Impairment of intracellular Ca(2+) homeostasis and mitochondrial function has been implicated in the development of cardiomyopathy. Mitochondrial Ca(2+) uptake is thought to be mediated by the Ca(2+) ...uniporter (MCU) and a thus far speculative non-MCU pathway. However, the identity and properties of these pathways are a matter of intense debate, and possible functional alterations in diseased states have remained elusive.
By patch clamping the inner membrane of mitochondria from nonfailing and failing human hearts, we have identified 2 previously unknown Ca(2+)-selective channels, referred to as mCa1 and mCa2. Both channels are voltage dependent but differ significantly in gating parameters. Compared with mCa2 channels, mCa1 channels exhibit a higher single-channel amplitude, shorter openings, a lower open probability, and 3 to 5 subconductance states. Similar to the MCU, mCa1 is inhibited by 200 nmol/L ruthenium 360, whereas mCa2 is insensitive to 200 nmol/L ruthenium 360 and reduced only by very high concentrations (10 micromol/L). Both mitochondrial Ca(2+) channels are unaffected by blockers of other possibly Ca(2+)-conducting mitochondrial pores but were activated by spermine (1 mmol/L). Notably, activity of mCa1 and mCa2 channels is decreased in failing compared with nonfailing heart conditions, making them less effective for Ca(2+) uptake and likely Ca(2+)-induced metabolism.
Thus, we conclude that the human mitochondrial Ca(2+) uptake is mediated by these 2 distinct Ca(2+) channels, which are functionally impaired in heart failure. Current properties reveal that the mCa1 channel underlies the human MCU and that the mCa2 channel is responsible for the ruthenium red-insensitive/low-sensitivity non-MCU-type mitochondrial Ca(2+) uptake.
Pulmonary hypertension (PH) is associated with progressive impairment of right ventricular function, reduced exercise capacity and a poor prognosis. Little is known about the prevalence, clinical ...manifestation and impact of atrial fibrillation (AF) on cardiac function in PH.
In a four year single-centre retrospective analysis 225 patients with confirmed PH of various origins were enrolled to investigate the prevalence of AF, and to assess the clinical manifestation, 6-minute walk distance, NT-proBNP levels, echocardiographic parameters and hemodynamics obtained by right heart catheterization in PH with AF.
AF was prevalent in 31.1%. In patients with PH and AF, parameters of clinical deterioration (NYHA/WHO functional class, 6-minute walk distance, NT-proBNP levels) and renal function were significantly compromised compared to patients with PH and sinus rhythm (SR). In the total PH cohort and in PH not related to left heart disease occurrence of AF was associated with an increase of right atrial pressure (RAP) and right atrial dilatation. While no direct association was found between pulmonary artery pressure (PAP) and AF in these patients, right ventricular function was reduced in AF, indicating more advanced disease. In PH due to left heart failure the prevalence of AF was particularly high (57.7% vs. 23.1% in other forms of PH). In this subgroup, left atrial dilatation, increase of pulmonary capillary wedge pressure, PAP and RAP were more pronounced in AF than in SR, suggesting that more marked backward failure led to AF in this setting.
PH is associated with increased prevalence of AF. Occurrence of AF in PH indicates clinical deterioration and more advanced disease.
Potassium (K+) channels in the inner mitochondrial membrane influence cell function and survival. Increasing evidence indicates that multiple signaling pathways and pharmacological actions converge ...on mitochondrial ATP-sensitive K+ (mitoKATP) channels and PKC to confer cytoprotection against necrotic and apoptotic cell injury. However, the molecular structure of mitoKATP channels remains unresolved, and the mitochondrial phosphoprotein(s) that mediate cytoprotection by PKC remain to be determined. As mice deficient in the main sarcolemmal gap junction protein connexin 43 (Cx43) lack this cytoprotection, we set out to investigate a possible link among mitochondrial Cx43, mitoKATP channel function, and PKC activation. By patch-clamping the inner membrane of subsarcolemmal murine cardiac mitochondria, we found that genetic Cx43 deficiency, pharmacological connexin inhibition by carbenoxolone, and Cx43 blockade by the mimetic peptide 43GAP27 each substantially reduced diazoxide-mediated stimulation of mitoKATP channels. Suppression of mitochondrial Cx43 inhibited mitoKATP channel activation by PKC. MitoKATP channels of interfibrillar mitochondria, which do not contain any detectable Cx43, were insensitive to both PKC activation and diazoxide, further demonstrating the role of Cx43 in mitoKATP channel stimulation and the compartmentation of mitochondria in cell signaling. Our results define a role for mitochondrial Cx43 in protecting cardiac cells from death and provide a link between cytoprotective stimuli and mitoKATP channel opening, making Cx43 an attractive therapeutic target for protection against cell injury.
Transcatheter aortic valve implantation (TAVI) represents an alternative option for elderly patients with severe aortic valve stenosis who are denied surgical aortic valve replacement (SAVR) because ...of high perioperative risk. The impact of TAVI on postprocedural atrial fibrillation is undefined.
In a single-center analysis, we assessed clinical data, preoperative risk scores (Society for Thoracic Surgeons score, logistic European System for Cardiac Operative Risk Evaluation), preprocedural electrocardiograms, and 72-hour postprocedural rhythm monitoring of 170 patients undergoing TAVI (n=84) or SAVR (n=86). In a subanalysis, transapical (n=43) and transfemoral TAVI (n=41) were compared.
Expectedly, TAVI patients were significantly older, presented with more severe symptoms, had higher Society for Thoracic Surgeons score, higher logistic European System for Cardiac Operative Risk Evaluation score, and revealed more frequently intermittent atrial fibrillation compared with SAVR patients. Despite this more compromised health state, prevalence of postprocedural atrial fibrillation was significantly lower in the TAVI group (6.0%, versus 33.7% after SAVR, p<0.05). More than two thirds of TAVI patients but no SAVR patient with atrial fibrillation in preprocedural electrocardiograms had stable sinus rhythm during 72-hour postprocedural monitoring. Notably, no atrial fibrillation was observed after transfemoral TAVI. Whereas atrial fibrillation onset in the SAVR group predominantly occurred on postoperative day 3, atrial fibrillation onset after transapical TAVI was obtained within the first 24 hours after the intervention.
Our results indicate that TAVI, compared with SAVR, reduces the risk of periprocedural atrial fibrillation. Furthermore, preprocedural atrial fibrillation may be converted into sinus rhythm particularly after transfemoral TAVI, suggesting an impact of decreased intracardiac pressures in the absence of adverse periprocedural factors that might promote atrial fibrillation.
Despite compelling evidence supporting key roles for glycogen synthase kinase 3β (GSK3β), mitochondrial adenosine triphosphate-sensitive K+ (mitoKATP) channels, and mitochondrial connexin 43 (Cx43) ...in cytoprotection, it is not clear how these signaling modules are linked mechanistically. By patch-clamping the inner membrane of murine cardiac mitochondria, we found that inhibition of GSK3β activated mitoKATP. PKC activation and protein phosphatase 2a inhibition increased the open probability of mitoKATP channels through GSK3β, and this GSK3β signal was mediated via mitochondrial Cx43. Moreover, (i) PKC-induced phosphorylation of mitochondrial Cx43 was reduced in GSK3β-S9A mice; (ii) Cx43 and GSK3β proteins associated in mitochondria; and (iii) SB216763-mediated reduction of infarct size was abolished in Cx43 KO mice in vivo, consistent with the notion that GSK3β inhibition results in mitoKATP opening via mitochondrial Cx43. We therefore directly targeted mitochondrial Cx43 by the Cx43 C-terminal binding peptide RRNYRRNY for cardioprotection, circumventing further upstream pathways. RRNYRRNY activated mitoKATP channels via Cx43. We directly recorded mitochondrial Cx43 channels that were activated by RRNYRRNY and blocked by the Cx43 mimetic peptide 43GAP27. RRNYRRNY rendered isolated cardiomyocytes in vitro and the heart in vivo resistant to ischemia/reperfusion injury, indicating that mitochondrial Cx43- and/or mitoKATP-mediated reduction of infarct size was not undermined by RRNYRRNY-related opening of sarcolemmal Cx43 channels. Our results demonstrate that GSK3β transfers cytoprotective signaling through mitochondrial Cx43 onto mitoKATP channels and that Cx43 functions as a channel in mitochondria, being an attractive target for drug treatment against cardiomyocyte injury.
Hyperpolarization-activated cation (HCN) channels give rise to an inward current with similar but not identical characteristics compared with the pacemaker current (I(f)), suggesting that HCN channel ...function is modulated by regulatory beta-subunits in native tissue. KCNE2 has been proposed to serve as a beta-subunit of HCN channels; however, available data remain contradictory. To further clarify this situation, we therefore analyzed the effect of KCNE2 on whole cell currents, single channel properties, and membrane protein expression of all cardiac HCN isoforms in the CHO cell system. On the whole cell level, current densities of all HCN isoforms were significantly increased by KCNE2 without altering voltage dependence or current reversal. While these results correlated well with the KCNE2-mediated 2.2-fold and 1.6-fold increases of membrane protein levels of HCN2 and HCN4, respectively, no effect of KCNE2 on HCN1 expression was obtained. All HCN subtypes displayed faster activation kinetics upon coexpression with KCNE2. Most importantly, for the first time, we demonstrated modulation of single channel function by KCNE2, thus supporting direct functional interaction with HCN subunits. In the presence of KCNE2, the single channel amplitudes and conductance of HCN1, HCN2, and HCN4 were significantly increased versus control recordings. Mean open time was significantly increased in cells coexpressing HCN2 + KCNE2, whereas it was unaffected in HCN1 + KCNE2 cotransfected cells and reduced in HCN4 + KCNE2 cotransfected cells compared with the respective HCN subunits alone. Thus, we demonstrate KCNE2-mediated distinct effects on HCN membrane expression and direct functional modulation of HCN isoforms, further supporting that KCNE2 surves as a regulatory beta-subunit of HCN channels.
Objectives
We aimed to compare indirect mitral annuloplasty using the Carillon Mitral Contour System and edge‐to‐edge repair via MitraClip in atrial functional mitral regurgitation (aFMR).
Background
...In patients with left ventricular dilation, both edge‐to‐edge repair and indirect mitral annuloplasty are effective in reducing mitral regurgitation, while no clinical trial has compared both interventional methods in aFMR.
Methods
In a retrospective single‐center analysis, 41 patients with aFMR underwent either edge‐to‐edge mitral valve repair (MitraClip group, n = 20) or indirect annuloplasty (Carillon group, n = 21).
Results
Both treatment groups showed high procedural success (100%) and low complication rates. Both treatment groups showed a comparable reduction of New York Heart Association (NYHA) classification postimplantation, after 3‐ and 12‐months follow‐up. Quantitative reduction in echocardiographic FMR parameters was significantly pronounced in the MitraClip group (reduction in vena contracta MitraClip vs. Carillon: postimplantation −74.6 ± 25.8 vs. −29.1 ± 17.8%, 3‐months follow‐up −65.8 ± 31.2 vs. −33.9 ± 17.5%, 12‐months follow‐up −50.8 ± 27.9 vs. −23.9 ± 17.0%, p < 0.05). Qualitative mitral valve assessment showed improved FMR class postimplantation, at 3‐and 12‐months follow‐up in both treatment groups. Edge‐to‐edge repair revealed better results with lower average FMR classification compared to indirect coronary sinus‐based annuloplasty. After 12‐months left atrial (LA) volume was significantly reduced in the Carillon group, while in the MitraClip group no LA remodeling was found (reduction in LA volume MitraClip vs. Carillon at 12 months: +9.6 ± 25.1% vs. −12.3 ± 12.7%, p < 0.05).
Conclusions
Both indirect mitral valve annuloplasty and edge‐to‐edge repair are feasible and safe in patients with aFMR, while the reduction in FMR was pronounced in the edge‐to‐edge repair group.
Residual mitral regurgitation (MR) is thought to be an important predictor of long-term survival following transcatheter edge-to-edge repair (TEER). Intraprocedural MR assessment using ...transesophageal echocardiography could be limited by image quality, hemodynamics, and patient sedation. The MitraScore is a validated multimodal approach for intraprocedural MR assessment during TEER.
This study aimed to assess the impact of residual MR using the MitraScore on 1-year mortality.
Patients undergoing mitral TEER were eligible for inclusion in the prospective, multicenter MITRA-PRO registry (A Prospective Registry Study on 1-Year Mortality and the Prognostic Significance of MitraScore After MitraClip Implantation in Patients With Mitral Regurgitation). Patients with a MitraScore ≤3 were defined as patients with mild residual MR after mitral TEER, whereas a MitraScore ≥4 was considered as relevant residual MR. Mortality, rehospitalization, and major adverse events were assessed 1 year after TEER.
A MitraScore ≤3 was found in 1,059 patients (71.0%), whereas 432 patients revealed a MitraScore ≥4 (29.0%). One-year mortality was significantly lower in patients with nonrelevant residual MR (MitraScore ≤3 14.6% vs MitraScore≥4 22.1%). An almost linear relationship between intraprocedural MitraScore after TEER and mortality was observed. The combined clinical endpoint of mortality and rehospitalization within the 1-year follow-up was also significantly lower in the MitraScore ≤3 group (31.5%) than in the MitraScore ≥4 group (40.8%). A subgroup analysis confirmed the predictive value of the MitraScore in patients with primary, secondary, or mixed MR etiologies.
Residual MR assessed by intraprocedural MitraScore after TEER predicts 1-year mortality and rehospitalization. Therefore, the multimodal MitraScore improves MR assessment during mitral TEER and might improve patient survival.(A Prospective Registry Study on 1-Year Mortality and the Prognostic Significance of MitraScore After MitraClip Implantation in Patients With Mitral Regurgitation MITRA-PRO; DRKS00012288).
Objectives
Coronary sinus (CS) based mitral annuloplasty using the Carillon device could be limited by compromise of the left circumflex artery (Cx).
Background
Computed tomography (CT) might be a ...feasible tool for preprocedural planning of indirect mitral valve annuloplasty.
Methods
In a retrospective analysis, 25 patients underwent Carillon device implantation and received CT‐angiography (CTA) analysis prior to CS based percutaneous mitral valve repair. We used a retrospective approach with preprocedural CTA and intraprocedural coronary sinus angiography (CSA) measurements to determine the CS to Cx distance at the occlusion or compression point or in the distal landing zone in absence of Cx compromise.
Results
According to left coronary artery angiography, we identified 7 patients with Cx occlusion, 7 with Cx compression and 11 without Cx compromise. No difference in minimal CS to Cx distance between the three groups could be obtained. Also, neither distal CS diameter nor distal Carillon anchor size were related to Cx impingement. However, ROC analysis identified a CS to Cx distance of <8.6 mm specifically in the distal device landing zone to predict Cx compromise. Furthermore, CTA was accurate in assessing device length in comparison to CSA, but failed predicting Carillon device anchor size.
Conclusions
CTA derived CS to Cx distance in the device landing zone might be helpful to predict Cx occlusion during Carillon device implantation. Furthermore, CTA predicted CS length but not anchor size correctly. Therefore, CT‐angiographic procedural planning might help improving the results of percutaneous CS‐based mitral valve repair.
Transcatheter edge‐to‐edge repair (TEER) has emerged to address severe mitral and tricuspid valve regurgitation in patients who are at high perioperative risk for open‐heart surgery. No clinical data ...is available for continuous left and right atrial pressure monitoring using the steerable guiding catheter (SGC) during TEER. In a prospective single‐center study, 40 patients with severe mitral (n = 20) or tricuspid (n = 20) regurgitation underwent TEER with the registration of atrial pressure via the SGC. All patients had successful TEER using the PASCAL Ace repair system, while atrial pressure was monitored continuously via the SGC. Simultaneous right or left atrial pressure monitoring via the SGC and a pigtail catheter during mitral and tricuspid TEER showed excellent reliability for SGC pressure registration. While for mitral TEER the beneficial effects of continuous atrial pressure monitoring are well known, we further evaluated the outcome of patients with tricuspid TEER. Echocardiographic and clinical results after tricuspid TEER showed a reduction of quantitative echocardiographic tricuspid regurgitation parameters and improved New York Heart Association classification after 3‐month follow‐up. Also, qualitative tricuspid valve assessment showed improved tricuspid regurgitation classification postimplantation and at 3‐month follow‐up. Furthermore, right atrial pressure was reduced by 37.6% and mean right atrial pressure by 30.6% after successful tricuspid TEER using the PASCAL Ace device. Continuous atrial pressure monitoring using the SGC of the PASCAL Ace repair system is reliable during mitral and tricuspid TEER. Furthermore, successful tricuspid TEER leads to reduced right atrial pressure.
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