Matthias Thielmann

Silent and Apparent Cerebral Ischemia After Percutaneous Transfemoral Aortic Valve Implantation A Diffusion-Weighted Magnetic Resonance Imaging Study

Background— The risk of stroke after transfemoral aortic valve implantation (TAVI) due to dislodgement and subsequent embolization of debris from aortic arch atheroma or from the calcified valve itself ranges between 2% and 10%. The rate of clinically silent cerebral ischemia is unknown but may be even higher. Methods and Results— Thirty-two patients who underwent TAVI with the use of a balloon-expandable (n=22) or self-expandable (n=10) stent valve prosthesis were included in this descriptive study and compared with a historical control group of 21 patients undergoing open surgical aortic valve replacement. Periprocedural apparent and silent cerebral ischemia was assessed by neurological testing and serial cerebral diffusion-weighted magnetic resonance imaging at baseline, at 3.4 (2.5 to 4.4) days after the procedure, and at 3 months. TAVI was successful in all patients. After the procedure, new foci of restricted diffusion on cerebral diffusion-weighted magnetic resonance imaging were found in 27 of 32 TAVI patients (84%) and were more frequent than after open surgery (10 of 21 patients [48%]; P=0.011). These lesions were usually multiple (1 to 19 per patient) and dispersed in both hemispheres in a pattern suggesting cerebral embolization. Volumes of these lesions were significantly smaller after TAVI than after surgery (77 [59 to 94] versus 224 [111 to 338] mm3; P<0.001). There were neither measurable impairments of neurocognitive function nor apparent neurological events during the in-hospital period among TAVI patients, but there was 1 stroke (5%) in the surgical patient group. On 3-month follow-up diffusion-weighted magnetic resonance imaging, there were no new foci of restricted diffusion, and there was no residual signal change associated with the majority (80%) of the foci detected in the periprocedural period. Conclusions— Clinically silent new foci of restricted diffusion on cerebral magnetic resonance imaging were detected in almost all patients (84%) undergoing TAVI. Although typically multiple, these foci were not associated with apparent neurological events or measurable deterioration of neurocognitive function during 3-month follow-up. Further work needs to be directed to determine the clinical significance of these findings in a larger patient population.

One year follow-up of the multi-centre European PARTNER transcatheter heart valve study

Background Transcatheter aortic valve implantation (TAVI) has emerged as a new therapeutic option in high-risk patients with severe aortic stenosis. Aims PARTNER EU is the first study to evaluate prospectively the procedural and mid-term outcomes of transfemoral (TF) or transapical (TA) implantation of the Edwards SAPIEN® valve involving a multi-disciplinary approach. Methods and results Primary safety endpoints were 30 days and 6 months mortality. Primary efficacy endpoints were haemodynamic and functional improvement at 12 months. One hundred and thirty patients (61 TF, 69 TA), aged 82.1 ± 5.5 years were included. TA patients had higher logistic EuroSCORE (33.8 vs. 25.7%, P = 0.0005) and more peripheral disease (49.3 vs. 16.4%, P< 0.0001). Procedures were aborted in four TA (5.8%) and six TF cases (9.8%). Valve implantation was successful in the remaining patients in 95.4 and 96.4%, respectively. Thirty days and 6 months survival were 81.2 and 58.0% (TA) and 91.8 and 90.2% (TF). In both groups, mean aortic gradient decreased from 46.9 ± 18.1 to 10.9 ± 5.4 mmHg 6 months post-TAVI. In total, 78.1 and 84.8% of patients experienced significant improvement in New York Heart Association (NYHA) class, whereas 73.9 and 72.7% had improved Kansas City Cardiomyopathy Questionnaire (KCCQ) scores in TA and TF cohorts, respectively. Conclusion This first team-based multi-centre European TAVI registry shows promising results in high-risk patients treated by TF or TA delivery. Survival rates differ significantly between TF and TA groups and probably reflect the higher risk profile of the TA cohort. Optimal patient screening, approach selection, and device refinement may improve outcomes.

Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial

BACKGROUND Remote ischaemic preconditioning has been associated with reduced risk of myocardial injury after coronary artery bypass graft (CABG) surgery. We investigated the safety and efficacy of this procedure. METHODS Eligible patients were those scheduled to undergo elective isolated first-time CABG surgery under cold crystalloid cardioplegia and cardiopulmonary bypass at the West-German Heart Centre, Essen, Germany, between April, 2008, and October, 2012. Patients were prospectively randomised to receive remote ischaemic preconditioning (three cycles of 5 min ischaemia and 5 min reperfusion in the left upper arm after induction of anaesthesia) or no ischaemic preconditioning (control). The primary endpoint was myocardial injury, as reflected by the geometric mean area under the curve (AUC) for perioperative concentrations of cardiac troponin I (cTnI) in serum in the first 72 h after CABG. Mortality was the main safety endpoint. Analysis was done in intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov, number NCT01406678. FINDINGS 329 patients were enrolled. Baseline characteristics and perioperative data did not differ between groups. cTnI AUC was 266 ng/mL over 72 h (95% CI 237-298) in the remote ischaemic preconditioning group and 321 ng/mL (287-360) in the control group. In the intention-to-treat population, the ratio of remote ischaemic preconditioning to control for cTnI AUC was 0·83 (95% CI 0·70-0·97, p=0·022). cTnI release remained lower in the per-protocol analysis (0·79, 0·66-0·94, p=0·001). All-cause mortality was assessed over 1·54 (SD 1·22) years and was lower with remote ischaemic preconditioning than without (ratio 0·27, 95% CI 0·08-0·98, p=0·046). INTERPRETATION Remote ischaemic preconditioning provided perioperative myocardial protection and improved the prognosis of patients undergoing elective CABG surgery. FUNDING German Research Foundation.

Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol – a clinical trial

Remote ischemic preconditioning (RIPC) of the myocardium by limb ischemia/reperfusion may mitigate cardiac damage, but its interaction with the anesthetic regimen is unknown. We tested whether RIPC is associated with differential effects depending on background anesthesia. Specifically, we hypothesized that RIPC during isoflurane anesthesia attenuates myocardial injury in patients undergoing coronary artery bypass graft (CABG) surgery, and that effects may be different during propofol anesthesia.

Cerebral Embolization During Transcatheter Aortic Valve Implantation A Transcranial Doppler Study

Background— Transcatheter aortic valve implantation (TAVI) is associated with a higher risk of neurological events for both the transfemoral and transapical approach than surgical valve replacement. Cerebral magnetic resonance imaging has revealed more new, albeit clinically silent lesions from procedural embolization, yet the main source and predominant procedural step of emboli remain unclear. Methods and Results— Eighty-three patients underwent transfemoral (Medtronic CoreValve [MCVTF], n=32; Edwards Sapien [ESTF], n=26) and transapical (ESTA: n=25) TAVI. Serial transcranial Doppler examinations before, during, and 3 months after TAVI were used to identify high-intensity transient signals (HITS) as a surrogate for microembolization. Procedural HITS were detected in all patients, predominantly during manipulation of the calcified aortic valve while stent valves were being positioned and implanted. The balloon-expandable ES prosthesis caused significantly more HITS (mean [95% CI]) during positioning (ESTF, 259.9 [184.8–334.9]; ESTA, 206.1[162.5–249.7]; MCVTF, 78.5 [25.3–131.6]; P<0.001) and the self-expandable MCV prosthesis during implantation (MCVTF, 397.1 [302.1–492.2]; ESTF, 88.2 [70.2–106.3]; ESTA, 110.7 [82.0–139.3]; P<0.001). Overall, there were no significant differences between transfemoral and transapical TAVI or between the MCV and ES prostheses. No HITS were detected at baseline or 3-month follow-up. There was 1 major procedural stroke that resulted in death and 1 minor procedural stroke with full recovery at 3-month follow-up in the MCV group. Conclusions— Procedural HITS were detected by transcranial Doppler in all patients. Although no difference was observed between the transfemoral and the transapical approach with the balloon-expandable ES stent valve, transfemoral TAVI with the self-expandable MCV prosthesis resulted in the greatest number of HITS, predominantly during implantation.

Myocardial Dysfunction With Coronary Microembolization: Signal Transduction Through a Sequence of Nitric Oxide, Tumor Necrosis Factor-α, and Sphingosine

Coronary microembolization results in progressive myocardial dysfunction, with causal involvement of tumor necrosis factor-&agr; (TNF-&agr;). TNF-&agr; uses a signal transduction involving nitric oxide (NO) and/or sphingosine. Therefore, we induced coronary microembolization in anesthetized dogs and studied the role and sequence of NO, TNF-&agr;, and sphingosine for the evolving contractile dysfunction. Four sham-operated dogs served as controls (group 1). Eleven dogs received placebo (group 2), 6 dogs received the NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME, group 3), and 6 dogs received the ceramidase inhibitor N-oleoylethanolamine (NOE, group 4) before microembolization was induced by infusion of 3000 microspheres (42-&mgr;m diameter) per milliliter inflow into the left circumflex coronary artery. Posterior systolic wall thickening (PWT) remained unchanged in group 1 but decreased progressively in group 2 from 20.6±4.9% (mean±SD) at baseline to 4.1±3.7% at 8 hours after microembolization. Leukocyte count, TNF-&agr;, and sphingosine contents were increased in the microembolized posterior myocardium. In group 3, PWT remained unchanged (20.3±2.6% at baseline) with intracoronary administration of L-NAME (20.8±3.4%) and 17.7±2.3% at 8 hours after microembolization; TNF-&agr; and sphingosine contents were not increased. In group 4, PWT also remained unchanged (20.7±4.6% at baseline) with intravenous administration of NOE (19.5±5.7%) and 16.4±6.3% at 8 hours after microembolization; TNF-&agr;, but not sphingosine content, was increased. In all groups, systemic hemodynamics, anterior systolic wall thickening, and regional myocardial blood flow remained unchanged throughout the protocols. A signal transduction cascade of NO, TNF-&agr;, and sphingosine is causally involved in the coronary microembolization-induced progressive contractile dysfunction.

Valve-in-Valve Transcatheter Aortic Valve Implantation for Degenerated Bioprosthetic Heart Valves

OBJECTIVES We sought to analyze outcomes of patients with degenerated surgically implanted bioprosthetic heart valves undergoing valve-in-valve (viv) transcatheter aortic valve implantation (TAVI). BACKGROUND Redo cardiac surgery for degenerated bioprosthetic heart valves is associated with increased risks, particular in elderly patients with comorbidities. For these patients, TAVI may be an attractive, less invasive treatment option. METHODS Data from 47 patients age 64 to 97 years (logistic euroSCORE: 35.0 ± 18.5%) undergoing transfemoral (n = 25) or transapical (n = 22) viv-TAVI for failed bioprosthetic aortic valves 113 ± 65 months after initial surgery at 9 clinical sites in Germany and Switzerland were analyzed. RESULTS Valve-in-valve TAVI was technically successful in all patients, with 2 patients requiring bailout implantation of a second TAVI prosthesis for severe regurgitation during the procedure. There was 1 procedural death as the result of low-output failure. Valvular function after viv-TAVI was excellent with respect to valve competence, but increased transvalvular gradients ≥20 mm Hg were noted in 44% of patients. Vascular access complications occurred in 6 (13%) patients, and 5 (11%) patients required new pacemaker implantation after viv-TAVI. Renal failure requiring dialysis occurred in 4 (9%) patients. Mortality at 30 days was 17% (1 procedural and 7 post-procedural deaths), with 3 of 8 fatalities the result of non-valve-related septic complications. CONCLUSIONS Valve-in-valve TAVI can be performed with high technical success rates, acceptable post-procedural valvular function, and excellent functional improvement. However, in these predominantly elderly high-risk patients with multiple comorbidities, viv-TAVI was associated with 17% mortality, often because of septic complications arising in the post-operative phase.

STAT5 Activation and Cardioprotection by Remote Ischemic Preconditioning in Humans

Rationale: The heart can be protected from infarction by brief episodes of ischemia/reperfusion of a remote organ. Remote ischemic preconditioning (RIPC) by brief arm ischemia/reperfusion has been recruited in patients undergoing coronary artery bypass surgery or percutaneous coronary interventions and during transport to the hospital for acute myocardial infarction. Cardioprotective signaling has been extensively characterized in animal experiments. Objective: To identify cardioprotective signaling by RIPC in humans. Methods and Results: RIPC was induced by 3 cycles of 5 minutes of arm ischemia/5 minutes of reperfusion in patients undergoing coronary artery bypass surgery. Twelve patients each were randomly assigned to undergo RIPC or a sham control procedure. Protection was confirmed by reduced serum troponin I concentrations in patients with RIPC versus control patients. In myocardial biopsies, an array of established cardioprotective proteins was analyzed by Western immunoblotting. The phosphorylation of signal transducer and activator of transcription 5 (STAT5) increased from baseline before ischemic cardioplegic arrest to 10 minutes of reperfusion with RIPC, and STAT5 phosphorylation during reperfusion was greater in patients with RIPC than in control patients. Conclusions: The identification of this unique signaling signature of RIPC will facilitate the development of pharmacological cardioprotection. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01406678.

Interference of propofol with signal transducer and activator of transcription 5 activation and cardioprotection by remote ischemic preconditioning during coronary artery bypass grafting

OBJECTIVE Remote ischemic preconditioning protects the myocardium from ischemia/reperfusion injury. We recently identified protection by remote ischemic preconditioning to be associated with the activation of signal transducer and activator of transcription 5 in left ventricular biopsy specimens of patients undergoing coronary artery bypass grafting during isoflurane anesthesia. Because remote ischemic preconditioning did not protect the heart during propofol anesthesia, we hypothesized that propofol anesthesia interferes with signal transducer and activator of transcription 5 activation. METHODS In a randomized, single-blind, placebo-controlled, prospective study, we analyzed an array of established cardioprotective proteins during propofol anesthesia with or without remote ischemic preconditioning in 24 nondiabetic patients with 3-vessel coronary artery disease. RESULTS Remote ischemic preconditioning (n = 12) compared with no remote ischemic preconditioning (n = 12) failed to decrease the area under the troponin I time curve (273 ± 184 ng/mL × 72 hours vs 365 ± 301 ng/mL × 72 hours; P = .374). Although phosphorylation of several protein kinases was increased from baseline to reperfusion, signal transducer and activator of transcription 5 phosphorylation was not increased and was not different between the remote ischemic preconditioning and no remote ischemic preconditioning groups. CONCLUSIONS Remote ischemic preconditioning during propofol anesthesia did not evoke either signal transducer and activator of transcription 5 activation or cardioprotection, implying interaction of propofol with cardioprotective signaling upstream of signal transducer and activator of transcription 5.

Vascular Access Site Complications after Percutaneous Transfemoral Aortic Valve Implantation

Background and Purpose:Transcatheter aortic valve implantation (TAVI) is a rapidly emerging treatment option for patients with aortic valve stenosis and high surgical risk. Different access routes have been proposed for TAVI including transapical, transsubclavian and transfemoral, with percutaneous transfemoral being the preferred because least invasive and nonsurgical. However, vascular access site complications due to the large-bore delivery catheters remain an important clinical issue, particularly with respect to the elderly patient collective typically considered for TAVI. In the study, the authors analyzed their 4-year TAVI experience with respect to vascular complications and their management in patients undergoing completely percutaneous transfemoral TAVI procedures.Patients and Methods:Since 2006, TAVI was performed in 101 consecutive patients at the West German Heart Center Essen. 33 patients underwent transapical TAVI, eight patients transfemoral TAVI with surgical access or closure, and 60 patients percutaneous transfemoral TAVI using two commercially available prosthetic valve devices.Results:Completely percutaneous TAVI was technically successful in all but one patient with malpositioning in the aortic arch during valve retrieval. There was no intraprocedural death and 30-day mortality was 12% (7/60). Vascular access site complications occurred in 19 patients (32%), necessitating surgical repair in six of them (10%). Complications included retroperitoneal hematoma (n = 2), iliac or femoral artery dissection (n = 10), (pseudo)aneurysm formation (n = 3), and closure device-induced vessel stenosis/ occlusion (n = 6). Of these, 13 cases could be managed either conservatively (n = 5) or by contralateral endovascular treatment (n = 8).Conclusion:Completely percutaneous TAVI has a high acute success rate with low intraprocedural and 30-day mortality. The patient collective appears to be prone to vascular complications which remain an important limitation of this novel technique. Although conservative or endovascular management is possible in the majority of cases, further technological developments are obliged to reduce the vascular complication rate.ZusammenfassungHintergrund und Fragestellung:Die katheterbasierte Aortenklappenimplantation ist eine neue, in der klinischen Routine bereits breit angewandte Therapieoption für Hochrisikopatienten mit kalzifizierter Aortenklappenstenose. Während in der Anfangsphase noch eine chirurgische Freilegung der arteriellen Zugangsgefäße und damit verbunden eine Vollnarkose nötig waren, ist die Durchführung heute in einer rein perkutanen Technik und somit sogar unter Analgosedierung möglich. Aufgrund der großen Kaliber der zur Einführung und zum Vorschieben der Prothese benötigten Schleusen und Katheter birgt diese Prozedur jedoch das Risiko einer Verletzung der arteriellen Zugangsgefäße, insbesondere da diese bei den betroffenen, älteren Patienten häufig atherosklerotische Veränderungen aufweisen. Die vorliegende Untersuchung gibt einen Überblick über die vaskulären Komplikationen und mögliche Managementstrategien an einem Kollektiv von 60 konsekutiven Patienten, bei denen in rein perkutaner Technik eine transfemorale Aortenklappenimplantation durchgeführt wurde.Patienten und Methodik:Seit 2006 wurde am Westdeutschen Herzzentrum Essen bei insgesamt 101 konsekutiven Patienten eine kathetergesteuerte Aortenklappenimplantation durchgeführt, bei 33 Patienten über den transapikalen, bei 68 Patienten über den transfemoralen Zugang. Während bei den initialen acht in transfemoraler Technik behandelten Patienten noch eine chirurgische Freilegung und/oder ein chirurgischer Verschluss der Zugangsgefäße durchgeführt wurde, erfolgte die Implantation der ballonexpandierbaren Edwards-Sapien- (n = 41) und der selbstexpandierbaren CoreValve-Prothese (n = 19) bei de hemofolgenden 60 Patienten in rein perkutaner Technik unter Verwendung von Nahtverschlusssystemen.Ergebnisse:Bis auf eine Fehlpositionierung im Aortenbogen konnten alle Aortenklappenprothesen erfolgreich in rein perkutaner Technik und ohne intraprozeduralen Todesfall implantiert werden. Die 30-Tage-Mortalität betrug 12%. Postinterventionell zeigte sich eine signifikante Verbesserung der Hämodynamik mit Abfall des mittleren transaortalen Druckgradienten von 52 ± 18 auf 13 ± 6 mmHg und einer Zunahme der Klappenöffnungsfläche von 0,6 ± 0,2 auf 1,5 ± 0,3 cm2. Die Rate an vaskulären Komplikationen betrug 32% (19 von 60 Patienten). Die Komplikationen beinhalteten zwei retroperitoneale Hämatome, zehn Dissektionen der Femoral- und Iliakal gefäße, drei Aneurysmabildungen und sechs ver schluss systeminduzierte Komplikationen. In fünf Fällen erfolgte eine konservative Therapie, bei acht Patienten konnte eine katheterinterventionelle Behandlung durchgeführt werden. Eine operative Sanierung war bei sechs Patienten (10%) nötig.Schlussfolgerung:Die transfemorale Aortenklappenimplantation kann heutzutage in rein perkutaner Technik mit einer hohen Erfolgsrate, geringer Mortalität und guten hämodynamischen und klinischen Ergebnissen durchgeführt werden. Vaskuläre Komplikationen sind jedoch noch häufig und stellen eine wichtige Limitation dieser neuen Technik dar. Obwohl ein konservatives oder interventionelles Management dieser Komplikationen in der Regel möglich ist, müssen zukünftige Weiterentwicklungen in besonderem Maße auch auf eine Reduktion der vaskulären Komplikationsrate gerichtet sein.