General Anesthesia Leads to Underestimation of Regurgitation Severity in Patients With Secondary Mitral Regurgitation Undergoing Transcatheter Mitral Valve Repair.

OBJECTIVES: To evaluate the effect of general anesthesia (GA) on severity of mitral regurgitation (MR) in patients undergoing transcatheter mitral valve repair (TMVR). DESIGN: Retrospective cohort study. SETTING: Tertiary care university hospital. PARTICIPANTS: Fifty consecutive patients with symptomatic severe MR and extremely high surgical risk. INTERVENTION: TMVR under GA. MEASUREMENTS AND RESULTS: Transesophageal echocardiography was performed during the preprocedural workup under conscious sedation and during TMVR under GA. After the parameters of MR were assessed, color-flow jet area (CJA), vena contracta (VC), effective regurgitant orifice area (EROA), regurgitant volume (RVOL), three-dimensional (3D) vena contracta area (VCA), and severity of MR were compared between the two examinations. In patients with primary MR (n = 11), there were no significant differences in CJA, VC, EROA, RVOL, or 3D-VCA between pre- and intraprocedural transesophageal echocardiography. In patients with secondary MR (n = 39), GA led to significant decreases of CJA (10 ± 7 v 7 ± 3 cm², p < 0.001), VC (5.5 ± 1.6 v 4.7 ± 1.5 mm, p = 0.002), EROA (30 ± 11 v 24 ± 10 mm², p < 0.001), and RVOL (47 ± 17 v 34 ± 13 mL/beat, p < 0.001). Consequently, GA led to a downgrade of regurgitation severity classification in 44% of patients when assessed by two-dimensional analysis. When evaluated by 3D analysis, GA also led to a significant but less extensive decrease of MR (3D-VCA: 66 ± 27 v 60 ± 29 mm², p = 0.002), and subsequent downgrade of MR classification in 20% of patients. CONCLUSIONS: GA underestimates regurgitation severity in patients with secondary, but not primary MR, undergoing TMVR. This effect must be considered when evaluating the immediate result of the procedure.

Hemodynamic support with Impella ventricular assist device in patients undergoing TAVI: A single center experience.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has become a well-established therapeutic option for patients with severe aortic stenosis (AS) at high to intermediate surgical risk. Although TAVI is associated with low mortality of 1.2-6.5%, cardiogenic shock (CS) as a peri-interventional complication remains a challenging problem with very high morbidity and mortality. AIM: This study evaluated the clinical outcome of the use of Impella ventricular assist device in patients undergoing TAVI. METHODS: Between 11/2015 and 08/2018, all patients undergoing TAVI requiring temporary circulatory during the same index hospitalization were included. Primary endpoint was 30-day all-cause mortality. Secondary endpoints were peri-interventional mortality and 30-day stroke rate. RESULTS: Of the 390 patients undergoing TAVI, 13 (3%) required hemodynamic support with an Impella device. Of these, 3 (23%) underwent protected high-risk PCI before TAVI and 10 patients (77%) needed emergency periprocedural hemodynamic support due to cardiogenic shock. Mortality at 30 days was 0% in Impella-protected PCI and 40% with Impella use for periprocedural CS. No stroke occurred in the cohort up to 30 days. Insertion of the Impella device in the setting of TAVI was fast with a mean insertion time of 10 min. Eight patients (80%) in the periprocedural CS group required cardiopulmonary resuscitation prior to Impella use. There was only one device-related complication. CONCLUSIONS: Temporary hemodynamic support with the Impella device in patients with severe aortic valve stenosis or in CS secondary to complicated TAVI was technically doable and allowed stabilization and treatment of salvageable patients.

Autoantibodies in dilated cardiomyopathy induce vascular endothelial growth factor expression in cardiomyocytes.

BACKGROUND: Autoantibodies have been identified as major predisposing factors for dilated cardiomyopathy (DCM). Patients with DCM show elevated serum levels of vascular endothelial growth factor (VEGF) whose source is unknown. Besides its well-investigated effects on angiogenesis, evidence is present that VEGF signaling is additionally involved in fibroblast proliferation and cardiomyocyte hypertrophy, hence in cardiac remodeling. Whether autoimmune effects in DCM impact cardiac VEGF signaling needs to be elucidated. METHODS: Five DCM patients were treated by the immunoadsorption (IA) therapy on five consecutive days. The eluents from the IA columns were collected and prepared for cell culture. Cardiomyocytes from neonatal rats (NRCM) were incubated with increasing DCM-immunoglobulin-G (IgG) concentrations for 48 h. Polyclonal IgG (Venimmun N), which was used to restore IgG plasma levels in DCM patients after the IA therapy was additionally used for control cell culture purposes. RESULTS: Elevated serum levels of VEGF decreased significantly after IA (Serum VEGF (ng/ml); DCM pre-IA: 45 ± 9.1 vs. DCM post-IA: 29 ± 6.7; P < 0.05). In cell culture, pretreatment of NRCM by DCM-IgG induced VEGF expression in a time and dose dependent manner. Biologically active VEGF that was secreted by NRCM significantly increased BNP mRNA levels in control cardiomyocytes and induced cell-proliferation of cultured cardiac fibroblast (Fibroblast proliferation; NRCM medium/HC-IgG: 1 ± 0.0 vs. NRCM medium/DCM-IgG 100 ng/ml: 5.6 ± 0.9; P < 0.05). CONCLUSION: The present study extends the knowledge about the possible link between autoimmune signaling in DCM and VEGF induction. Whether this observation plays a considerable role in cardiac remodeling during DCM development needs to be further elucidated.

Electrical stimulation of sympathetic neurons induces autocrine/paracrine effects of NGF mediated by TrkA.

Neuronal remodeling with increased sympathetic innervation density has been implicated in the pathogenesis of atrial fibrillation (AF). Recently, increased transcardiac nerve growth factor (NGF) levels were observed in a canine model of AF. Whether atrial myocytes or cardiac sympathetic neurons are the source of neurotrophins, and whether NGF is the main neurotrophic factor contributing to sympathetic nerve sprouting (SNS) in AF still remains unclear. Therefore, neonatal rat atrial myocytes were cultured under conditions of high frequency electrical field stimulation (HFES) to mimic rapid atrial depolarization. Likewise, sympathetic neurons from the superior cervical ganglia of neonatal rats were exposed to HFES to simulate the physiological effect of sympathetic stimulation. Real-time PCR, ELISA and Western blots were performed to analyze the expression pattern of NGF and neurotrophin-3 (NT-3). Baseline NGF and NT-3 content was 3-fold higher in sympathetic neurons than in atrial myocytes (relative NGF protein expression: 1+/-0.0 vs. 0.37+/-0.11, all n=5, p<0.05). HFES of sympathetic neurons induced a frequency dependent NGF and NT-3 gene and protein up-regulation (relative NGF protein expression: 0Hz=1+/-0.0 vs. 5Hz=1.13+/-0.19 vs. 50Hz=1.77+/-0.08, all n=5, 0Hz/5Hz vs. 50Hz p<0.05), with a subsequent increase of growth associated protein 43 (GAP-43) expression and morphological SNS. Moreover, HFES of sympathetic neurons increased the tyrosine kinase A (TrkA) receptor expression. HFES induced neurotrophic effects could be abolished by lidocaine, TrkA blockade or NGF neutralizing antibodies, while NT-3 neutralizing antibodies had no significant effect on SNS. In neonatal rat atrial myocytes, HFES resulted in myocyte hypertrophy accompanied by an increase in NT-3 and a decrease in NGF expression. In summary, this study provides evidence that high-rate electrical stimulation of sympathetic neurons mediates nerve sprouting by an increase in NGF expression that targets the TrkA receptor in an autocrine/paracrine manner.

Three-year follow-up after treatment of bare-metal stent restenosis with first-generation or second-generation drug-eluting stents.

AIMS: First-generation drug-eluting stents have been proven to be very effective for the treatment of bare-metal stent in-stent restenosis (BMS ISR). Efficacy of second-generation drug-eluting stents in this setting remains less well defined. This study compared 3-year clinical outcomes after treatment of BMS ISR using second-generation everolimus-eluting stents (EES) to first-generation paclitaxel-eluting stents (PES) or sirolimus-eluting stents (SES). METHODS: This was a retrospective observational study. A total of 264 consecutive patients with BMS ISR underwent percutaneous coronary intervention using EES (75 patients), PES (95 patients), or SES (94 patients) from 2003 to 2009. The primary endpoint of the study was survival free of major adverse cardiac events (MACE) at 3 years. Secondary endpoints were survival free of need for revascularization of the target lesion and definite stent thrombosis. Clinical follow-up could be obtained in 99% of patients. RESULTS: Baseline clinical and angiographic parameters were comparable between the three groups. MACE at the 3-year follow-up were 27, 30, and 27%, for the EES, PES, and SES groups, respectively (P=0.874). The target lesion revascularization rates for EES, PES, and SES groups were 15, 20, and 23%, respectively (P=0.429). Rates of definite stent thrombosis at the 3-year follow-up were comparable between the three groups at 0, 2.1, and 1.0%, respectively (P=0.437). Rates of myocardial infarction and death were also similar between the three groups. Diabetes mellitus was the only independent predictor of MACE at the 3-year follow-up (odds ratio=1.14, 95% confidence interval 1.00-1.30; P=0.038), whereas renal insufficiency was the only independent predictor for death (odds ratio=1.10, 95% confidence interval 0.850-1.274; P=0.011). CONCLUSION: Second-generation EES is as effective and safe as the first-generation PES or SES in the treatment of BMS ISR. Diabetes mellitus is the only independent predictor for MACE at the long-term follow-up.

Neurofilament light chain as an early and sensitive predictor of long-term neurological outcome in patients after cardiac arrest.

BACKGROUND: Neurofilament light chain (NF-L) is the major intermediate filament specifically expressed in neurons and their axons. No data are available concerning serum levels of NF-L after global cerebral ischemia due to cardiac arrest. To find a specific neuronal marker of long-term neurological outcome, we examined serum levels of NF-L in patients after cardiac arrest. METHODS: A prospective observational cohort study was conducted. Blood samples for the measurement of NF-L were analyzed from 85 patients within 2h after admission, as well as on 2nd, 3rd, 5th, and 7th day. Neurological outcome was assessed 6 months after cardiac arrest by employing the Modified Glasgow Outcome Score (MGOS). RESULTS: The serum course of NF-L in patients with poor neurological outcome (MGOS 1+2) was significantly augmented compared to patients with good neurological outcome (MGOS 3+4+5) (on admission (pg/ml): good: 125 ± 11.7 vs. poor: 884.4 ± 86.2 pg/ml; 3rd day: good: 153.1 ± 13.2 vs. poor: 854.4 ± 119.1; 7th day: good: 112.5 ± 10.4 vs. poor: 1011.8 ± 100.8; P<0.001). Intermediate NF-L serum values were found in patients with MGOS 0, which represents a mixture of patients who died with and without certified brain damage (on admission (pg/dl): 433.7 ± 49.8; 3rd day: 598.3 ± 86.6; 7th day: 474 ± 77.4). A prediction power of 0.93 (c-statistic, 95%-CI 0.87-0.99) on 1st, 0.85 (0.81-0.95) on 2nd, 0.92 (0.85-0.99) on 3rd, 0.97 (0.92-1) on 5th and 0.99 (0.98-1) on 7th day was achieved for NF-L predicting poor neurological outcome. CONCLUSIONS: The present data suggest that within 7 days after cardiac arrest serum NF-L is a valuable marker of long-term neurological outcome.

The Modified Glasgow Outcome Score for the prediction of outcome in patients after cardiac arrest: a prospective clinical proof of concept study.

The Glasgow-Pittsburgh cerebral performance categories (GP-CPC) and the Glasgow Outcome Score (GOS) have been used to categorize patients according to their neurological outcome for prognostic predictors in patients after cardiac arrest (CA). We postulated that inclusion of deaths without knowing the cerebral status into the group of patients with poor outcome after CA using the GP-CPC and GOS will lead to dilution of the prognostic power of the investigated biochemical marker. The present study was conducted to verify this issue by employing a modified outcome score, which we termed as Modified Glasgow Outcome Score (MGOS). In the present study, 97 patients were enrolled in a prospective manner. Serum NSE and S100B levels were measured daily for 7 days after admission to the intensive care unit. Neurological outcome was assessed by employing the GOS and MGOS after 6 months. By employing the GOS, 46 patients were categorized into the group of patients with poor outcome and 51 patients survived with good neurological outcome. Patients who died without certified brain damage or with unknown cerebral status after CA (n = 20) were separated from patients with poor outcome in the MGOS. The magnitude of NSE (S100B) elevation in patients with poor outcome categorized by the MGOS was approximately 1.7-fold (1.5) higher as compared with patients divided by the GOS. The mean calculated sensitivities and area under the curve values of NSE and S100B predicting poor outcome classified by the MGOS were significantly higher as compared with the GOS. Conclusively, inclusion of deaths without certified brain damage or with unknown cerebral status into the group of patients with poor outcome will lead to underestimation of the prognostic power of investigated biochemical markers such as NSE and S100B. The MGOS will help to avoid this bias.

Everolimus-eluting versus paclitaxel-eluting stents for treatment of bare metal stent restenosis.

First-generation drug-eluting stents have been proved to be very effective for the treatment of bare metal stent in-stent restenosis (BMS ISR). The efficacy of second-generation drug-eluting stents in this setting remains less well defined. The present study compared the long-term clinical outcome after treatment of BMS ISR using the second-generation everolimus-eluting stent (EES) to that after treatment using the paclitaxel-eluting stent (PES). A total of 174 patients with BMS ISR underwent percutaneous coronary intervention using a PES (95 patients) or an EES (79 patients) from 2003 to 2010. The patients in the PES and EES groups were followed up for 42.2 ± 22.2 and 18.3 ± 8.2 months, respectively. The primary end point of the study was survival free of major adverse cardiac events at 1 year. The secondary end points were survival free of the need for revascularization of the target lesion and definite stent thrombosis. The baseline clinical and angiographic parameters were comparable between the 2 groups. The freedom from major adverse cardiac event rate at 1 year of follow-up was 4.5% and 13.6% (p = 0.0663) for the EES and PES groups, respectively. The target lesion revascularization (TLR) rates were greater in the PES group at 1 year of follow-up compared to the EES group (1% vs 11.5%, p = 0.0193). The rate of myocardial infarction, death, and definite stent thrombosis for the EES and PES groups at 1 year of follow-up was 0% versus 4.2% (p = 0.0984), 3% versus 2.1% (p = 0.6855), and 0% versus 2.1% (p = 0.2382), respectively. The use of a PES for treatment of ISR was the only independent predictor of recurrent TLR at 1 year of follow-up (odds ratios 1.11, 95% confidence interval 1.05 to 1.18; p = 0.0193). During the complete follow-up period, the rates of TLR, myocardial infarction, death, major adverse cardiac events, and definite stent thrombosis were not different between the 2 treatment groups. In conclusion, EES resulted in reduced rates of TLR at 1 year of follow-up compared to PES when used for treatment of BMS ISR. However, at long-term follow-up, the event rates between EES and PES were comparable after treatment of BMS ISR.

Mechanical stretch induces nerve sprouting in rat sympathetic neurocytes.

Sympathetic nerve sprouting (SNS) has been shown to occur after myocardial infarction (MI) and heart failure (HF) and is known to be responsible for the development of lethal arrhythmias. During MI or HF intracardiac cells are exposed to increased mechanical stretch. Molecular mechanisms which trigger sympathetic neural growth are largely unknown. Therefore, this study aimed to investigate the impact of mechanical stretch on rat neonatal sympathetic neurocytes of the superior cervical ganglion (SCG). Mechanical stretch resulted in an increased growth of sympathetic neurocytes. Furthermore, we could demonstrate that SCG neurocytes express nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), neurotrophin-3 (NT-3) and glial derived neurotrophic factor (GDNF) on mRNA and protein level. An increased NGF and CNTF expression, a down-regulated GDNF expression and an unchanged NT-3 expression were identified in the neurocyte cell culture supernatant of neurocytes exposed to mechanical stretch. However, neither brain derived neurotrophic factor (BDNF) mRNA and protein was expressed in SCG neurocytes, nor BDNF could be detected in the cell culture supernatant of SCG neurons. By anti-neurotrophin neutralizing experiments NGF and CNTF were identified as important stretch-induced growth-inducing factors. Losartan, an angiotensin-II type 1 receptor inhibitor, abolished the stretch-induced increase of NGF and CNTF expression and thereby prevented the stretch-induced neural growth. This study provides new molecular mechanisms by which the inhibitory effect of angiotensin-II type 1 receptor blockers on the neural/arrhythmogenic remodeling can be explained. However, further in-vivo studies are required to address this important issue.

Acetylcholine as an age-dependent non-neuronal source in the heart.

In the heart, acetylcholine (ACh) slows pacemaker activity, depresses contractility and slows conduction in the atrioventricular node. Beside these cardiovascular effects, ACh has also been associated with an anti-inflammatory and anti-apoptotic pathway. There is no evidence for ACh synthesis and excretion in other cell types than neuronal cells in the heart. Therefore, this study investigates whether cardiomyocytes are able to synthesize, transport and excrete ACh in the heart. We chose a rat model of different aged rats (neonatal, 6-8 week = young, 20-24 month = old). By real-time PCR, Western blot and immunofluorescence experiments we could demonstrate that adult, but not neonatal cardiomyocytes, express the choline acetyltransferase (ChAT). The expression level of ChAT is down-regulated in old cardiomyocytes. Furthermore, we found that young and old cardiomyocytes express the ACh transport proteins choline transporter-1 (CHT-1) and the vesicular acetylcholine transporter (VAChT). The amount of ACh excretion detected by high performance liquid chromatography (HPLC) is significantly down-regulated in old cardiomyocytes. Bromo-acetylcholine (BrACh), a specific ChAT inhibitor, significantly decreased ACh concentrations in cardiomyocyte supernatants demonstrating that ChAT is the main ACh synthesizing enzyme in cardiomyocytes. In conclusion, we could demonstrate that adult, but not neonatal, cardiomyocytes are able to synthesize, transport and excrete ACh in the rat heart. The expression level of ChAT and the ACh excretion amount are significantly down-regulated in old cardiomyocytes. This finding may provide new physiological/pathological aspects in the communication between cardiomyocytes and other cell types in the myocardium, e.g. fibrocytes, neurocytes or endothelial cells.