Treatment of late paravalvular regurgitation after transcatheter aortic valve implantation: prognostic implications.

AIMS: Paravalvular regurgitation (PVR) after transcatheter aortic valve implantation (TAVI) is associated with increased morbidity and mortality. The effect of transcatheter interventions to treat PVR after the index TAVI was investigated. METHODS AND RESULTS: A registry of consecutive patients who underwent transcatheter intervention for ≥ moderate PVR after the index TAVI at 22 centers. The principal outcomes were residual aortic regurgitation (AR) and mortality at 1 year after PVR treatment. A total of 201 patients were identified: 87 (43%) underwent redo-TAVI, 79 (39%) plug closure, and 35 (18%) balloon valvuloplasty. Median TAVI-to-re-intervention time was 207 (35; 765) days. The failed valve was self-expanding in 129 (63.9%) patients. The most frequent devices utilized were a Sapien 3 valve for redo-TAVI (55, 64%), an AVP II as plug (33, 42%), and a True balloon for valvuloplasty (20, 56%). At 30 days, AR ≥ moderate persisted in 33 (17.4%) patients: 8 (9.9%) after redo-TAVI, 18 (25.9%) after plug, and 7 (21.9%) after valvuloplasty (P = 0.036). Overall mortality was 10 (5.0%) at 30 days and 29 (14.4%) at 1 year: 0, 8 (10.1%), and 2 (5.7%) at 30 days (P = 0.010) and 11 (12.6%), 14 (17.7%), and 4 (11.4%) at 1 year (P = 0.418), after redo-TAVI, plug, and valvuloplasty, respectively. Regardless of treatment strategy, patients in whom AR was reduced to ≤ mild had lower mortality at 1 year compared with those with AR persisting ≥ moderate [11 (8.0%) vs. 6 (21.4%); P = 0.007]. CONCLUSION: This study describes the efficacy of transcatheter treatments for PVR after TAVI. Patients in whom PVR was successfully reduced had better prognosis. The selection of patients and the optimal PVR treatment modality require further investigation.

Tako-Tsubo Cardiomyopathy during a series of Electroconvulsive Therapy (ECT) applications: A case report, systematic literature research and discussion of specific risk factors.

BACKGROUND: Tako-Tsubo Cardiomyopathy (TTC) is an acute, reversible disease of the myocardium. It seems to be caused by an excess of epinephrine, norepinephrine and dopamine. Psychological or physiological stress is considered as a risk factor. Several cases of Tako-Tsubo cardiomyopathy in the context of seizures and electroconvulsive therapy have been reported. METHODS: We describe the case of a 63-year-old patient who developed TTC during a second series of ECT applications with etomidate anaesthesia and continued antidepressant medication with tranylcypromine. Potential pathophysiological correlations are discussed on the basis of the available literature. Given the increased risk of TTC recurrence, the question on reinitiation of ECT treatment after remission of the heart disease is also addressed. RESULTS: At least in theory, depressive disorders, ECT applications with seizures, the application of the anaesthetic etomidate, as well as tranylcypromine treatment may all be causally related to the development of TTC. Etomidate is known to interfere with cortisol synthesis, resulting in sympathomimetic and pro-inflammatory effects. To date, 19 cases of TTC in conjunction with ECT applications have been published. As in our patient, ECT was reinitiated successfully without complications in eight of them. DISCUSSION: ECT-related TTC seems to be caused by multiple factors. Circumstantial evidence in our case as well as published data does not support the conclusion that a single risk factor can be held responsible for the development of TTC. Based on theoretical considerations and preliminary findings on a potential role of a relative cortisol deficit, future studies should be encouraged to provide relevant evidence. If careful risk-benefit considerations are done and specific precautions are taken, previous TTC does not exclude reinitiation of ECT.

Transcatheter Mitral Valve Repair via MitraClip in Patients Aged <65 Years: Multicentre 2-year Outcomes.

Background: Transcatheter mitral valve repair (TMVR) using the MitraClip has become a well-established interventional therapy and is usually performed in elderly patients. The objective of this study was to assess 2-year clinical outcomes of TMVR in patients aged <65 years at three heart centres with severe mitral regurgitation (MR) and no surgical options. Methods: A retrospective study analysed data of 36 patients aged <65 years treated with TMVR . All patients were refused surgery by Heart Team decision. Baseline MR was assessed by biplane vena contracta width in two perpendicular views (mean 8.35 ± 1.87 mm). Degenerative MR was detected in 11 patients (30.6%); functional MR was detected in 25 patients (69.4%). Results: Acute procedural success was accomplished in 88.9% of patients. No procedure-related mortality during the first 30 days was detected. Over an average of 2 years of follow-up, all-cause mortality was 19.4% and cardiovascular death was 11.1% owing to advanced heart failure. The average follow-up period was 25.8 months (median was 20 months). Statistically significant difference (p-value <0.01) was detected for N-terminal prohormone of brain natriuretic peptide (pg/ml) at baseline (mean 9,870 ± 10,819; median 7,748) compared to follow-up visits (mean 7,645 ± 11,292; median 3,263). New York Heart Association functional class improvement was achieved in 69% of patients. A second intervention (reclipping) was required in two patients to correct recurrent significant MR. Conclusion: TMVR in patients aged <65 years refused surgical repair provides satisfactory clinical outcomes at 2 years. Future studies should evaluate the outcomes of MitraClip in this population in a larger cohort.

Impact of balloon predilatation in patients with reduced versus preserved ejection fraction during transcatheter aortic valve implantation.

BACKGROUND: Although there is a trend toward direct transcatheter aortic valve implantation (TAVI), still balloon predilatation is necessary in some cases, especially in patients with severe calcification. However, predilatation including rapid ventricular pacing may have adverse outcomes, especially in patients with reduced ejection factor (EF). OBJECTIVE: To evaluate the impact of predilatation on in-hospital outcomes in patients with reduced versus preserved EF underwent TAVI. METHODS: This was a prospective observational study including 110 patients (72 patients with preserved EF (≥50%) and 38 patients with reduced EF (<50%)) who underwent TAVI. The two groups were compared regarding in-hospital outcomes. RESULTS: Predilatation was done routinely in all 110 patients. The mean age was significantly higher in patients with preserved EF (82.76 ± 5.74 vs. 80.13 ± 6.51 years; p = 0.03). The majority (51.4%) of patients with preserved EF were females but the majority (73.7%) of those with reduced EF were males (P < 0.001). Predilatation showed no statistical difference regarding in-hospital mortality (2.6% vs. 1.4%; p = 0.29), hemodynamic instability (5.3% vs. 0.0%; p = 0.11), stroke (0% vs. 1.4%; p = 0.67), conduction defects (13.2% vs. 19.4%; p = 0.29), permanent pacemaker implantation (7.9% vs. 5.5%; p = 0.45), paravalvular leakage (5.3% vs. 2.8%; p = 0.42), vascular complications (7.9% vs. 11.1%; p = 0.43), and acute kidney injury (7.9% vs. 7%; p = 0.4) in patients with reduced versus preserved EF, respectively. CONCLUSION: When balloon predilatation is inevitable during TAVI it is safe in patients with reduced as well as preserved EF with no added risk of hemodynamic instability or other outcomes.

Transcatheter aortic valve-in-valve implantation to treat aortic para-valvular regurgitation after TAVI.

BACKGROUND: Para-valvular regurgitation (PVR) after transcatheter aortic valve (TAV) implantation is associated with increased mortality. Redo-TAVI may be applied to treat PVR, yet with unknown efficacy. We thought to assess redo-TAVI efficacy in reducing PVR using the Redo-TAVI registry (45 centers; 600 TAV-in-TAV cases). METHODS: Patients were excluded if redo-TAVI was done urgently (N = 253), for isolated TAV stenosis (N = 107) or if regurgitation location at presentation remained undetermined (N = 123). The study group of patients with PVR (N = 70) were compared against patients with intra-valvular regurgitation (IVR) (N = 41). Echocardiographic examinations of 67 (60%) patients were reassessed in a core-lab for data accuracy validation. RESULTS: Core-lab examination validated the jet location in 66 (98.5%) patients. At 30 days, the rate of residual AR ≥ moderate was 7 (10%) in the PVR cohort vs. 1 (2.4%) in the IVR cohort, p = 0.137. The rate of procedural success was 53 (75.7%) vs. 33 (80.5%), p = 0.561; procedural safety 51 (72.8%) vs. 31 (75.6%), p = 0.727; and mortality 2 (2.9%) vs. 1 (2.4%), p = 0.896 at 30 days and 7 (18.6%) vs. 2 (11.5%), p = 0.671 at 1 year, respectively. Of patients with residual PVR ≥ moderate at 30 days, 5/7 occurred after implanting balloon-expandable in self-expanding TAV and 2/7 after balloon-expandable in balloon-expandable TAV. CONCLUSIONS: This study puts in perspective redo-TAVI efficacy and limitations to treat PVR after TAVI. Patient selection for this and other therapies for PVR needs further investigation.

Outcomes of Redo Transcatheter Aortic Valve Replacement According to the Initial and Subsequent Valve Type.

BACKGROUND: As transcatheter aortic valve (TAV) replacement is increasingly used in patients with longer life expectancy, a sizable proportion will require redo TAV replacement (TAVR). The unique configuration of balloon-expandable TAV (bTAV) vs a self-expanding TAV (sTAV) potentially affects TAV-in-TAV outcome. OBJECTIVES: The purpose of this study was to better inform prosthesis selection, TAV-in-TAV outcomes were assessed according to the type of initial and subsequent TAV. METHODS: Patients from the Redo-TAVR registry were analyzed using propensity weighting according to their initial valve type (bTAV [n = 115] vs sTAV [n = 106]) and subsequent valve type (bTAV [n = 130] vs sTAV [n = 91]). RESULTS: Patients with failed bTAVs presented later (vs sTAV) (4.9 ± 2.1 years vs 3.7 ± 2.3 years; P < 0.001), with smaller effective orifice area (1.0 ± 0.7 cm2 vs 1.3 ± 0.8 cm2; P = 0.018) and less frequent dominant regurgitation (16.2% vs 47.3%; P < 0.001). Mortality at 30 days was 2.3% (TAV-in-bTAV) vs 0% (TAV-in-sTAV) (P = 0.499) and 1.7% (bTAV-in-TAV) vs 1.0% (sTAV-in-TAV) (P = 0.612); procedural safety was 72.6% (TAV-in-bTAV) vs 71.2% (TAV-in-sTAV) (P = 0.817) and 73.2% (bTAV-in-TAV) vs 76.5% (sTAV-in-TAV) (P = 0.590). Device success was similar according to initial valve type but higher with subsequent sTAV vs bTAV (77.2% vs 64.3%; P = 0.045), primarily because of lower residual gradients (10.3 mm Hg [8.9-11.7 mm Hg] vs 15.2 mm Hg [13.2-17.1 mm Hg]; P < 0.001). Residual regurgitation (moderate or greater) was similar after bTAV-in-TAV and sTAV-in-TAV (5.7%) and nominally higher after TAV-in-bTAV (9.1%) vs TAV-in-sTAV (4.4%) (P = 0.176). CONCLUSIONS: In selected patients, no association was observed between TAV type and redo TAVR safety or mortality, yet subsequent sTAV was associated with higher device success because of lower redo gradients. These findings are preliminary, and more data are needed to guide valve choice for redo TAVR.

Transient repolarization instability following the initiation of cardiac resynchronization therapy.

AIMS: Cardiac resynchronization therapy (CRT) may cause changes in ventricular repolarization (VR), particularly in the initial phase of treatment. This study investigated the effect of CRT cessation and re-initiation on parameters of VR duration and heterogeneity at different paced heart rates. METHODS: Cardiac resynchronization therapy was inactivated for 2 weeks in 16 treatment responders to CRT. QT and JT intervals were measured on the surface electrocardiogram at 60, 70, and 80 bpm (randomized order) and vectorcardiography (VCG) was performed with CRT 'on' (day 0), 'off' (day 0, 1, 7, and 14) and after CRT re-initiation (day 14, 15, 16, and 21). On day 0 ('on') and 14 ('off') echocardiography, the 6 min walking distance and brain natriuretic peptide were assessed. RESULTS: The QT interval at baseline (CRT 'on'), measured at 60, 70, and 80 bpm, was 482 ± 31, 468 ± 37, and 457 ± 39 ms, respectively, and decreased by 5, 5, and 6% during the first week following CRT cessation (all P< 0.05). Immediately after re-initiation on day 14, it increased again by 20 ± 18 (4%; P< 0.05), 34 ± 39 (8%; P< 0.01), and 16 ± 38 ms (4%, ns) followed by a gradual decrease towards previous 'off' levels. Similar changes were observed for the JT interval. Ventricular repolarization duration was significantly shortened by increasing the paced heart rate from 60 to 70 and 80 bpm. Vectorcardiography parameters reflecting VR gradients (ST-vector magnitude, Tarea, and Tavplan) increased significantly (by 31, 45, and 71%) after CRT cessation. A similar but non-significant pattern was observed after CRT re-initiation. CONCLUSION: The increase in repolarization duration and gradients observed after CRT initiation suggests a transient state of VR instability that can be attenuated by programming of higher paced heart rates during the initial phase of treatment.

A safe and simple technique for crossing stenotic aortic valves.

OBJECTIVES: To describe and to validate a new technique for crossing stenotic aortic valves (AV). BACKGROUND: Current techniques for crossing the AV may be time-consuming and hazardous. METHODS: One hundred consecutive patients with severe aortic stenosis treated by transfemoral TAVI were prospectively selected to have an initial attempt of 5 min to cross the AV with a novel pigtail/J-wire technique before switching to the conventional Amplatz®/straight wire approach. For the pigtail/J-wire technique, the catheter is placed 3-4 cm above the AV and turned anteriorly in the 30° RAO view. A J-wire pushed out of the pigtail-catheter will reach the anterior wall of the ascending aorta, forming a u-shaped curve above the AV. The height of the pigtail catheter determines the width of the curve, rotation will help to find an orientation, where the vertex of the curved J-wire easily passes the AV. We analyzed the primary success rate within 5 min and the mean crossing time required. RESULTS: Patients were 83.5 ± 5.5 years of age and predominantly male (62%). Primary success rate was 86%, AV crossing took 48.2 ± 34.6 s without complications. Fourteen failed cases were successfully managed with AL1- (6) and both, AL1- and AL2-catheters (8), respectively CONCLUSIONS: The pigtail/J-wire technique for AV crossing is safe, simple and fast. Primary placement of a pigtail catheter into the left ventricle at a success rate of 86% facilitates TAVI procedures.

Transcatheter Replacement of Transcatheter Versus Surgically Implanted Aortic Valve Bioprostheses.

BACKGROUND: Surgical aortic valve replacement and transcatheter aortic valve replacement (TAVR) are now both used to treat aortic stenosis in patients in whom life expectancy may exceed valve durability. The choice of initial bioprosthesis should therefore consider the relative safety and efficacy of potential subsequent interventions. OBJECTIVES: The aim of this study was to compare TAVR in failed transcatheter aortic valves (TAVs) versus surgical aortic valves (SAVs). METHODS: Data were collected on 434 TAV-in-TAV and 624 TAV-in-SAV consecutive procedures performed at centers participating in the Redo-TAVR international registry. Propensity score matching was applied, and 330 matched (165:165) patients were analyzed. Principal endpoints were procedural success, procedural safety, and mortality at 30 days and 1 year. RESULTS: For TAV-in-TAV versus TAV-in-SAV, procedural success was observed in 120 (72.7%) versus 103 (62.4%) patients (p = 0.045), driven by a numerically lower frequency of residual high valve gradient (p = 0.095), ectopic valve deployment (p = 0.081), coronary obstruction (p = 0.091), and conversion to open heart surgery (p = 0.082). Procedural safety was achieved in 116 (70.3%) versus 119 (72.1%) patients (p = 0.715). Mortality at 30 days was 5 (3%) after TAV-in-TAV and 7 (4.4%) after TAV-in-SAV (p = 0.570). At 1 year, mortality was 12 (11.9%) and 10 (10.2%), respectively (p = 0.633). Aortic valve area was larger (1.55 ± 0.5 cm2 vs. 1.37 ± 0.5 cm2; p = 0.040), and the mean residual gradient was lower (12.6 ± 5.2 mm Hg vs. 14.9 ± 5.2 mm Hg; p = 0.011) after TAV-in-TAV. The rate of moderate or greater residual aortic regurgitation was similar, but mild aortic regurgitation was more frequent after TAV-in-TAV (p = 0.003). CONCLUSIONS: In propensity score-matched cohorts of TAV-in-TAV versus TAV-in-SAV patients, TAV-in-TAV was associated with higher procedural success and similar procedural safety or mortality.

Repeat Transcatheter Aortic Valve Replacement for Transcatheter Prosthesis Dysfunction.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) use is increasing in patients with longer life expectancy, yet robust data on the durability of transcatheter heart valves (THVs) are limited. Redo-TAVR may play a key strategy in treating patients in whom THVs fail. OBJECTIVES: The authors sought to examine outcomes following redo-TAVR. METHODS: The Redo-TAVR registry collected data on consecutive patients who underwent redo-TAVR at 37 centers. Patients were classified as probable TAVR failure or probable THV failure if they presented within or beyond 1 year of their index TAVR, respectively. RESULTS: Among 63,876 TAVR procedures, 212 consecutive redo-TAVR procedures were identified (0.33%): 74 within and 138 beyond 1 year of the initial procedure. For these 2 groups, TAVR-to-redo-TAVR time was 68 (38 to 154) days and 5 (3 to 6) years. The indication for redo-TAVR was THV stenosis in 12 (16.2%) and 51 (37.0%) (p = 0.002) and regurgitation or combined stenosis-regurgitation in 62 (83.8%) and 86 (62.3%) (p = 0.028), respectively. Device success using VARC-2 criteria was achieved in 180 patients (85.1%); most failures were attributable to high residual gradients (14.1%) or regurgitation (8.9%). At 30-day and 1-year follow-up, residual gradients were 12.6 ± 7.5 mm Hg and 12.9 ± 9.0 mm Hg; valve area 1.63 ± 0.61 cm2 and 1.51 ± 0.57 cm2; and regurgitation ≤mild in 91% and 91%, respectively. Peri-procedural complication rates were low (3 stroke [1.4%], 7 valve malposition [3.3%], 2 coronary obstruction [0.9%], 20 new permanent pacemaker [9.6%], no mortality), and symptomatic improvement was substantial. Survival at 30 days was 94.6% and 98.5% (p = 0.101) and 83.6% and 88.3% (p = 0.335) at 1 year for patients presenting with early and late valve dysfunction, respectively. CONCLUSIONS: Redo-TAVR is a relatively safe and effective option for selected patients with valve dysfunction after TAVR. These results are important for applicability of TAVR in patients with long life expectancy in whom THV durability may be a concern.

Transcatheter aortic valve-in-valve implantation in degenerative rapid deployment bioprostheses.

AIMS: The aim of this study was to evaluate transcatheter aortic valve-in-valve (ViV) implantation performance in rapid deployment (ViVr) vs. conventional (ViVc) surgical heart valves. METHODS AND RESULTS: A multicentre registry was developed as part of the VIVID international registry. A total of 30 ViVr patients (Perceval, n=24, ATS 3f Enable™, n=5, and the INTUITY, n=1) were evaluated and compared with 2,288 ViVc patients. Propensity score (PS) matching was performed to adjust further for bias. Compared with ViVc, ViVr patients presented twice as early after surgical heart valve (SHV) implantation (55.2±36.1 vs. 118.4±57.7 months, p<0.001), were more commonly female (82.8% vs. 41.3%, p<0.001), and had shorter body stature and reduced body weight (p<0.05 for both) prior to PS. Implantation was successful in all ViVr cases and, compared with ViVc, was associated with equally favourable haemodynamic outcomes (mean gradient: 14.6±8.3 vs. 16.2±8.9 mmHg, p=0.356; regurgitation ≥mild: 3.7% vs. 5.2%, p=0.793). Periprocedural complication rates were similar and low in both groups. There was no coronary obstruction event in any ViVr case; one patient (3.6%) died during one year of follow-up. CONCLUSIONS: ViVr appears effective, safe and associated with favourable haemodynamic outcome.

Current Generation Balloon-Expandable Transcatheter Valve Positioning Strategies During Aortic Valve-in-Valve Procedures and Clinical Outcomes.

OBJECTIVES: This study sought to evaluate SAPIEN 3 (S3) (Edwards Lifesciences, Irvine, California) positioning using different strategies. BACKGROUND: Aortic valve-in-valve (ViV) is associated with high risk of elevated gradients. METHODS: S3 aortic ViV procedures in stented bioprostheses were studied. Transcatheter heart valve (THV) positioning was analyzed in a centralized core lab blinded to clinical outcomes. A combined endpoint of severely elevated mean gradient (≥30 mm Hg) or pacemaker need was established. Two positioning strategies were compared: central marker method and top of S3 method. Optimal final depth was defined as S3 depth ≤20%. RESULTS: A total of 113 patients met inclusion criteria and were analyzed (76.5 ± 9.7 years of age, 65.8% male, STS score 8 ± 7.6%). THVs had incomplete shortening in comparison to fully expanded valves (92 ± 3.4%), and expansion was more complete in optimal positioning cases compared with others (93.2 ± 2.7% vs. 91.5 ± 3.5%; p = 0.027). The central marker method demonstrated greater correlation with final implantation depth than the top of S3 method (R2 of 0.48 and 0.14; p < 0.001 and p = 0.001, respectively). The combined endpoint rate was 4.3% in the optimal (higher than 3 mm) implantation group, 12% in the intermediate group, and 50% in the low group (p < 0.001). There were no cases of THV embolization. In cases with central marker higher than 3 mm, 72.4% had optimal final depth. In those with central marker higher than 6 mm, 90% had optimal final depth. CONCLUSIONS: Optimal S3 positioning in aortic ViV is associated with better outcomes. Central marker positioning is more reliable than top of S3 positioning. Central marker bottom position should be 3 mm to 6 mm above the ring.

Green tea flavonoid epigallocatechin-3-gallate (EGCG) inhibits cardiac hERG potassium channels.

The catechin EGCG is the main flavonoid compound of green tea and has received enormous pharmacological attention because of its putative beneficial health effects. This study investigated for the first time the effect of EGCG on hERG channels, the main pharmacological target of drugs that cause acquired long QT syndrome. Cloned hERG channels were expressed in Xenopus oocytes and in HEK293 cells. Heterologous hERG currents were inhibited by EGCG with an IC50 of 6.0 micromol/l in HEK293 cells and an IC50 of 20.5 micromol/l in Xenopus laevis oocytes. Onset of effect was slow and only little recovery from inhibition was observed upon washout. In X. laevis oocytes EGCG inhibited hERG channels in the open and inactivated states, but not in the closed states. The half-maximal activation voltage of hERG currents was shifted by EGCG towards more positive potentials. In conclusion, EGCG is a low-affinity inhibitor of hERG sharing major electrophysiological features with pharmaceutical hERG antagonists.

Optimizing implantable cardioverter-defibrillator treatment of rapid ventricular tachycardia: antitachycardia pacing therapy during charging.

BACKGROUND: Previous studies in implantable cardioverter-defibrillator (ICD) patients demonstrated the efficacy and safety of antitachycardia pacing (ATP) for rapid ventricular tachycardias (VT). To prevent shock delay in case of ATP failure, a new feature (ATP during charging) was developed to deliver ATP for rapid VT while charging for shock. OBJECTIVE: The purpose of this study was to determine the efficacy and safety of this new feature. METHODS: In a prospective, nonrandomized trial, patients with standard ICD indication received an EnTrust ICD. VT and ventricular fibrillation (VF) episodes were reviewed for appropriate detection, ATP success, rhythm acceleration, and related symptoms. RESULTS: In 421 implanted patients, 116 VF episodes occurred in 37 patients. Eighty-four (72%) episodes received ATP during or before charging. ATP prevented a shock in 58 (69%) of 84 episodes in 15 patients. ATP stopped significantly more monomorphic (77%) than polymorphic VTs (44%, P = .05). Five (6%) episodes accelerated after ATP but were terminated by the backup shock(s). No symptoms were related to ATP during charging. In four patients, 38 charges were saved by delivering ATP before charging. Of 98 induced VF episodes, 28% were successfully terminated by ATP versus 69% for spontaneous episodes (P <.01). CONCLUSION: Most VTs detected in the VF zone can be painlessly terminated by ATP delivered during charging, with a low risk of acceleration or symptoms. ATP before charging allows delivery of two ATP attempts before shock in the same time that would otherwise be required to deliver only one ATP plus a shock. It also offers potential battery energy savings.

Regulation of cardiac inwardly rectifying potassium current IK1 and Kir2.x channels by endothelin-1.

To elucidate the ionic mechanism of endothelin-1 (ET-1)-induced focal ventricular tachyarrhythmias, the regulation of I(K1) and its main molecular correlates, Kir2.1, Kir2.2 and Kir2.3 channels, by ET-1 was investigated. Native I(K1) in human atrial cardiomyocytes was studied with whole-cell patch clamp. Human endothelin receptors were coexpressed with human Kir2.1, Kir2.2 and Kir2.3 channels in Xenopus oocytes. Currents were measured with a two-microelectrode voltage clamp. In human cardiomyocytes, ET-1 induced a marked inhibition of I(K1) that could be suppressed by the protein kinase C (PKC) inhibitor staurosporine. To investigate the molecular mechanisms underlying this regulation, we studied the coupling of ET(A) receptors to homomeric and heteromeric Kir2.1, Kir2.2 and Kir2.3 channels in the Xenopus oocyte expression system. ET(A) receptors coupled functionally to Kir2.2 and Kir2.3 channels but not to Kir2.1 channels. In Kir2.2 channels lacking functional PKC phosphorylation sites, the inhibitory effect was abolished. The inhibition of Kir2.3 currents could be suppressed by the PKC inhibitors staurosporine and chelerythrine. The coupling of ET(A) receptors to heteromeric Kir2.1/Kir2.2 and Kir2.2/Kir2.3 channels resulted in a strong inhibition of currents comparable with the effect observed in Kir2.2 homomers. Surprisingly, in heteromeric Kir2.1/Kir2.3 channels, no effect was observed. ET-1 inhibits human cardiac I(K1) current via a PKC-mediated phosphorylation of Kir2.2 channel subunits and additional regulatory effects on Kir2.3 channels. This mechanism may contribute to the intrinsic arrhythmogenic potential of ET-1.

QTc prolongation by grapefruit juice and its potential pharmacological basis: HERG channel blockade by flavonoids.

BACKGROUND: A high intake of dietary flavonoids, which are abundant in fruits, vegetables, tea, and wine, is known to reduce cardiovascular mortality. The effects of flavonoids on cardiac electrophysiology, which theoretically may have both antiarrhythmic and proarrhythmic consequences, have not been studied systematically to date. METHODS AND RESULTS: We screened a broad spectrum of flavonoids for their inhibitory activity on HERG channels by using heterologous expression in Xenopus oocytes. At a concentration of 1 mmol/L, 10 compounds caused a significant inhibition of HERG currents, whereas 11 other flavonoids had no effect. The IC50 value for HERG block by naringenin, the most potent inhibitor, was 102.3 micromol/L in Xenopus oocytes and 36.5 micromol/L in HEK cells. To demonstrate the physiological relevance of these findings, we studied the effects of pink grapefruit juice, which contains large amounts of naringenin glycosides (>1000 micromol/L), in human volunteers. In 10 persons, we observed a peak QTc prolongation of 12.5+/-4.2 ms 5 hours after oral ingestion of 1 L of grapefruit juice. This effect was significant (P=0.02). CONCLUSIONS: We found a significant QTc prolongation by grapefruit juice in healthy volunteers, probably caused by block of HERG channels by flavonoids. These findings reveal new perspectives on the potential for dietary modification of cardiac electrophysiology.

Dominant-negative I(Ks) suppression by KCNQ1-deltaF339 potassium channels linked to Romano-Ward syndrome.

OBJECTIVE: Hereditary long QT syndrome (LQTS) is a genetically heterogeneous disease characterized by prolonged QT intervals and an increased risk for ventricular arrhythmias and sudden cardiac death. Mutations in the voltage-gated potassium channel subunit KCNQ1 induce the most common form of LQTS. KCNQ1 is associated with two different entities of LQTS, the autosomal-dominant Romano-Ward syndrome (RWS), and the autosomal-recessive Jervell and Lange-Nielsen syndrome (JLNS) characterized by bilateral deafness in addition to cardiac arrhythmias. In this study, we investigate and discuss dominant-negative I(Ks) current reduction by a KCNQ1 deletion mutation identified in a RWS family. METHODS: Single-strand conformation polymorphism analysis and direct sequencing were used to screen LQTS genes for mutations. Mutant KCNQ1 channels were heterologously expressed in Xenopus oocytes, and potassium currents were recorded using the two-microelectrode voltage clamp technique. RESULTS: A heterozygous deletion of three nucleotides (CTT) identified in the KCNQ1 gene caused the loss of a single phenylalanine residue at position 339 (KCNQ1-deltaF339). Electrophysiological measurements in the presence and absence of the regulatory beta-subunit KCNE1 revealed that mutant and wild type forms of an N-terminal truncated KCNQ1 subunit (isoform 2) caused much stronger dominant-negative current reduction than the mutant form of the full-length KCNQ1 subunit (isoform 1). CONCLUSION: This study highlights the functional relevance of the truncated KCNQ1 splice variant (isoform 2) in establishment and mode of inheritance in long QT syndrome. In the RWS family presented here, the autosomal-dominant trait is caused by multiple dominant-negative effects provoked by heteromultimeric channels formed by wild type and mutant KCNQ1-isoforms in combination with KCNE1.

Lactate accumulation rather than ATP depletion predicts ischemic myocardial necrosis: implications for the development of lethal myocardial injury.

In ischemia, the myocardial metabolic status determines the expansion of necrosis. Decreased ATP levels and increased lactate contents in ischemic myocardium undergoing lethal injury are known to be related to the expansion of irreversible damage. However, their individual contributions have not yet been firmly established. Using two differently effective protocols of ischemic preconditioning (IP short and IP long), ischemic cardioplegic arrest (CP) and their combination (IP+CP) to directly influence the metabolic status of porcine myocardium, graded preservations in ATP content and decreases in lactate accumulation during 45 min ischemia could be achieved (control: ATP, 0.15+/-0.03; lactate, 60.53+/-4.89 micromol/g wet weight; IP short, 0.33+/-0.10/27.42+/-3.90; IP long, 0.60+/-0.10/17.49+/-2.14; CP, 0.98+/-0.12/11.82+/-0.96; IP+CP, 2.24+/-0.28/10.88+/-0.89; all P<0.001 vs. control). At the same time, a graded reduction of myocardial necrosis was observed (90.0+/-3.1 vs. 31.7+/-4.55 vs. 5.05+/-2.1 vs. 0.0 [isolated patchy necroses] vs. none). Regression analysis revealed only a weak correlation of infarct size and ATP preservation (r=0.567). In fact, there was a biphasic relation: with ATP levels above 1 micromol/g wet weight, no infarction occurred. ATP levels below this threshold value were associated with steep increase in infarct size. However, even for this latter range, the regression coefficient remained low (r=0.654). Instead, over the entire range, there was a close, rectilinear correlation of infarct size and lactate accumulation (r=0.939). These data indicate that lactate accumulation rather than ATP depletion determines the development of lethal myocardial injury. However, the biphasic relation between ATP depletion and infarct size suggests the latter to play a permissive role, since above a threshold value of 1 micromol/g wet weight neither substantial lactate accumulation nor infarction was observed. Below this threshold, however, infarct size increased as lactate accumulated.

Patient alert in implantable cardioverter defibrillators: toy or tool?

OBJECTIVES: The purpose of this study was to analyze the utility of patient-alert features in implantable cardioverter defibrillators (ICDs). BACKGROUND: Various alert features producing acoustic warning signals have been implemented in newer generation ICDs, but their role in early detection of system-related complications has not been systematically evaluated. METHODS: In 240 patients implanted with Medtronic ICD devices, the following alert features were routinely activated: pacing lead impedance <200 or >2,000 Omega, high-voltage lead impedance <10 or >200 Omega, low battery voltage (elective replacement indicator), long charge time (>18 s), >3 shocks delivered per episode, and all therapies in a zone delivered. Alert events occurring during follow-up were assessed in relation to actual findings (hospital charts, chest X-rays, ICD printouts including sensing/pacing/defibrillation threshold tests, episode data) to determine incidence, sensitivity, and specificity of the alert function. RESULTS: During 12.2 +/- 8.9 months, 24 alert events occurred in the 240 patients (pacing lead impedance, n = 4; high-voltage lead impedance, n = 7; low battery voltage, n = 1; >3 shocks, n = 6; all therapies, n = 6). A total of 22 serious complications (necessitating reprogramming or device/lead replacement) were observed, 14 of which were primarily identified through a patient alert (lead fracture, n = 11; connector defect, n = 1; T-wave oversensing, n = 1; battery depletion, n = 1). This reflects a sensitivity of 64% and a specificity of 96% of the alert function for serious complications. With 14 of 24 patient alerts being caused by serious complications, the positive predictive value reached 58%. CONCLUSIONS: Patient-alert features are a useful additional tool facilitating early detection of serious ICD complications, but they do not substitute for regular ICD follow-up, because of their low sensitivity.

Inhibition of cardiac HERG channels by grapefruit flavonoid naringenin: implications for the influence of dietary compounds on cardiac repolarisation.

Flavonoids are naturally occurring food ingredients that have been associated with reduced cardiovascular mortality in epidemiological studies. In a previous study, we demonstrated for the first time that flavonoids are inhibitors of cardiac human ether-à-go-go-related gene (HERG) channels. Furthermore, we observed that grapefruit juice induced mild QTc prolongation in healthy subjects. HERG blockade by grapefruit flavonoid naringenin is most likely to be the mechanism underlying this effect. Therefore, the electrophysiological properties of HERG blockade by naringenin were analysed in detail. HERG potassium currents expressed in Xenopus oocytes were measured with a two-microelectrode voltage clamp. Naringenin blocked HERG potassium channels with an IC50 value of 102.6 microM in Xenopus oocytes. The onset of blockade was fast. The effect was completely reversible upon wash-out. Naringenin binding to HERG required aromatic residue F656 in the putative pore binding site. Channels were blocked in the open and inactivated states but not in the closed states. Naringenin did not affect HERG current activation. However, the half maximal inactivation voltage was shifted by 14.9 mV towards more negative potentials and current inactivation at negative potentials was accelerated. No frequency dependence of blockade was observed. Naringenin inhibits HERG channels with pharmacological characteristics similar to those of well-known HERG antagonists. From a clinical point of view, this effect could have both proarrhythmic and antiarrhythmic consequences. This may have important implications for phytotherapy and for dietary recommendations for cardiologic patients. Therefore, electrophysiological effects of flavonoids deserve further investigation.