Lenard Conradi

Human Engineered Heart Tissue as a Versatile Tool in Basic Research and Preclinical Toxicology

Human embryonic stem cell (hESC) progenies hold great promise as surrogates for human primary cells, particularly if the latter are not available as in the case of cardiomyocytes. However, high content experimental platforms are lacking that allow the function of hESC-derived cardiomyocytes to be studied under relatively physiological and standardized conditions. Here we describe a simple and robust protocol for the generation of fibrin-based human engineered heart tissue (hEHT) in a 24-well format using an unselected population of differentiated human embryonic stem cells containing 30–40% α-actinin-positive cardiac myocytes. Human EHTs started to show coherent contractions 5–10 days after casting, reached regular (mean 0.5 Hz) and strong (mean 100 µN) contractions for up to 8 weeks. They displayed a dense network of longitudinally oriented, interconnected and cross-striated cardiomyocytes. Spontaneous hEHT contractions were analyzed by automated video-optical recording and showed chronotropic responses to calcium and the β-adrenergic agonist isoprenaline. The proarrhythmic compounds E-4031, quinidine, procainamide, cisapride, and sertindole exerted robust, concentration-dependent and reversible decreases in relaxation velocity and irregular beating at concentrations that recapitulate findings in hERG channel assays. In conclusion this study establishes hEHT as a simple in vitro model for heart research.

Echocardiographic and Clinical Outcomes of MitraClip Therapy in Patients Not Amenable to Surgery

OBJECTIVESnThe aim of this study was to assess the outcomes of patients at prohibitive surgical risk undergoing MitraClip therapy (Abbott Vascular, Redwood City, California) for severe mitral regurgitation (MR).nnnBACKGROUNDnThe safety of percutaneous mitral valve repair has been documented. However, midterm development of mitral valve function, ventricular remodeling, and clinical outcomes in patients not amenable to surgery are unknown.nnnMETHODSnA total of 104 consecutive patients (mean age 74 ± 9 years; 64 men; 49 and 54 with MR 3+ and 4+, respectively; 69 with functional MR; 59 and 45 in New York Heart Association classes III and IV, respectively) were followed for a median of 359 days.nnnRESULTSnDevice success was achieved in 96 patients (92%). In patients with successful index procedures, MR grade ≤2+ was present at follow-up in 82.5%, left ventricular end-diastolic and -systolic volumes were reduced, and forward stroke volumes were significantly increased. Improvements in New York Heart Association functional class were observed in 80% of patients, with 69% in class I or II; 75% improved in the 6-min walk test; and 74% reported improvements in quality of life. One-year estimates of mortality and rehospitalization were 22% and 31%, respectively. Forward stroke volume at discharge emerged as a predictor of event-free survival.nnnCONCLUSIONSnMitraClip therapy improves clinical and echocardiographic outcomes at 1 year in about three-quarters of critically ill, elderly patients with moderate to severe MR not amenable to surgery.

Surgical or percutaneous mitral valve repair for secondary mitral regurgitation: comparison of patient characteristics and clinical outcomes.

OBJECTIVESnCorrective surgery for secondary mitral regurgitation (MR) by restrictive annuloplasty has proven beneficial in that it improves New York Heart Association (NYHA) functional class and induces reverse left ventricular remodelling. However, proof of a survival benefit for these patients is still pending. Percutaneous techniques of mitral valve repair (MVR) have become a viable treatment alternative for selected high-risk patients with severe secondary MR.nnnMETHODSnWe retrospectively analysed our prospective hospital database of patients with severe secondary MR undergoing either surgical MVR or percutaneous treatment using the MitraClip device. Patient characteristics and 6-month clinical and effectiveness outcomes are reported.nnnRESULTSnFrom March 2002 through June 2010, 76 patients with secondary MR underwent isolated surgical MVR, while 95 were treated using the MitraClip device at our centre. Patients undergoing MitraClip treatment were significantly older (mean 72.8 ± 8.2 vs 64.5 ± 11.4 years, P < 0.001), had a lower left ventricular ejection fraction (mean 36.2 ± 12.5 vs 42.1 ± 16.2%, P = 0.014) and were generally more high risk, with a significantly higher mean logistic EuroSCORE I compared with surgical candidates (33.7 ± 18.7 vs 10.1 ± 8.7%, P < 0.001). Procedural success was 98.7 (75 of 76) for MVR and 95.8% (91 of 95) for MitraClip treatment (P = 0.383). Thirty-day mortality was 4.2 (4 of 95) and 2.6% (2 of 76; P = 0.557), and the mean grade of residual MR was 1.4 ± 0.8 and 0.2 ± 0.4 (P < 0.001) after MitraClip treatment and surgical MVR, respectively. Six-month survival rates after adjustment for baseline differences were not significantly different in the respective groups (P = 0.642).nnnCONCLUSIONSnIn our experience, characteristics and risk factors of patients with severe secondary MR undergoing surgery differ significantly from those considered for percutaneous therapy. Surgery was more effective compared with MitraClip in reducing MR. However, a large proportion of patients benefits from percutaneous intervention with sustained MR Grade <2+ and improvement in NYHA functional class at 6 months. MitraClip therapy seems to be an adequate alternative to surgery, especially for elderly patients with reduced left ventricular function and relevant comorbidities. Assessment, treatment and postprocedural care of patients by an interdisciplinary team are of paramount importance for clinical success.

Transcatheter valve-in-valve therapy using 6 different devices in 4 anatomic positions: Clinical outcomes and technical considerations

OBJECTIVESnTranscatheter valve-in-valve implantation (ViV) is emerging as a novel treatment option for patients with deteriorated bioprostheses. We report our cumulative experience using 6 types of transcatheter heart valves (THVs) in all anatomic positions.nnnMETHODSnSeventy-five consecutive patients (74.1 ± 12.9 years, 50.7% male (38/75), logEuroSCORE I 26.2% ± 17.8%, STS-PROM 8.8% ± 7.4%) receiving ViV procedures from 2008 to 2014 were included for analysis. Data were prospectively gathered and retrospectively analyzed.nnnRESULTSnViV was performed in aortic (72.0%, 54/75), mitral (22.7%, 17/75), tricuspid (2.7%, 2/75), and pulmonary (2.7%, 2/75) positions. THVs used were Edwards SAPIEN (XT)/SAPIEN3 (52.0%, 39/75), Medtronic Core Valve/Core Valve Evolut(R) (34.7%, 26/75), St Jude Portico (4.0%, 3/75), Boston Scientific Lotus (4.0%, 3/75), Jena Valve (2.7%, 2/75), and Medtronic Engager (2.7%, 2/75). Interval from index procedure to ViV was 9.3 ± 4.9 years. Access was transapical in 53.3% (40/75), transfemoral (transarterial or transvenous) in 42.7% (32/75), transaortic in 2.7% (2/75), and transjugular in 1.3% (1/75). ViV was successful in 97.3% (73/75) with 2 patients requiring sequential THV implantation for initial malpositioning. Overall immediate procedural (≤72 hours) and all-cause 30-day mortality were 2.7% (2/75) and 8.0% (6/75). Corresponding values after aortic ViV were 1.9% (1/54) and 5.6% (3/54). No periprocedural strokes or cases of coronary obstruction occurred. Paravalvular leakage was less than or equal to mild in all cases. After aortic ViV, gradients were max/mean 34.1 ± 14.2/20.1 ± 7.1 mm Hg and effective orifice area (EOA) was 1.5 ± 1.4 cm(2). Corresponding values after mitral ViV were gradients max/mean 14.2 ± 8.2/4.7 ± 3.1 mm Hg and EOA 2.4 ± 0.9 cm(2).nnnCONCLUSIONSnViV can be performed in all anatomic positions with acceptable hemodynamic and clinical outcome in high-risk patients. Increasing importance of ViV can be anticipated considering growing use of surgical bioprostheses.

Review on balloon aortic valvuloplasty: a surgeon’s perspective in 2008

The article by Sack and co-workers published in this issue presents the results of a retrospective study on the treatment of severe calcified aortic stenosis (AS) by means of balloon aortic valvuloplasty (BAV) in the elderly patient. While arguing that BAV should be used in patients unfit for surgical aortic valve replacement (AVR) due to relative contraindications their results reveal widely unfavourable outcomes particularly with regard to survival and mortality rates. In contrast, surgical AVR yields excellent results in the mid- and long-term follow-up even in a high-risk patient population. In the rare case of real contraindications to surgical AVR transcatheter valve implantation techniques seem to be the more adequate alternative today.

Towards an integrated approach to mitral valve disease: implementation of an interventional mitral valve programme and its impact on surgical activity †

OBJECTIVESnTranscatheter-based treatment of valvular heart disease has increasingly been implemented for the treatment of high-risk patients. The impact of these new treatment modalities on surgical valve programmes is unclear at present. We sought to evaluate the impact of an interventional mitral valve programme on surgical mitral valve activity and to assess the risk profiles of the respective patient populations.nnnMETHODSnBetween 2007 and 2011, 1112 patients underwent mitral valve surgery for isolated or combined procedures. An interventional mitral valve programme was initiated in 2008, with 270 patients treated from 2008 to 2011. Data were prospectively entered into a database and retrospectively analysed.nnnRESULTSnFrom 2007 to 2011, surgical mitral valve activity increased by 29.9% compared with a 9.8% increase nationwide (P = 0.09). Compared with the year before the introduction of a MitraClip programme, mean logistic EuroSCORE I of surgical patients was similar in 2011 (2007: 9.4 ± 10.4 vs 2011: 9.5 ± 10.5; P = 0.92), while overall 30-day mortality decreased from 7.2 to 4.4% (P = 0.22). The risk profile of surgical patients decreased significantly regarding several parameters. For isolated mitral valve repair, 30-day mortality was 1.5% (6 of 406) in all patients during the study period. Mean logistic EuroSCORE I of transcatheter patients was significantly higher when compared with that of surgical patients (28.8 ± 18.8 vs 9.5 ± 10.5%; P < 0.01).nnnCONCLUSIONSnSince the implementation of an interventional mitral valve programme, surgical mitral valve activity has increased over the following years. The risk profile of surgical patients decreased regarding several important parameters, although the overall logistic EuroSCORE I remained unchanged. An integrated approach to mitral valve disease with complementary surgical and non-surgical treatment options may possibly help in relieving the undertreatment of patients with severe mitral regurgitation.

Best way to revascularize patients with main stem and three-vessel lesions. Patients should be operated!

Despite established guidelines for the treatment of coronary artery disease (CAD) by either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), everyday clinical practice has proven to differ substantially with even the most complex coronary lesions being targeted by PCI today. However, an abundancy of clinical trials, both observational and randomized has proven the superiority of coronary surgery over PCI in almost every type of multivessel or left main CAD in symptomatic patients. This holds true also for ‘hard’ endpoints like cardiac death or myocardial infarction as recently demonstrated by the landmark SYNTAX trial. These results have lead to the wording of appropriateness criteria, which integrate current guidelines, evidence from clinical trials and interdisciplinary expert opinion and which express essentially the same message as the SYNTAX trial: “CABG remains the standard of care for patients with three-vessel or left main coronary artery disease” (Serruys et al. in N Engl J Med 360:961–972, 2009).

Spontaneous Formation of Extensive Vessel-Like Structures in Murine Engineered Heart Tissue.

Engineered heart tissue (EHT) from primary heart cells contains endothelial cells (ECs), but the extent to which ECs organize into vessel-like structures or even functional vessels remains unknown and is difficult to study by conventional methods. In this study, we generated fibrin-based mini-EHTs from a transgenic mouse line (Cdh5-CreERT2 × Rosa26-LacZ), in which ECs were specifically and inducibly labeled by applying tamoxifen (EC(iLacZ)). EHTs were generated from an unpurified cell mix of newborn mouse hearts and were cultured under standard serum-containing conditions. Cre expression in 15-day-old EHTs was induced by addition of o-hydroxytamoxifen to the culture medium for 48 h, and ECs were visualized by X-gal staining. EC(iLacZ) EHTs showed a dense X-gal-positive vessel-like network with distinct tubular structures. Immunofluorescence revealed that ECs were mainly associated with cardiomyocytes within the EHT. EC(iLacZ) EHT developed spontaneous and regular contractility with forces up to 0.1 mN. Coherent contractility and the presence of an extensive vessel-like network were both dependent on the presence of animal sera in the culture medium. Contractile EC(iLacZ) EHTs successfully served as grafts in implantation studies onto the hearts of immunodeficient mice. Four weeks after implantation, EHTs showed X-gal-positive lumen-forming vessel structures connected to the host myocardium circulation as they contained erythrocytes on a regular basis. Taken together, genetic labeling of ECs revealed the extensive formation of vessel-like structures in EHTs in vitro. The EC(iLacZ) EHT model could help simultaneously study biological effects of compounds on cardiomyocyte function and tissue vascularization.