Michael Huntgeburth

Cardioband, a transcatheter surgical-like direct mitral valve annuloplasty system: early results of the feasibility trial

AIMS Cardioband system is a direct annuloplasty adjustable device that is implanted in the beating heart on the posterior annulus under fluoroscopic and transoesophageal echocardiographic (TEE) guidance. We report the early (1 month) outcomes of the first-in-man pre-CE-mark feasibility and safety trial. METHODS AND RESULTS The study enrolled high-risk adult individuals at five institutions in Europe with symptomatic secondary mitral regurgitation (MR) despite optimal medical therapy. The primary efficacy endpoints included the technical success rate of implantation, feasibility of the Cardioband adjustment (technical performance), and ability to reduce the annular septolateral dimension and MR grade at hospital discharge and at 30 days. The study group included 31 consecutively enrolled high-risk patients with moderate-to-severe or severe secondary MR with at least 1 month of follow-up (mean age 71.8 ± 6.9 years). All patients received the full implant of a Cardioband. Adjustment of the Cardioband resulted in a significant reduction in the septolateral dimension in all but two patients (septolateral dimension from 36.8 ± 4.8 to 29 ± 5.5 mm after the procedure, P < 0.01). Following Cardioband adjustment (29 of 31 patients) MR was none or trace in 6 (21%), mild in 21 (72%), and moderate in 2 (7%). No patient had severe MR after adjustment. Procedural mortality was zero and in-hospital mortality was 6.5% (2 of 31 patients, neither procedure- nor device-related). At 30 days, 22 of the 25 patients (88%) had MR ≤2+. CONCLUSIONS This study demonstrates the feasibility and safety of percutaneous direct mitral annuloplasty with the Cardioband device in high-risk patients with MR.

The Arg389Gly β1-adrenoceptor gene polymorphism determines contractile response to catecholamines

OBJECTIVES Recently, the Arg389Gly beta1-adrenoceptor (beta1AR) gene polymorphism has been detected. The Arg variant exhibited increased responsiveness to agonist-induced stimulation in vitro. Functional studies in isolated human atrial muscle strips and in-vivo studies revealed contradictory results regarding the functional relevance of this polymorphism. We sought to characterize the functional consequences of the Arg389Gly beta1-AR polymorphism in 30 consecutive healthy male volunteers in vivo. METHODS beta1-AR genotype was determined by PCR and restriction analysis, which was confirmed by DNA sequencing. We compared heart rate, blood pressure, and contractile response of the various genotype carriers with a modified dobutamine stress echocardiography protocol. RESULTS Subjects homozygous for the Arg389 beta1AR showed a significantly higher increase in fractional shortening upon cumulative doses of dobutamine as compared to subjects carrying one or two copies of the Gly389 allele. A statistically significant difference was observed at a dobutamine dose of 10 microg/kg/min (46.5 +/- 1.3 vs. 41.8 +/- 1.0 %; P = 0.023) and was maximal at 40 microg/kg/min (61.9 +/- 1.4 vs. 52.8 +/- 1.6; P = 0.001). As a result, the systolic blood pressure response to dobutamine was significantly enhanced in individuals homozygous for the Arg389 allele, whereas the effect on heart rate did not differ between the two groups. Normalization for changing afterload conditions by calculating the pressure-dimension ratio revealed similar effects, indicating that the beta1AR-mediated effects are mainly a result of increased myocardial inotropy. CONCLUSION These data indicate that the Arg389Gly beta1AR polymorphism is functionally relevant in vivo and determines contractile responsiveness to catecholamines in humans.

Liver adapts mitochondrial function to insulin resistant and diabetic states in mice

BACKGROUND & AIMS To determine if diabetic and insulin-resistant states cause mitochondrial dysfunction in liver or if there is long term adaptation of mitochondrial function to these states, mice were (i) fed with a high-fat diet to induce obesity and T2D (HFD), (ii) had a genetic defect in insulin signaling causing whole body insulin resistance, but not full blown T2D (IR/IRS-1(+/-) mice), or (iii) were analyzed after treatment with streptozocin (STZ) to induce a T1D-like state. METHODS Hepatic lipid levels were measured by thin layer chromatography. Mitochondrial respiratory chain (RC) levels and function were determined by Western blot, spectrophotometric, oxygen consumption and proton motive force analysis. Gene expression was analyzed by real-time PCR and microarray. RESULTS HFD caused insulin resistance and hepatic lipid accumulation, but RC was largely unchanged. Livers from insulin resistant IR/IRS-1(+/-) mice had normal lipid contents and a normal RC, but mitochondria were less well coupled. Livers from severely hyperglycemic and hypoinsulinemic STZ mice had massively depleted lipid levels, but RC abundance was unchanged. However, liver mitochondria isolated from these animals showed increased abundance and activity of the RC, which was better coupled. CONCLUSIONS Insulin resistance, induced either by obesity or genetic manipulation and steatosis do not cause mitochondrial dysfunction in mouse liver. Also, mitochondrial dysfunction is not a prerequisite for liver steatosis. However, severe insulin deficiency and high blood glucose levels lead to an enhanced performance and better coupling of the RC. This may represent an adaptation to fuel overload and the high energy-requirement of an unsuppressed gluconeogenesis.

Transforming Growth Factor β1 Oppositely Regulates the Hypertrophic and Contractile Response to β-Adrenergic Stimulation in the Heart

Background Neuroendocrine activation and local mediators such as transforming growth factor-β1 (TGF-β1) contribute to the pathobiology of cardiac hypertrophy and failure, but the underlying mechanisms are incompletely understood. We aimed to characterize the functional network involving TGF-β1, the renin-angiotensin system, and the β-adrenergic system in the heart. Methods Transgenic mice overexpressing TGF-β1 (TGF-β1-Tg) were treated with a β-blocker, an AT1-receptor antagonist, or a TGF-β-antagonist (sTGFβR-Fc), were morphologically characterized. Contractile function was assessed by dobutamine stress echocardiography in vivo and isolated myocytes in vitro. Functional alterations were related to regulators of cardiac energy metabolism. Results Compared to wild-type controls, TGF-β1-Tg mice displayed an increased heart-to-body-weight ratio involving both fibrosis and myocyte hypertrophy. TGF-β1 overexpression increased the hypertrophic responsiveness to β-adrenergic stimulation. In contrast, the inotropic response to β-adrenergic stimulation was diminished in TGF-β1-Tg mice, albeit unchanged basal contractility. Treatment with sTGF-βR-Fc completely prevented the cardiac phenotype in transgenic mice. Chronic β-blocker treatment also prevented hypertrophy and ANF induction by isoprenaline, and restored the inotropic response to β-adrenergic stimulation without affecting TGF-β1 levels, whereas AT1-receptor blockade had no effect. The impaired contractile reserve in TGF-β1-Tg mice was accompanied by an upregulation of mitochondrial uncoupling proteins (UCPs) which was reversed by β-adrenoceptor blockade. UCP-inhibition restored the contractile response to β-adrenoceptor stimulation in vitro and in vivo. Finally, cardiac TGF-β1 and UCP expression were elevated in heart failure in humans, and UCP – but not TGF-β1 – was downregulated by β-blocker treatment. Conclusions Our data support the concept that TGF-β1 acts downstream of angiotensin II in cardiomyocytes, and furthermore, highlight the critical role of the β-adrenergic system in TGF-β1-induced cardiac phenotype. Our data indicate for the first time, that TGF-β1 directly influences mitochondrial energy metabolism by regulating UCP3 expression. β-blockers may act beneficially by normalizing regulatory mechanisms of cellular hypertrophy and energy metabolism.

Clinical outcome of critically ill, not fully recompensated, patients undergoing MitraClip therapy

As periprocedural risk is low, MitraClip implantation is often performed in critically ill, not fully recompensated patients, who are in NYHA functional class IV at the time of the procedure, to accelerate convalescence. We herein sought to evaluate the procedural and 30‐day outcome of this patient group.

PI3-kinase/Akt-dependent antiapoptotic signaling by the PDGF α receptor is negatively regulated by Src family kinases

Regulation of growth factor dependent cell survival is crucial for development and disease progression. Here, we report a novel function of Src kinases as a negative regulator of platelet‐derived growth factor (PDGF) dependent cell survival. We characterized a series of PDGF α receptor (PDGFRA) mutants, which lack the binding sites for Src, phosphatidylinositol 3′‐kinase (PI3K), SHP‐2 or phospholipase C‐γ. We found that PDGFRA‐dependent cell survival was mainly mediated through activation of PI3K, and was negatively regulated by Src. Characterization of the downstream signaling events revealed that PI3K activates the protein kinase Akt, which in turn phosphorylates and thus inactivates proapoptotic Forkhead transcription factors. Src phosphorylates the ubiquitin‐ligase c‐Cbl, which is required for degradation of the activated receptor. Consequently, overexpression of c‐Cbl prevented PDGFRA‐mediated cell survival, whereas it did not affect this response, when Src was unable to associate with the receptor. This novel function of Src in antiapoptotic signaling introduces Src kinases as an interesting therapeutic target in apoptosis related diseases.

Bleeding Complications After Percutaneous Mitral Valve Repair With the MitraClip

Bleeding after cardiac surgery or cardiovascular interventions is associated with worse patient outcome. Only very limited data are available on the subject of bleeding after percutaneous edge-to-edge mitral valve repair (PMVR). We performed a single center analysis including 347 consecutive patients who underwent PMVR. Bleeding was defined according to the Mitral Valve Academic Research Consortium (MVARC) end point definition. The incidence of MVARC bleeding was 21.6% (n = 75), whereas major MVARC bleeding (hemoglobin decrease ≥3 g/dl) occurred in 7.4% (n = 26). Only 33.3% of all bleeding cases were access site-related. In multivariate regression analyses, independent predictors of MVARC bleeding were the presence of coronary artery disease (2.809, 95% CI 1.123 to 7.022, p = 0.027) and intervention duration (1.010, 95% CI 1.002 to 1.018, p = 0.010). Patients experiencing MVARC bleeding had longer hospital stays (p = 0.026); however, neither major nor extensive MVARC bleeding was associated with increased 30-day or 1-year mortality. A decrease in hemoglobin levels ≥3 g/dl without clinically visible bleeding sign-not considered in the MVARC bleeding definition-occurred in 9.5% of patients. A hemoglobin decrease of ≥4 g/dl had a strong association with worse survival in those patients with obscure bleeding. In conclusion, these data show a relevant incidence of bleeding after PMVR. In contrast to other cardiovascular interventions, the majority of bleedings were not access site-related. Particularly, patients with obscure bleeding, which are not included in the MVARC end point definitions, had worse outcomes and should therefore be considered for a more intensive workup.

Thrombus formation at the MitraClip system during percutaneous mitral valve repair.

Percutaneous mitral valve repair is increasingly used to improve mitral regurgitation in patients who are considered not suitable for surgery, without significant thrombus-related complications [(1,2)][1]. We report, for the first time, an acute thrombus formation on the right atrial side of the

The sGC-stimulator Riociguat for the treatment of Raynaud's phenomenon: A single-dose, double-blind, randomized, placebo-controlled cross-over study (DIGIT)

Background Raynaud’s phenomenon (RP) is a coldor stress-triggered digital ischemia caused by vasoconstriction in the digital blood vessels, severely affecting patient’s life. Medical therapeutic options for RP are limited and commonly unsatisfactory, with a large number of patients not responding to currently available treatment. In the present study we investigated the safety, efficacy and pharmacokinetics of a single dose of the soluble guanylate cyclase (sGC)-stimulator riociguat in patients with RP in a double-blind, randomized, placebo-controlled cross-over fashion.

End-Tidal CO2 Predicts Reduction in Mitral Regurgitation in Patients Undergoing Percutaneous Mitral Valve Edge-to-Edge Repair

Objectives: We evaluated end-tidal CO2 (etCO2), which has been proposed to assess acute hemodynamic changes, to guide percutaneous edge-to-edge mitral valve repair (PMVR) with the MitraClip system. Methods: Thirty-nine patients (aged 78 ± 14 years) undergoing PMVR for moderate-to-severe mitral regurgitation (MR) of primary and secondary etiology were included. General anesthesia was maintained with sevoflurane and constant ventilation parameters to ensure stable etCO2 tension. MR grade was determined semiquantitatively by transesophageal echocardiography by 2 experienced operators blinded to etCO2 measurements. etCO2 levels were measured 3, 5, 10, and 15 min after final MitraClip placement. Results: Overall, etCO2 increased from 32.2 ± 1.7 before to 35.4 ± 3.0, 34.6 ± 2.6, and 34.2 ± 2.4 mm Hg 3, 5, and 10 min after implantation. A significant correlation was noted between the echocardiographic reduction in MR grade and the increase in etCO2. ANOVA for repeated measures confirmed a significant increase in etCO2 after clip implantation (corrected F = 20.0; p < 0.001) and revealed a significantly greater increase in etCO2 in patients with MR reduction ≥2 grades as compared to lesser MR reductions (F = 6.47; p = 0.015). Blood pressure changes did not correlate with the degree of MR reduction. Conclusions: We observed a close correlation between the reduction in MR grade during PMVR and etCO2, which might evolve as a useful parameter to complement treatment guidance during PMVR.