prediction of an elevated LVMDP > 12 mmHg (AUC = 0.94, sensitivity of 92% and specificity of 86%, cut-off value 7.5 cm/s). E/A > 1 predicted LVEDP > 15 mmHg with a sensitivity of 87% and a specificity of 80%. E/E' was not correlated with LVMDP or LVEDP. CONCLUSION: Although linear correlation between echocardiographic parameters and diastolic LV pressures reached statistical significance, the correlation coefficients were low. However, in these patients with severely reduced LV function due to ischemic heart disease conventional echocardiographic parameters of transmitral flow showed higher predictive values for elevated LV filling pressures than E/E'.

Better outcome after cardiopulmonary resuscitation using percutaneous emergency circulatory support in non-coronary patients compared to those with myocardial infarction.

BACKGROUND & OBJECTIVES: Mobile heart-lung-machines applied by percutaneous cannulation are mostly used in patients suffering from acute myocardial infarction (AMI). Whether patients with non-coronary reasons for circulatory arrest benefit of percutaneous emergency circulatory support (PECS) in the same way is still unclear. METHODS: We included 22 consecutive patients who were treated by PECS during a registry period of two years. Primary study endpoint was 30-day mortality rate. RESULTS: Circulatory arrest was caused by AMI in 14 patients (64%). The remaining 8 patients suffered from cardiomyopathy/myocarditis, 4; pulmonary embolism, 2; acute pulmonary failure, 1; and tumor lysis syndrome, 1. Revascularization rate was 93% in the AMI group under PECS support. Overall survival rate was 36.4% at one month: it reached 62.5% among non-coronary patients, but only 21.4% in the AMI group (P = 0.02). Weaning was possible by direct heart transplantation in two patients. Additional two patients required implantation of a left ventricular assist device. Pumpless extracorporeal lung assist was used in one case. CONCLUSION: In this small retrospective study percutaneous emergency circulatory support provided sufficient hemodynamic stabilization in emergency situations. One fifth of AMI patients were saved by immediate restoration of circulation and causal treatment when other means of resuscitation failed. Higher survival rates were noted in non-coronary patients.

Low level myocardial parvovirus B19 persistence is a frequent finding in patients with heart disease but unrelated to ongoing myocardial injury.

While myocardial parvovirus B19 (B19V), aside from enteroviruses (EV) and adenoviruses (ADV), has recently been found often in patients with myocarditis and idiopathic dilated cardiomyopathy (IDC), the pathogenetic significance of B19V genomes in those patients has not yet been sufficiently elucidated. In the present study, left ventricular endomyocardial biopsies from 24 patients with left ventricular ejection fraction (LVEF) below 55% due to IDC, and tissue from the right atrial appendage of 10 control patients undergoing bypass surgery with normal LVEF (>55%) were investigated for B19V, ADV, and EV genomes by specific nested polymerase chain reaction (PCR), by real time PCR or by reverse-transcription PCR, respectively. The myocardial tissue samples from the 10 controls were analyzed each in three different virological laboratories for B19V. In the IDC group, the frequency of the myocardial virus genomes found in 54% (13/24) of the patients was as follows: B19V: 50% (12/24), EV: 8% (2/24), including one patient with B19V and EV, and ADV: 0% (0/24). For comparison, the prevalence of B19V genomes was between 30% and 60% in the control group as detected in three different laboratories, but all these control subjects were EV- and ADV-negative. The number of B19V gene copies, however, was very low and similar both in the IDC and control group. In the majority of patients myocardial B19V persistence was associated with a low virus load irrespective of the underlying heart disease so that it may be of no importance in the pathogenesis of IDC.