Performance of implantable loop recorders. Role of R vector and detection algorithms.

INTRODUCTION: We evaluated the performance of implantable loop recorders (ILRs) with different detection algorithms and looked for artifacts and therapeutic consequences and their dependence on patient factors. METHODS AND RESULTS: 586 RevealLinq™ ILRs (first generation (NT): n = 335; second generation with TruRhythm™ (TR): n = 251) were implanted during 2014-2021 (syncope n = 206; embolic stroke of unknown source (ESUS) n = 380). Automatically detected EGM episodes (n = 18,650) were classified as correct or incorrect for asystole (AS), atrial fibrillation (AF) or tachycardia (TA). Incorrect episodes were caused by loss of signal (LO), noise (NO), extrasystole (ES) and T-wave oversensing (TWO). Left directed R axes, lower R-amplitudes and older age were related to artifacts. Results were separated by indication. In ESUS patients TR reduced total median artifact episodes: 0.6 (0-7) vs 0 (0-5) (p < 0.03) and median artifact examination time: 0.3 (0-3.5) vs 0 (0-2.5) (p = 0.03) per patient-year. This benefit is caused by significant reductions in total AS and ES-AS artifacts. The total positive predictive value (PPV) improved only in syncope patients (45 vs 71%, p = 0.002). Accordingly in syncope patients with TR more therapeutic consequences could be established (log rank 0.003). DISCUSSION: Patients R-axis and measured R-amplitudes during implantation predicted artifacts. This should be taken into account during ILR implantation. Total artifacts, AS artifacts and time spent for artifact analysis was reduced by the new TR detection algorithm in ESUS patients, whereas total artifacts remained unchanged in syncope patients despite reduction of AS artifacts. However TR had no effect on AF and TA episode detection and therefore has to be improved.

Slow wall motion rather than electrical conduction delay underlies mechanical dyssynchrony in postinfarction patients with narrow QRS complex.

INTRODUCTION: The mechanism of mechanical dyssynchrony in postinfarction patients with a narrow QRS complex is not defined but essential for cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Left ventricular electrical activation and subsequent wall motion were recorded for 16 patients with ischemic cardiomyopathy during intrinsic rhythm using a modified NOGA electromechanical mapping system. Ten patients presented mechanical dyssynchrony on tissue Doppler imaging, while 6 patients served as control subjects. The local activation time (LAT) was set by the maximum downslope of the unipolar electrogram. Local wall motion time (LMT) was defined as the time needed for the catheter tip to traverse half of its maximum inward deflection during systole. LAT and LMT were measured relative to the onset of the QRS complex. Electrical activation showed a septal-to-lateral pattern in all patients with a mean endocardial activation time of 65 +/- 13 ms. Control subjects exhibited 97.5% of all LMTs <290 +/- 17 ms. Delayed motion areas (cut-off LMT > 300 ms) showed no slowing of conduction. Wall motion time corrected for differences in electrical activation (LMT-LAT) was significantly longer in delayed (289 +/- 34 ms) than in regular (204 +/- 24 ms) motion areas (P = 0.002). Delayed motion segments were hypokinetic on echocardiography and presented a lower maximum inward motion (9.9 +/- 1.1 mm) compared to regular segments (10.9 +/- 1.2 mm) on electromechanical maps (P = 0.004). Viability, however, was preserved with unipolar and bipolar voltage amplitude >7 mV and >1.5 mV for 79% of all delayed motion areas. CONCLUSION: Dyssynchronous segments of an ischemic myocardium show unimpaired local activation but slow wall motion, thereby limiting the benefit of ventricular preexcitation via CRT.

Regional diastolic and systolic function by strain rate imaging for the detection of intramural viability during dobutamine stress echocardiography in a porcine model of myocardial infarction.

The aim of this study was to evaluate diastolic and systolic strain rate measurements for differentiation of transmural/nontransmural infarction during dobutamine stress echocardiography (DSE). An ameroid constrictor was placed around the circumflex artery in 23 pigs inducing chronic vessel occlusion. Five pigs without constrictor served as controls. During high-dose DSE systolic strain rates (SR(sys)), systolic and postsystolic strain values (epsilon(sys), epsilon(ps)) and early and late diastolic strain rates (SR(E) and SR(A)) were determined. At week 6, animals were evaluated regarding myocardial fibrosis. Histology revealed nontransmural in 14 and transmural infarction in 9 animals. In controls, dobutamine induced a linear increase of SR(sys) to 12.3 + or - 0.4 s(-1) at 40 microg/kg per minute (P = 0.001) and a linear decrease of SR(E) to -6.6 + or - 0.3 s(-1) (P = 0.001). In the nontransmural group, SR(sys), epsilon(sys), epsilon(ps) at rest, and during DSE were higher and SR(E) was lower than in the transmural infarction group (P = 0.01). Best predictors for viability were SR(sys) (ROC 0.96, P = 0.0003), SR(E) at 10 microg/kg per minute dobutamine stimulation (ROC 0.94, P = 0.001) and positive SR values during isovolumetric relaxation at 40 microg/kg per minute dobutamine (ROC 0.86, P = 0.004). The extension of fibrosis correlated with SR(sys) at rest, epsilon(sys) at rest, and SR(E) at rest (P < 0.001). For the detection of viability similar diagnostic accuracies of SR(E) and SRsys were seen (sensitivity 93%/93%, specificity 96%/94%, respectively). Diastolic SR analysis seems to be equipotent for the identification of viable myocardium in comparison to systolic SR parameters and allows the differentiation of nontransmural from transmural myocardial infarction with high diagnostic accuracy. (Echocardiography 2010;27:552-562).

Endocardial electrogram analysis after intramyocardial injection of mesenchymal stem cells in the chronic ischemic myocardium.

BACKGROUND: Cell injection therapies have been introduced for the treatment of patients with coronary heart disease. However, intramyocardial injection of bone marrow (BM)-derived cells may generate proarrhythmogenicity. METHODS: Two weeks after the placement of a circumflex artery-ameroid constrictor, 21 pigs received mesenchymal stem cells (MSC, n = 9), mononuclear (BM)-derived stem cells (MNC, n = 6), and placebo (n = 6) using a electromechanical mapping (EMM)-guided percutaneous transendocardial injection catheter. At week 6, EMM was repeated and the injected areas were analyzed in detail to evaluate local bipolar electrogram fragmentation, duration, and amplitude. Myocardial fibrosis was evaluated by a quantitative histological analysis. RESULTS: At week 6, the injection of MSC or MNC did not increase local electrogram fragmentation (MSC group: 1.4 +/- 0.3 vs. 1.3 +/- 0.2; MNC group: 1.4 +/- 0.2 vs. 1.3 +/- 0.2; P = NS), prolong electrogram duration (MSC group: 27.1 +/- 7.8 ms vs. 23.7 +/- 2.0 ms; MNC group: 27.8 +/- 3.5 ms vs. 26.8 +/- 5.6 ms; P = NS), or decrease bipolar voltages (MSC group 2.7 +/- 0.9 mV vs. 2.8 +/- 1.0 mV; MNC group 2.0 +/- 1.0 mV vs. 1.7 +/- 0.4 mV). From week 2 to week 6, mean left ventricular ejection fraction increased in the MSC group (37.9 +/- 4.2% vs. 45.9 +/- 2.2%; P = 0.039) only. Histological analysis of the ischemic regions revealed 17.6 +/- 5% myocardial fibrosis in the MNC group vs. 13.6 +/- 3.4% MSC vs. 28.7 +/- 8.7% in the control group (P = 0.038 and P = 0.013). No death occurred in any animal after the injection procedure. CONCLUSION: Intramyocardial injection of MSC or MNC do not increase fragmentation and duration of endocardial electrograms in the injected ischemic myocardium but attenuate ischemic damage and therefore may not create an electrophysiological substrate for reentry tachycardias.

Strain rate imaging for functional quantification of the left atrium: atrial deformation predicts the maintenance of sinus rhythm after catheter ablation of atrial fibrillation.

AIMS: The aim of the study was to investigate the atrial myocardial deformation properties using ultrasound strain rate (SR) imaging in patients after catheter ablation of atrial fibrillation (AF) and to compare its prognostic value in maintaining sinus rhythm. METHODS AND RESULTS: A total of 118 patients with AF (74 paroxysmal AF, 44 persistent AF) underwent transthoracic echocardiography with Doppler-derived SR examinations before and after ablation as well as during 3 months of follow-up (FU). Peak SR and strain (S) were measured at each left atrium (LA) segment (septal, lateral, anterior, inferior) during systole (LAs) and at early (LAe) and late diastole (LAa). Clinical and echocardiographic parameters of patients with maintained sinus rhythm during FU were compared with those with recurrent AF and controls (n = 25 patients). Of 118 patients 82 (69%) showed stable sinus rhythm during FU. Atrial myocardial properties after catheter ablation differed significantly in patients with paroxysmal AF (SR-LAs 2.5 s(-1), S-LAs 30%, SR-LAa -2.2 s(-1)) from patients with persistent AF (SR-LAs 2.3 s(-1), S-LAs 25%, SR-LAa -1.9 s(-1)) and controls (SR-LAs 4.1 s(-1), S-LAs 88%, SR-LAa -2.9 s(-1)) (P = 0.011). Best individual predictors of sinus rhythm maintenance were cut-off values of >2.25 s(-1) for septal and inferior SR-LAs and of >19.5% for inferior S-LAs (P < 0.001). LA deformation properties increased in patients with maintained sinus rhythm during FU in contrast to patients with recurrent AF (P = 0.001). CONCLUSION: SR imaging enables the quantitative assessment of the LA function and can be considered as a potential marker of atrial reverse remodelling. Patients with higher atrial S and SR after catheter ablation appear to have a greater likelihood of maintenance of sinus rhythm. This may have further implications for the anticoagulation regime and the risk of cardioembolic complications.

Intramyocardial transplantation of bone marrow-derived stem cells: ultrasonic strain rate imaging in a model of hibernating myocardium.

BACKGROUND: The aim of this study was to evaluate potential cardioprotective effects of bone marrow-derived stem cells in chronic ischemic myocardium regarding strain rate parameters during dobutamine stress echocardiography. METHODS: An ameroid constrictor was placed around the circumflex artery in 23 pigs to induce hibernating myocardium. Pigs received autologous mesenchymal stem cells (auto MSCs), allogeneic MSC (allo MSC), autologous mononuclear cells (auto MNCs), or placebo injections into the ischemic region. During dobutamine stress echocardiography, peak systolic strain rates (SR(sys)) and systolic and postsystolic strain values (epsilon(sys), epsilon(ps)) were determined. The animals were evaluated regarding myocardial fibrosis, neovascularization, apoptosis, and myocardial beta-adrenergic receptor density. RESULTS: The median ejection fraction was reduced in the control group compared with the auto MSC-, allo MSC-, and auto MNC-treated pigs (36.5% vs 46.0% vs 46.0% vs 41.5%; P = .001, respectively). Histopathology revealed a decreased myocardial fibrosis in auto MSC- (16.3%), allo MSC- (11.3%), and auto MNC- (16.7%) treated pigs compared with controls (31.0%; P = .004). The fibrosis and echocardiographic deformation data correlated in the posterior walls: rest peak SR(sys)r = -0.92; epsilon(sys)r = -0.86; 10 microg dobutamine stimulation peak SR(sys)r = -0.88, epsilon(sys), r = -0.87 (P = .0001). CONCLUSION: Endocardial injection of stem cells may induce cardioprotective effects in chronic ischemic myocardium and helps to keep the ischemic myocardium viable.

Stenting of unprotected left main stem stenosis: Results from a German single-centre registry.

OBJECTIVE: To elucidate the influence of drug-eluting stents (DESs) on interventional therapy of de novo unprotected left main stem (LMS) lesions in a hospital with on-site cardiac surgery. METHODS AND RESULTS: A retrospective study of all patients with unprotected LMS angioplasty from 1999 to 2005 was conducted with regard to clinical and procedural data, and follow-up data. Fifty-four patients with unprotected LMS stenosis were treated inter-ventionally. Of these patients, 16 were treated with DESs. Seven patients presented with cardiogenic shock. During their hospital stay, four patients died (all treated with bare metal stents [BMSs], three initially presenting with cardiogenic shock). Follow-up data for 53 patients (98%) were obtained. Median follow-up time was 24 months (25th percentile, 12 months; 75th percentile, 35 months). Survival after nine months was 87% (81% from the BMS-treated group, and 100% from the DES-treated group). Control angiography had been performed in 36 patients (67%). Patients with unprotected LMS with an angiographic follow-up had a higher nine-month survival rate than patients without (36 of 36 patients [100%] versus 10 of 17 patients [59%], respectively; P<0.0001). Target lesion revascularization rate was 19% in both the BMS and the DES groups. Methods of revascularization did not vary significantly between the groups. CONCLUSIONS: In the present study of selected patients with LMS stenosis, the use of DESs showed a low mortality rate but did not have a clear effect on target lesion revascularization rate compared with BMSs. A close follow-up appears to be mandatory to achieve acceptable results.

Design and rationale for the Myocardial Stem Cell Administration After Acute Myocardial Infarction (MYSTAR) Study: a multicenter, prospective, randomized, single-blind trial comparing early and late intracoronary or combined (percutaneous intramyocardial and intracoronary) administration of nonselected autologous bone marrow cells to patients after acute myocardial infarction.

BACKGROUND: Previous data suggest that bone marrow-derived stem cells (BM-SCs) decrease the infarct size and beneficially affect the postinfarction remodeling. METHODS: The Myocardial Stem Cell Administration After Acute Myocardial Infarction Study is a multicenter, prospective, randomized, single-blind clinical trial designed to compare the early and late intracoronary or combined (percutaneous intramyocardial and intracoronary) administration of BM-SCs to patients after acute myocardial infarction (AMI) with reopened infarct-related artery. The primary end points are the changes in resting myocardial perfusion defect size and left ventricular ejection fraction (gated single photon emission computed tomography [SPECT] scintigraphy) 3 months after BM-SCs therapy. The secondary end points relate to evaluation of (1) the safety and feasibility of the application modes, (2) the changes in left ventricular wall motion score index (transthoracic echocardiography), (3) myocardial voltage and segmental wall motion (NOGA mapping), (4) left ventricular end-diastolic and end-systolic volumes (contrast ventriculography), and (5) the clinical symptoms (Canadian Cardiovascular Society [CCS] anina score and New York Heart Association [NYHA] functional class) at follow-up. Three hundred sixty patients are randomly assigned into 1 of 4 groups: group A, early treatment (21-42 days after AMI) with intracoronary injection; group B, early treatment with combined application; group C, late treatment (3 months after AMI) with intracoronary delivery; and group D, late treatment with combined administration of BM-SCs. Besides the BM-SCs therapy, the standardized treatment of AMI is applied in all patients. CONCLUSIONS: The Myocardial Stem Cell Administration After Acute Myocardial Infarction Trial is the first randomized trial to investigate the effects of the combined (intramyocardial and intracoronary) and the intracoronary mode of delivery of BM-SCs therapy in the early and late periods after AMI.

Transesophageal echocardiography: a follow-up tool after catheter ablation of atrial fibrillation and interventional therapy of pulmonary vein stenosis and occlusion.

BACKGROUND: Pulmonary vein stenosis (PVS) has been described as a complication after primary catheter ablation of atrial fibrillation (Afib). The purpose of this study was to evaluate the utility of transesophageal echocardiography (TEE) as follow-up tool after catheter ablation of Afib and interventional therapy of PVS and pulmonary vein occlusion (PVO). METHODS: We report on 28 patients with stenosis (PVS) of 33 pulmonary veins (PVs) and total PVO of 4 veins complicating ablation of Afib assessed by angiography and/or magnetic resonance imaging (MRI). Subsequently, transseptal PV angiograms were performed, followed by recanalization of three totally occluded PVs and balloon dilatation of seven severe PVS (in four cases combined with PV stenting). PVs were analyzed by multiplane TEE in an intraindividual comparison of preablation/preintervention and follow-up measurements of mean and peak flow velocity, velocity time integrals, and diameters. RESULTS: Of a total of 28 patients, 14 had mild PVS (n = 14), 9 had moderate PVS (n = 10), 6 had severe PVS (n = 8), and 4 patients showed totally occluded PVs (n = 4). In multivariate analysis flow velocities and vessel diameters showed significant differences (mild, moderate, and severe PVS and PVO; p = 0.001). Interventional benefits of balloon dilatation (n = 10) and stent implantation (n = 4), as well as in-stent restenosis could be detected (p = 0.014). In all recanalized vessels TEE showed reestablished flow. In occluded PVs no flow was detectable. The TEE vessel diameters correlated with angiography data (r = 0.87) and computed tomography/MRI (r = 0.90). CONCLUSIONS: TEE can be used as a follow-up tool after interventional therapy in patients after catheter ablation and acquired PVS/PVO. Restenosis/in-stent restenosis can be identified by analyzing the vessel diameters and blood flow characteristics.

Tricuspid regurgitation is a predictor of mortality after percutaneous mitral valve edge-to-edge repair.

AIMS: The aim of this study was to determine the impact of tricuspid regurgitation (TR) on mortality after edge-to-edge percutaneous mitral valve repair (PMVR), and also to analyse whether there is a difference in outcome between patients with improvement of TR after PMVR compared to patients without. METHODS AND RESULTS: Out of 197 consecutive patients who underwent PMVR, 139 patients with available follow-up (mean 428±386 days) were included in the study. Concomitant moderate/severe TR was present in 58.3% of patients. Kaplan-Meier analysis showed significantly reduced overall survival for patients with moderate/severe TR, compared to patients with none/mild TR (p=0.003). Cox multivariate regression analysis revealed severe TR at baseline as the strongest independent predictor of mortality (HR 4.367, p=0.003). An improvement of the baseline moderate/severe TR was observed in 45.5% of patients at 30-day follow-up. Patients with no improvement of TR after PMVR had a higher midterm mortality compared to patients in whom TR improved (40.5% versus 11.4%, p=0.005). CONCLUSIONS: More than half of patients undergoing PMVR have concomitant moderate/severe TR, which is associated with a worse outcome. Among predictors of mortality after edge-to-edge PMVR, severe TR at baseline is the most important. Patients with no improvement of TR at 30 days after PMVR have a significantly higher mortality at follow-up.

Percutaneous endocardial injection of erythropoietin: assessment of cardioprotection by electromechanical mapping.

BACKGROUND: Apart from its well-known stimulation of erythropoiesis, erythropoietin (EPO) exhibits angiogenic and anti-apoptotic effects. These cellular protective effects have also been described in experimental acute myocardial infarction models. We investigated the effects of EPO in a porcine model of chronic progressive myocardial ischaemia. METHODS: At weeks 2 and 6 after implantation of a circumflex ameroid constrictor, endocardial electromechanical NOGA system (Biosense Webster, Inc., California, USA) mapping of the left ventricle, coronary and ventricular angiography, as well as echocardiography were performed. Two weeks after ameroid placement, 13 pigs were randomized with 7 pigs receiving 10.000 U EPO and 6 pigs receiving placebo into the ischaemic region using a NOGA guided percutaneous transendocardial injection catheter, MYOSTAR. After 6 weeks, histology (Masson's Trichrome) was analyzed. RESULTS: Endocardial electromechanical mapping showed an increase of mean unipolar voltage (UV) amplitude in the ischaemic myocardial segments in the EPO-treated animals (8.5 mV pre and 10.6 mV post treatment) and a significantly reduced ischaemic surface area compared to the control group (19% vs. 41%) suggesting a decline in ischaemic injury. Echocardiography revealed 2,2 hypokinetic segments of the lateral wall in the EPO group vs. 3,3 in the control groups. The mean ejection fraction was 64% in the EPO group and 55% in the placebo group. Quantitative histological analysis of the ischaemic regions revealed a reduction of myocardial fibrosis (8% vs. 28%) in the EPO group. CONCLUSION: Endocardial EPO injection may induce cardioprotective effects in hibernating myocardium and may attenuate the progression of ischaemic tissue damage.

Reduction of myocardial scar size after implantation of mesenchymal stem cells in rats: what is the mechanism?

The use of a cellular therapy offers a promising approach for the treatment of heart disease. Besides other precursor cells, bone marrow (BM)-derived stem cells were discovered that migrate into ischemic myocardium and participate in myogenesis as well as angiogenesis. A subpopulation of those are the mesenchymal stem cells (MSC), which may be potential candidates for repairing ischemic heart tissue. MSC are easy to prepare and can be used in an autologous strategy. Here we demonstrate the effect of transplanted MSC in our autologous rat model of myocardial injury. BM was isolated from tibiae and femurs of Wistar rats. After 24 h, the adhering MSC were separated, expanded, retrovirally transduced using green fluorescent protein (GFP), and cloned. A cryo-infarct was generated in the rat hearts, and immediately after this the cells were injected into the border zone of the lesion. After a 10-week follow up, the hearts were excised and the myocardial scar areas were measured using computer-guided morphometry. When comparing transplanted rats (n = 8) with control animals (n = 5) treated rats demonstrated a significant reduction in the width (p < 0.05) of the myocardial scar area. The depth of the scars of the cell therapy rats was less extended (p > 0.05) and the myocardium of these animals was thicker than in the controls (p > 0.05). Immunohistochemical analyses revealed neither evidence of MSC transdifferentiation into cardiomyocytes, nor could an increased neovascularization be found. In conclusion, MSC are responsible for a remarkable reduction of the myocardial scar size in the treated animals. But, whether this strategy is directly transferable to the patient suffering from heart disease has to be determined. In addition, the mechanism by which MSC act in the ischemic heart remains to be determined.

Analysis of progenitor cell mobilization and erythropoietin plasma levels in patients with acute myocardial infarction.

BACKGROUND: Experimental results from various animal models and preliminary clinical data have indicated the capacity of bone marrow-derived stem cells to home into infarcted heart tissue and promote cardiac repair. Erythropoietin (EPO) has been shown to increase the number of active endothelial progenitor cells in humans. OBJECTIVE: To determine if mobilization of hematopoietic progenitor cells (CD34-positive [CD34+], CD117+ or CD133+ cells) into peripheral blood represents a physiological reaction during acute myocardial infarction (AMI) and if EPO is involved in the regulation of this process. METHODS: Peripheral blood samples taken from 10 patients with AMI, seven patients with angina pectoris (AP) and five patients without coronary artery disease who underwent coronary angiography (controls) were analyzed for the presence of CD34+, CD117+ or CD133+ cells using flow cytometry. In addition, EPO plasma levels were determined by an ELISA. Samples were drawn between days 1 and 3 and days 4 and 8 after ischemic events. RESULTS: Increased mean values of CD34+ and CD133+ cells were found in patients with either AMI or AP compared with the control group. Subjects with AMI had augmented cell counts of CD117+ and CD34+ progenitor cells compared with patients with AP. EPO levels were higher in patients with AMI or AP compared with the control group. CONCLUSIONS: AMI in humans appears to serve as a stimulus for CD117+ and CD34+ progenitor cell mobilization. Increased EPO levels may play a role in the regulation of this process.

Increased Risk of Cerebral Embolization After Implantation of a Balloon-Expandable Aortic Valve Without Prior Balloon Valvuloplasty.

OBJECTIVES: The purpose of this study was to analyze the effect of transcatheter aortic valve replacement (TAVR) without versus with prior balloon aortic valvuloplasty (BAV) on the risk of cerebral embolization in patients who receive a balloon-expandable valve. BACKGROUND: Avoiding BAV prior to TAVR may simplify the procedure, but the risk of cerebral embolization is currently unknown. METHODS: A total of 87 consecutive high surgical-risk patients with no contraindications for diffusion-weighted magnetic resonance imaging (DW-MRI) were enrolled. Thirty-two patients received a balloon-expandable aortic valve with and 55 patients without BAV. The incidence, number, and volume of new ischemic lesions in DW-MRI performed 2 to 7 days after TAVI were evaluated. RESULTS: Mean age (83.8 ± 5.2 years vs. 82.9 ± 6.8 years) and sex (43.8% vs. 52.7% male) of the patients with versus without BAV, respectively, as well as other demographic and hemodynamic data were not significantly different between both groups. The procedural success rate was 93.5% with and 98.2% without BAV, and procedure duration and contrast volume were significantly lower without BAV. The incidence of new cerebral ischemic lesions in the total cohort was 66.7%. Compared with patients with BAV, those without BAV had a significantly higher total volume of cerebral ischemic lesions (235.4 ± 331.4 mm(3) vs. 89.5 ± 128.2 mm(3); p = 0.01). CONCLUSIONS: The implantation of a balloon-expandable aortic valve without versus with prior BAV, although performed with a shorter procedure time and lower contrast volume, is associated with a significantly higher volume of cerebral ischemic lesions.

Percutaneous, transendocardial injection of bone marrow-derived mononuclear cells in heart failure patients following acute ST-elevation myocardial infarction: ALSTER-Stem Cell trial.

AIMS: Patients with symptomatic heart failure following acute ST-elevation myocardial infarction (STEMI) received transendocardial application of bone marrow-derived mononuclear cells (BMC) to improve left ventricular (LV) function and clinical outcome. METHODS AND RESULTS: Patients (n=12) with LV ejection fraction (EF) <45% and NYHA Class ≥II received NOGA-guided transendocardial injection of BMC into the infarction border zone 17.5±0.8 days following successful interventional revascularisation after STEMI. A matched control group (n=11) was generated from the source data of the previously published LIPSIAbciximab-STEMI trial. Primary and secondary endpoints were derived from comparisons of baseline vs. six-month follow-up cardiac magnetic resonance imaging (CMR) measurements and clinical assessments. Following cell therapy we observed a significant increase of EF (+7.9±1.5%, p=0.001) while the control group showed no change. This effect was driven by a reduction of LV end-systolic volume (ESV) by -27.5±6.5 ml (p=0.001); LV end-diastolic volume (EDV) and scar volu-me remained unchanged. A significant decrease of NYHA Class was found only in the cell therapy group (-0.75 vs. -0.18, p=0.04). Findings were also translated into enhancement of clinical assessments (rehospitalisation for decompensated heart failure, six-minute walk test, NT-proBNP levels). CONCLUSION: The data suggest transendocardial injection of BMC can be used safely in patients with sympto-matic heart failure following acute STEMI. These prospective, preliminary data of a well-characterised, small cohort suggest efficiency compared to routine treatment.

Ablation surgery in patients with persistent atrial fibrillation: an 8-year clinical experience.

OBJECTIVE: This analysis was undertaken to evaluate the results of persistent atrial fibrillation ablation procedures concomitant to open surgery and to identify risk factors for persistent atrial fibrillation recurrence. METHODS: Since 2001, a total of 325 consecutive patients with persistent atrial fibrillation (duration, 0.5-33 years) have undergone persistent atrial fibrillation ablation concomitant to open surgery by creating 2 encircling isolation lesions around the left and right pulmonary veins and a connecting lesion between both with the use of radiofrequency ablation procedures. Patients were restudied at discharge, 3 months, and 3 years after surgery. RESULTS: Survivals at the time of reexamination at discharge, 3 months, and 3 years were 97.8%, 96.2%, and 94.4%, respectively. Stable sinus rhythm could be documented in 72.1%, 73.9%, and 75.6% of surviving patients, respectively. Long-term persistent atrial fibrillation before surgery and a larger left atrium were predictive of postoperative persistent atrial fibrillation return (P<.001). Statistical analysis demonstrated cutoff points of 5 years for persistent atrial fibrillation and 55 mm for left atrium diameter; 89.7% of patients with persistent atrial fibrillation duration of less than 5 years and 84.5% of patients with left atrium size of 55 mm or less were in stable sinus rhythm at late follow-up. Cardiac rhythm at discharge and at 3 months was predictive of long-term rhythm prognosis (P<.001). Age, gender, concomitant diseases (eg, arterial hypertension, diabetes, renal insufficiency, or pulmonary disease), and the underlying cause of heart disease did not significantly influence the postoperative cardiac rhythm. CONCLUSIONS: The duration of persistent atrial fibrillation and the size of the left atrium are the most reliable preoperative variables to predict the success rate of ablation concomitant to open surgery. The probability of reestablishing stable sinus rhythm is excellent when persistent atrial fibrillation duration is short and left atrium size is small.

Stem cell therapy in cardiovascular disorders.

Heart insufficiency remains the leading cause of death despite pharmacological and interventional therapy as well as primary and secondary prevention. Laboratory research on cardiac repair implementing stem cells and progenitor cells has raised great expectations as well as controversies. The potential of diverse progenitor cells to repair damaged heart tissue includes replacement (tissue transplant), restoration (activation of resident cardiac progenitor cells, paracrine effects), and regeneration (stem cell engraftment forming new myocytes). Based on promising experimental results clinical trials including several hundreds of patients with ischemic heart disease have been initiated using mostly bone marrow-derived cells. Probably, due to a lack of standardization of cell isolation and delivery methods these trials showed controverse results regarding effectiveness. However, significant therapeutic regeneration of human myocardium could not be proven until now. Several issues are at debate concerning the translation of the experimental data into the clinic discussing the adequate cell type, dosing, timing, and delivery mode of myocardial stem cell therapy. This review focuses on the potential and clinical translation of cell based therapies in cardiovascular disease.

Potential and clinical utility of stem cells in cardiovascular disease.

The recent identification of bone marrow-derived adult stem cells and other types of stem cells that could improve heart function after transplantation have raised high expectations. The basic mechanisms have been studied mostly in murine models. However, these experiments revealed controversial results on transdifferentiation vs transfusion of adult stem cells vs paracrine effects of these cells, which is still being debated. Moreover, the reproducibility of these results in precisely translated large animal models is still less well investigated. Despite these weaknesses results of several clinical trials including several hundreds of patients with ischemic heart disease have been published. However, there are no solid data showing that any of these approaches can regenerate human myocardium. Even the effectiveness of cell therapy in these approaches is doubtful. In future we need in this important field of regenerative medicine: i) more experimental data in large animals that are closer to the anatomy and physiology of humans, including data on dose effects, comparison of different cell types and different delivery routes; ii) a better understanding of the molecular mechanisms involved in the fate of transplanted cells; iii) more intensive research on genuine regenerative medicine, applying genetic regulation and cell engineering.

Limited immune-modulating activity of porcine mesenchymal stromal cells abolishes their protective efficacy in acute kidney injury.

We demonstrated previously that administration of mesenchymal stromal cells (MSCs) after renal ischemia/reperfusion injury (IRI) in rats protected renal function and hastened repair through complex paracrine mechanisms. Here we investigated kidney-protective actions of MSCs in a porcine IRI model that may have relevance to human acute kidney injury (AKI). Groups of female pigs with bilateral IRI were infused with autologous or male allogeneic MSCs. No acute or late complications were observed, but unexpectedly, MSC therapy also had no beneficial effects on kidney function and histology. In vitro, we demonstrated substantial functional and phenotypic overlaps between rodent, human, and porcine MSCs, all of which exhibited trilineage differentiation, characteristic antigen profiles, and secretion of renoprotective vascular endothelial growth factor (VEGF)-A and insulin-like growth factor-1 (IGF-1). However, in striking contrast to human MSCs, porcine MSCs failed to inhibit the mixed lymphocyte reaction (MLR) and induced robust production of proinflammatory interleukin-6 (IL-6). In summary, in contrast to rodent models, treatment of porcine IRI with MSCs was not kidney-protective. This, we conclude, is due to the fact that porcine MSCs exert inadequate immune-modulating effects, further demonstrating that successful therapy of IRI with MSCs critically depends on their anti-inflammatory actions. As a consequence, treatment of AKI with MSCs is not informative regarding the investigation of the underlying mechanisms in this large animal model. We expect, however, that the treatment of human IRI of the kidney with immune-modulating MSCs will be as effective as in rodent models.

Transplantation of bone marrow-derived stem cells improves myocardial diastolic function: strain rate imaging in a model of hibernating myocardium.

BACKGROUND: The aim of this study was to evaluate the cardioprotective effects of bone marrow-derived stem cells on myocardial compliance in a chronic ischemia model regarding strain rate (SR) parameters during dobutamine stress echocardiography (DSE). METHODS: Ameroid constrictors were placed around the circumflex arteries of 23 domestic pigs to induce chronic vessel occlusions. Fifteen pigs received transendocardially bone marrow derived stem cells, and 8 received placebo injections (a 0.9% solution of NaCl) into the ischemic region. At week 6, the animals were evaluated regarding myocardial fibrosis, neovascularization, apoptosis, and diastolic function during DSE. RESULTS: Stem cell-injected hearts showed significantly less fibrosis, higher ejection fractions, significant neovascularization, and less ventricular dilatation than controls (P < .05). Strain rate imaging revealed improved diastolic function, with higher early diastolic SR values and lower E/Ea ratios compared with controls (P < .05). Early diastolic SR during DSE identifies viable myocardium (extent of fibrosis, r = 0.86, P = .0001). CONCLUSION: The endocardial injection of stem cells improves diastolic function in chronic ischemic myocardium and helps attenuate postinfarction remodeling.