Valve in valve implantation of the CoreValve Evolut R in degenerated surgical aortic valves

Background: The new CoreValve Evolut R has an improved design to minimize paravalvular leak­age and allows repositioning of the valve. For patients with degenerated bioprosthetic aortic valves, transcatheter aortic valve implantation (TAVI) represents a less invasive option. Herein reported are valve-in-valve (ViV) implantations of this new valve. Methods: A total of 26 patients (mean age 79.4 ± 6.1 years, 17 males and 9 females) were treated for severe prosthesis stenosis (n = 9), severe regurgitation (n = 8) or severe combination of stenosis and regurgitation (n = 9). All patients underwent transthoracic echocardiography before and after ViV implantation. Results: Valve-in-valve implantation of a CoreValve Evolut R was performed successfully in all pa­tients. The mean transaortic gradient for stenotic valves determined by transthoracic echocardiography was reduced significantly from 37.5 ± 15.3 mmHg in patients with prosthesis stenosis to 16.3 ± 8.2 mmHg (p < 0.001). In all cases with severe prosthesis regurgitation, regurgitation was reduced to none or mild. All-cause mortality after 30 days was 0%. Conclusions: It was concluded that CoreValve Evolut R is well suited for ViV implantation

Renal and hepatic function of patients with severe tricuspid regurgitation undergoing inferior caval valve implantation

Due to progressive abdominal-venous congestion severe tricuspid regurgitation (TR) is a common cause of cardiorenal and cardiohepatic syndrome. We initiated the TRICAVAL study to compare interventional valve implantation into the inferior vena cava (CAVI) versus optimal medical therapy (OMT) in severe TR. In the present subanalysis, we aimed to evaluate the effects of CAVI on clinical signs of congestion, renal and hepatic function. TRICAVAL was an investigator-initiated, randomized trial. Twenty-eight patients with severe TR were randomized to OMT or CAVI using an Edwards Sapien XT valve. Probands who completed the 3-month follow-up (CAVI [n = 8], OMT [n = 10]) were evaluated by medical history, clinical examination, and laboratory testing at baseline, 3 and 12 months. After 3 months, the CAVI group exhibited a significant reduction of body weight (from 80.7 [69.0-87.7] kg to 75.5 [63.8-84.6] kg, p < 0.05) and abdominal circumference (from 101.5 +/- 13.8 cm to 96.3 +/- 15.4 cm, p <= 0.01) and a trend to lower doses of diuretics compared to OMT. Renal and hepatic function parameters did not change significantly. Within a short-term follow-up, CAVI led to an improvement of clinical signs of venous congestion and a non-significant reduction of diuretic doses compared to OMT

Impact of inferior caval valve implantation on severity of tricuspid regurgitation and right heart function

Aims: Severe tricuspid regurgitation (TR) is a common finding in heart failure patients and associated with increased mortality. New interventional therapeutic options are needed as many heart failure patients are unfit for surgery. The TRICAVAL study compared valve implantation into the inferior vena cava (CAVI) with optimal medical therapy (OMT) in patients with severe TR. Here, we report details on the impact of CAVI on TR severity as well as right heart function and morphology. Methods and results: We randomized 28 patients with severe TR to CAVI (n = 14) with transfemoral implantation of an Edwards Sapien XT valve into the inferior vena cava or OMT (n = 14). Inclusion and exclusion criteria were based on anatomical and clinical parameters. Echocardiographic measurements were performed at baseline, at the first postoperative day and one, three, and twelve months after randomization. As proof of concept of an effective sealing of the inferior vena cava, we detected a significant decrease in systolic hepatic vein reflux volume (11.0 [6.2-21.9] mL vs 3.5 [0.6-8.5] mL,P = .016) and hepatic vein diameter (11.5 [10.0-14.8] mm vs 10.0 [9.3-11.8] mm,P = .034) at thirty-day follow-up. However, CAVI had no significant impact on TR, cardiac function, and morphology. Conclusions: Caval valve implantation significantly reduced systolic reflux into the hepatic veins but was not associated with an improvement in cardiac function, morphology, or TR severity

Rapid progression of aortic and mitral stenosis in a patient with AA amyloidosis: a case report

Background: Aortic stenosis is a common finding in cardiac amyloidosis (CA). Younger patients often remain asymptomatic. If unrecognized, this can lead to serious complications such as heart failure. Progression of aortic stenosis can be accelerated in patients with chronic kidney disease and need for dialysis. Perioperative risk in these patients is often high due to the underlying systemic disease. Case summary: A 40-year-old Caucasian man with known AA amyloidosis, highly active Ankylosing Spondylitis and need for chronic dialysis due to end-stage chronic renal failure presented for echocardiographic routine exam without reporting any cardiac symptoms. At the last visit 4 years ago, a normal heart valve function was noted and no echocardiographic follow-up was performed in the following. Now, rapid progression with severe aortic valve and mitral valve stenosis was stated and the patient underwent combined aortic and mitral surgical valve replacement following discussion in the multidisciplinary cardiology meeting. Macroscopic examination of the valves revealed significant calcification and histological examination showed the high presence of amyloid by Congo-red staining and immunohistological staining for AA-Amyloid. Both valve prosthetic devices showed normal function as well as a normal left ventricular ejection fraction in initial post-operative transoesophageal echocardiography. After prolonged and complicated post-operative course in the intensive care unit the patient died 3 months after surgery due to intractable multiorgan failure in combined severe abdominal septic and cardiogenic shock. Discussion: Concomitant CA and chronic dialysis can accelerate the onset of severe aortic valve stenosis. Young patients, as in this case, often stay asymptomatic, perioperative risk increases with duration of chronic dialysis and severity of valve stenosis. This increases the need for regular short-term echocardiographic examinations even in clinical stable patients

PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells

Endothelial pro-inflammatory activation plays a pivotal role in atherosclerosis, and many pro-inflammatory and atherogenic signals converge upon mechanistic target of rapamycin (mTOR). Inhibitors of mTOR complex 1 (mTORC1) reduced atherosclerosis in preclinical studies, but side effects including insulin resistance and dyslipidemia limit their clinical use in this context. Therefore, we investigated PRAS40, a cell type-specific endogenous modulator of mTORC1, as alternative target. Indeed, we previously found PRAS40 gene therapy to improve metabolic profile; however, its function in endothelial cells and its role in atherosclerosis remain unknown. Here we show that PRAS40 negatively regulates endothelial mTORC1 and pro-inflammatory signaling. Knockdown of PRAS40 in endothelial cells promoted TNFα-induced mTORC1 signaling, proliferation, upregulation of inflammatory markers and monocyte recruitment. In contrast, PRAS40-overexpression blocked mTORC1 and all measures of pro-inflammatory signaling. These effects were mimicked by pharmacological mTORC1-inhibition with torin1. In an in vivo model of atherogenic remodeling, mice with induced endothelium-specific PRAS40 deficiency showed enhanced endothelial pro-inflammatory activation as well as increased neointimal hyperplasia and atherosclerotic lesion formation. These data indicate that PRAS40 suppresses atherosclerosis via inhibition of endothelial mTORC1-mediated pro-inflammatory signaling. In conjunction with its favourable effects on metabolic homeostasis, this renders PRAS40 a potential target for the treatment of atherosclerosis

No role for epigallocatechin gallate (EGCG)

Consumption of tea is inversely associated with cardiovascular diseases. However, the active compound(s) responsible for the protective effects of tea are unknown. Although many favorable cardiovascular effects in vitro are mediated by epigallocatechin gallate (EGCG), its contribution to the beneficial effects of tea in vivo remains unresolved. In a randomised crossover study, a single dose of 200 mg EGCG was applied in three different formulas (as green tea beverage, green tea extract (GTE), and isolated EGCG) to 50 healthy men. Flow-mediated dilation (FMD) and endothelial-independent nitro-mediated dilation (NMD) was measured before and two hours after ingestion. Plasma levels of tea compounds were determined after each intervention and correlated with FMD. FMD significantly improved after consumption of green tea containing 200 mg EGCG (p < 0.01). However, GTE and EGCG had no significant effect on FMD. NMD did not significantly differ between interventions. EGCG plasma levels were highest after administration of EGCG and lowest after consumption of green tea. Plasma levels of caffeine increased after green tea consumption. The results show that EGCG is most likely not involved in improvement of flow-mediated dilation by green tea. Instead, other tea compounds, metabolites or combinations thereof may play a role

Role of Kozak sequence polymorphism of platelet glycoprotein Ibα as a risk factor for coronary artery disease and catheter interventions

AbstractOBJECTIVESWe sought to determine the role of the −5T/C polymorphism of the platelet glycoprotein (GP) Ibα as a potential risk factor for coronary artery disease (CAD) and adverse events complicating a coronary catheter intervention.BACKGROUNDThe platelet GP Ib-IX-V receptor complex plays a crucial role in arterial thrombus formation. The −5T/C polymorphism of GP Ibα is associated with increased receptor density.METHODSWe genotyped 1,000 patients with angiographically confirmed CAD, as well as 1,000 age- and gender-matched control subjects, for this polymorphism by polymerase chain reaction/restriction fragment length polymorphism. Among the patients with CAD, 269 underwent percutaneous transluminal coronary angioplasty (PTCA), 103 underwent directional coronary atherectomy and 278 underwent stenting. This intervention group was followed for a 30-day composite end point of target vessel revascularization, myocardial infarction or death.RESULTSCarriers of the −5C allele were significantly over-represented in the group of patients developing acute coronary syndromes (relative risk [RR] 1.43, 95% confidence interval [CI] 1.05 to 1.95, p = 0.02). The −5C allele furthermore predicted an increased risk for developing complications after PTCA (RR 3.75, 95% CI 1.15 to 12.27, p = 0.029).CONCLUSIONSThe −5C allele of the GP Ibα Kozak polymorphism may represent a risk factor in clinical conditions in which thrombosis plays an important role, such as in acute coronary syndromes and in complications after PTCA

Associations of 2D speckle tracking echocardiography-based right heart deformation parameters and invasively assessed hemodynamic measurements in patients with pulmonary hypertension

Background: We aimed to evaluate associations of right atrial (RA) and right ventricular (RV) strain parameters assessed by 2D speckle tracking echocardiography (2D STE) with invasively measured hemodynamic parameters in patients with and without pulmonary hypertension (PH). Methods: In this study, we analyzed 78 all-comer patients undergoing invasive hemodynamic assessment by left and right heart catheterization. Standard transthoracic echocardiographic assessment was performed under the same hemodynamic conditions. RA and RV longitudinal strain parameters were analyzed using 2D STE. PH was defined as invasively obtained mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest and was further divided into pre-capillary PH (pulmonary capillary wedge pressure [PCWP] ≤ 15 mmHg), post-capillary PH (PCWP > 15 mmHg) and combined PH (PCWP > 15 mmHg and difference between diastolic PAP and PCWP of ≥7 mmHg). Correlation analyses between variables were calculated with Pearson's or Spearman's correlation coefficient as applicable. Results: Out of 78 patients, 45 presented with PH. Within the PH group, 39 had post-capillary, five had combined pre- and post-capillary PH, and one had pre-capillary PH. Patients with PH had a significantly increased RA area (PH 22.0 ± 9.2 cm2, non-PH 17.3 ± 10.7 cm2; p = 0.003) and end-systolic RV area (PH 14.7 ± 6.1, non-PH 11.9 ± 4.8 cm2; p = 0.022). RV mid strain was significantly reduced in PH (PH -17.4 ± 7.8, non-PH: - 21.6 ± 5.5; p = 0.019). Average peak systolic RA strain (RAS) and average peak systolic RV strain (RVS) showed a significant association with mPAP (r = - 0.470, p = 0.001 and r = 0.490, p = 0.001, respectively) and with PCWP (r = - 0.296, p = 0.048 and r = 0.365, p = 0.015, respectively) in patients with PH. Furthermore, RV apical, mid and basal strain as well as RV free wall strain showed moderate associations with mPAP. In patients without PH, there were no associations detectable between RA or RV strain parameters and mPAP and PCWP. Conclusion: In an all-comer cohort, RA and RV strain parameters showed significant associations with invasively assessed mPAP and PCWP in patients with predominantly post-capillary PH. These associations may be useful in clinical practice to assess the impact of post-capillary PH on myocardial right heart function

Phasic left atrial strain to predict worsening of diastolic function: Results from the prospective Berlin Female Risk Evaluation follow-up trial

Purpose: The predictive value of maximum left atrial volume index (LAVI), phasic left atrial strain (LAS) and other standard echocardiographic parameters assessing left ventricular (LV) diastolic function to discriminate a future worsening of diastolic function (DD) in patients at risk is unclear. We aimed to prospectively assess and compare the clinical impact of these parameters in a randomly selected study sample of the general urban female population. Methods and results: A comprehensive clinical and echocardiographic evaluation was performed in 256 participants of the Berlin Female Risk Evaluation (BEFRI) trial after a mean follow up time of 6.8 years. After an assessment of participants' current DD status, the predictive impact of an impaired LAS on the course of DD was assessed and compared with LAVI and other DD parameters using receiver operating characteristic (ROC) curve and multivariate logistic regression analyses. Subjects with no DD (DD0) who showed a decline of diastolic function by the time of follow-up showed a reduced LA reservoir (LASr) and conduit strain (LAScd) compared to subjects who remained in the healthy range (LASr 28.0% +/- 7.0 vs. 41.9% +/- 8.5; LAScd -13.2% +/- 5.1 vs. -25.4% +/- 9.1; p < 0.001). With an area under the curve (AUC) of 0.88 (95%CI 0.82-0.94) and 0.84 (95%CI 0.79-0.89), LASr and LAScd exhibited the highest discriminative value in predicting worsening of diastolic function, whereas LAVI was only of limited prognostic value [AUC 0.63 (95%CI 0.54-0.73)]. In logistic regression analyses, LAS remained a significant predictor for a decline of diastolic function after controlling for clinical and standard echocardiographic DD parameters, indicating its incremental predictive value. Conclusion: The analysis of phasic LAS may be useful to predict worsening of LV diastolic function in DD0 patients at risk for a future DD development.GRAPHICAL ABSTRAC

Hypoxic Induction of Receptor Activity-Modifying Protein 2 Alters Regulation of Pulmonary Endothelin-1 by Adrenomedullin: Induction under Normoxia Versus Inhibition under Hypoxia

ABSTRACT The vasodilator adrenomedullin (AM) is up-regulated in pulmonary hypertension, and inhaled AM is beneficial in patients. Therefore, we investigated the effects of AM on pulmonary endothelin-1 (ET-1). In normoxic isolated rat lungs (IRL) and rat pulmonary artery endothelial cells (RPAEC), the calcitonin gene-related peptide type-1 receptor (CGRP1R) antagonist human (h)CGRP(8-37) decreased ET-1 secretion, and the AM receptor antagonist hAM(22-52) had no effect. Exogenous AM (1 and 10 pM) increased ET-1 levels, which was abolished by hCGRP(8-37) and protein kinase A (PKA) inhibition. At 50 and 100 pM, AM decreased ET-1, an effect sensitive to hAM(22-52), NO inhibition, and protein kinase G (PKG) inhibition. In RPAEC, these results were attributed to altered ET-1 gene expression; low exogenous AM also promoted activity of endothelin-converting enzyme, and high AM increased the number of endothelin type-B (ETB) receptor sites. Hypoxia significantly elevated AM and ET-1 levels in IRL and RPAEC, and hAM(22-52), NO inhibition, or PKG inhibitors caused a further ET-1 rise. These interventions also prevented the hypoxia-related increase in ETB sites in RPAEC. In RPAEC, both high AM and hypoxia down-regulated receptor activity-modifying protein (RAMP)1, but they up-regulated RAMP2 protein and AM receptor sites, and RAMP2 silencing by small interference RNA proved its pivotal role for signal switching. In conclusion, endogenous pulmonary AM up-regulates ET-1 and endothelinconverting enzyme activity under physiological conditions, via CGRP1R and PKA. In contrast, hypoxia-induced high AM levels, via AM1 receptor and NO/PKG, down-regulate ET-1 gene expression and promote expression of ETB receptors. This hypoxia-related switch of AM signaling can be attributed to up-regulation of the RAMP2/AM1 receptor system. Adrenomedullin (AM), first discovered b