Andreas Rolf

Clinical Outcome 2 Years After Intracoronary Administration of Bone Marrow–Derived Progenitor Cells in Acute Myocardial Infarction

Background—The aim of this study was to investigate the clinical outcome 2 years after intracoronary administration of autologous progenitor cells in patients with acute myocardial infarction (AMI). Methods and Results—Using a double-blind, placebo-controlled, multicenter trial design, we randomized 204 patients with successfully reperfused AMI to receive intracoronary infusion of bone marrow–derived progenitor cells (BMC) or placebo medium into the infarct artery 3 to 7 days after successful infarct reperfusion therapy. At 2 years, the cumulative end point of death, myocardial infarction, or necessity for revascularization was significantly reduced in the BMC group compared with placebo (hazard ratio, 0.58; 95% CI, 0.36 to 0.94; P=0.025). Likewise, the combined end point death and recurrence of myocardial infarction and rehospitalization for heart failure, reflecting progression toward heart failure, was significantly reduced in the BMC group (hazard ratio, 0.26; 95% CI, 0.085 to 0.77; P=0.015). Intracoronary administration of BMC remained a significant predictor of a favorable clinical outcome by Cox regression analysis when adjusted for classical predictors of poor outcome after AMI. There was no evidence of increased restenosis or atherosclerotic disease progression after BMC therapy nor any evidence of increased ventricular arrhythmias or neoplasms. In addition, regional left ventricular contractility of infarcted segments, as assessed by MRI in a subgroup of patients at 2-year follow-up, was significantly higher in the BMC group compared with the placebo group (P<0.001). Conclusions—Intracoronary administration of BMC is associated with a significant reduction of the occurrence of major adverse cardiovascular events maintained for 2 years after AMI. Moreover, functional improvements after BMC therapy may persist for at least 2 years. Larger studies focusing on clinical event rates are warranted to confirm the effects of BMC administration on mortality and progression of heart failure in patients with AMIs. Clinical Trial Registration—clinicaltrials.gov. Identifier: NCT00279175.

Abnormalities in intracellular Ca2+ regulation contribute to the pathomechanism of Tako-Tsubo cardiomyopathy

AIMS The Tako-Tsubo cardiomyopathy (TTC) is characterized by a transient contractile dysfunction that has been assigned to excessive catecholamine levels after episodes of severe emotional or physical stress. Several studies have indicated that beta-adrenoceptor stimulation is associated with alteration in gene expression of Ca(2+)-regulatory proteins. Thus, the present study investigated the gene expression of crucial proteins [sarcoplasmic Ca(2+) ATPase (SERCA2a), sarcolipin (SLN), phospholamban (PLN), ryanodine receptor (RyR2), and sodium-calcium exchanger (NCX)] involved in the Ca(2+)-regulating system in TTC. METHODS AND RESULTS In 10 consecutive patients, TTC was diagnosed by coronary angiography, ventriculography, and echocardiography. Endomyocardial biopsies were taken during the phase of severely impaired left ventricular (LV) function and after functional recovery. Non-diseased LV tissue from three donor hearts not used for transplantation served as healthy controls. Expression levels of Ca(2+)-regulatory proteins were analysed by means of real-time PCR, western blot, and immunohistochemistry. SLN, predominantly expressed in the atrial component, showed a remarkable ventricular expression in TTC patients. Gene expression of SERCA2a was significantly down-regulated. Conversely, PLN/SERCA2a ratio was increased. For PLN, dephosphorylation was documented using western blot and immunostaining of PLN-Ser(16) and PLN-Thr(17). No changes could be documented for NCX and RyR2. CONCLUSION In TTC, ventricular expression of SLN and dephosphorylation of PLN potentially result in a reduced SERCA2a activity and its Ca(2+) affinity. Thus, the TTC is associated with specific alteration of Ca(2+)-handling proteins, which might be crucial for contractile dysfunction.

Immunohistological basis of the late gadolinium enhancement phenomenon in tako-tsubo cardiomyopathy

AIMS Tako-tsubo cardiomyopathy is characterized by transient contractile dysfunction after emotional or physical stress. Only few patients show late gadolinium enhancement (LGE) in cardiovascular magnetic resonance imaging (MRI). It was the purpose of this study to elucidate the histological basis of this phenomenon. METHODS AND RESULTS The study included 15 patients. Tako-tsubo cardiomyopathy was diagnosed by coronary angiography and ventriculography. Cardiac MRI was performed within 24 h of admission. Endomyocardial biopsies were taken during the acute phase and after recovery. The content of fibrosis was determined by immunohistochemical staining of collagen-1. In the acute phase, cardiac MRI revealed LGE in five patients. This was completely reversed at follow-up [14, inter-quartile range (IQR) 11-14.5 days]. All patients showed a significant increase of collagen-1 compared with control tissue. Moreover, the amount of collagen-1 was significantly higher in LGE positive patients (LGE positive: 18.84, IQR 13.82-19.75 AU/microm(2); LGE negative: 7.57, IQR 5.41-9.19 AU/microm(2), P = 0.001). The presence of LGE was not associated with poorer left ventricular function. CONCLUSION The presence of LGE cannot rule out tako-tsubo cardiomyopathy. Instead it defines a special subgroup of patients with a disproportionate increase of extracellular matrix.

MEDAFI-Trial (Micro-embolization during ablation of atrial fibrillation): comparison of pulmonary vein isolation using cryoballoon technique vs. radiofrequency energy

AIMS Cerebral embolism is a possible serious complication during catheter ablation of atrial fibrillation (AF). The purpose of this prospective pilot study was to analyse the incidence and possible impact of cryo ablation on cerebral lesions and possible differences to radiofrequency (RF) ablation during pulmonary vein isolation (PVI). METHODS AND RESULTS Pulmonary vein isolation was performed in 89 patients, either with the cryoballoon technique (n = 45) or with RF ablation (n = 44). Phenprocoumon was stopped 3 days before intervention and replaced by subcutaneous low-molecular-weight heparin. During the catheter procedure, an infusion of unfractionated heparin was maintained to achieve an activated clotting time (ACT) of > 300 s. Cerebral magnetic resonance imaging scans were performed 1 day before and after PVI, and at 3-month follow-up. Chronic lesions were observed in 11 patients (12.3%) before PVI without statistically significant difference between the two groups. None of the patients had neurological symptoms during or following the procedure. Seven patients (7.9%) developed acute lesions 1 day after PVI, without statistically significant difference between the group treated by cryoenergy (8.9%) and RF ablation (6.8%). Patients with acute lesions were significantly older compared with those without acute cerebral lesions. No additional cerebral lesions during follow-up were observed. CONCLUSION A considerable portion of patients with AF but without any neurological symptoms had chronic cerebral lesions before PVI. Additional acute lesions could be added after the procedure. Both ablation techniques showed additional cerebral acute lesions with no neurological symptoms after PVI.

Use of automatic exposure control in multislice computed tomography of the coronaries: comparison of 16-slice and 64-slice scanner data with conventional coronary angiography

Objective: To evaluate the radiation-dose-reduction potential of automatic exposure control (AEC) in 16-slice and 64-slice multislice computed tomography (MSCT) of the coronary arteries (computed tomography angiography, CTA) in patients. The rapid growth in MSCT CTA emphasises the necessity of adjusting technique factors to reduce radiation dose exposure. Design: A retrospective data analysis was performed for 154 patients who had undergone MSCT CTA. Group 1 (n = 56) had undergone 16-slice MSCT without AEC, and group 2 (n = 51), with AEC. In group 1, invasive coronary angiography (ICA) had been performed in addition. Group 3 (n = 47) had been examined using a 64-slice scanner (with AEC, without ECG-triggered tube current modulation). Results: In group 1, the mean (SD) effective dose (ED) for MSCT CTA was 9.76 (1.84) mSv and for ICA it was 2.6 (1.27) mSv. In group 2, the mean ED for MSCT CTA was 5.83 (1.73) mSv, which signifies a 42.8% dose reduction for CTA by the use of AEC. In comparison to ICA, MSCT CTA without AEC shows a 3.8-fold increase in radiation dose, and the radiation dose of CTA with AEC was increased by a factor of 1.9. In group 3, the mean ED for MSCT CTA was 13.58 (2.80) mSV. Conclusions: This is the first study to show the significant dose-reduction potential (42.8%) of AEC in MSCT CTA in patients. This relatively new technique can be used to optimise the radiation dose levels in MSCT CTA.

Release Kinetics of Circulating Muscle-Enriched MicroRNAs in Patients Undergoing Transcoronary Ablation of Septal Hypertrophy

OBJECTIVES This study sought to evaluate exact release kinetics of microRNAs (miRNAs) in acute myocardial infarction (AMI). BACKGROUND miRNAs may be useful as novel biomarkers in patients with cardiovascular disease, although it is difficult to establish the detailed release kinetics of miRNAs in patients with AMI. METHODS We analyzed the release kinetics of circulating cardiac-specific (miR-21, miR-208a) and muscle-enriched (miR-1, miR-133a) miRNAs using the TaqMan polymerase chain reaction in patients with hypertrophic obstructive cardiomyopathy who were undergoing transcoronary ablation of septal hypertrophy (TASH), a procedure mimicking AMI. Consecutive patients (n = 21) undergoing TASH were included. Serum samples were collected prior to and at 15, 30, 45, 60, 75, 90, and 105 min and 2, 4, 8, and 24 h after TASH. RESULTS Circulating concentrations of miR-1 were significantly increased (>3-fold; p = 0.01) after 15 min, with a peak after 75 min (>60-fold; p < 0.001). The miR-21 concentrations were not increased at any time point. Concentrations of miR-133a were significantly increased at 15 min (2.9-fold; p < 0.001) and reached a plateau between 75 and 480 min (>50-fold change). The miR-208a concentrations were elevated at 105 min (>2-fold; p = 0.01), without a further increase. CONCLUSIONS miR-1, miR-133a, and miR-208a were continuously increased during the first 4 h after the induction of MI. In particular, miR-1 and miR-133a were significantly increased at early time points. These results demonstrate the release kinetics of miRNAs, which are helpful for developing their potential use as biomarkers in patients with acute coronary syndromes.

Activated cell survival cascade protects cardiomyocytes from cell death in Tako-Tsubo cardiomyopathy

Tako‐Tsubo cardiomyopathy (TTC) is characterized by rapid regeneration of contractile dysfunction. From recent studies it is known that excessive catecholamine levels due to emotional or physical stress might play a central role. After sympathetic activation, the PIK3/AKT pathway is a key regulator of many cellular responses, including cytoprotective effects. Thus, the purpose of this study was to investigate whether the PIK3/AKT pathway plays a pivotal role in TTC.

Coronary Computed Tomographic Prediction Rule for Time-Efficient Guidewire Crossing Through Chronic Total Occlusion : Insights From the CT-RECTOR Multicenter Registry (Computed Tomography Registry of Chronic Total Occlusion Revascularization)

OBJECTIVES This study sought to establish a coronary computed tomography angiography prediction rule for grading chronic total occlusion (CTO) difficulty for percutaneous coronary intervention (PCI). BACKGROUND The uncertainty of procedural outcome remains the strongest barrier to PCI in CTO. METHODS Data from 4 centers involving 240 consecutive CTO lesions with pre-procedural coronary computed tomography angiography were analyzed. Successful guidewire (GW) crossing ≤30 min was set as an endpoint to eliminate operator bias. The CT-RECTOR (Computed Tomography Registry of Chronic Total Occlusion Revascularization) score was developed by assigning 1 point for each independent predictor, and then summing all points accrued. Continuous distribution of scores was used to stratify CTO into 4 difficulty groups: easy (score 0); intermediate (score 1); difficult (score 2); and very difficult (score ≥3). Discriminatory performance was tested by 10-fold cross-validation and compared with the angiographic J-CTO (Multicenter CTO Registry of Japan) score. RESULTS Study endpoint was achieved in 55% of cases. Multivariable analysis yielded multiple occlusions, blunt stump, severe calcification, bending, duration of CTO ≥12 months, and previously failed PCI as independent predictors for GW crossing. The probability of successful GW crossing ≤30 min for each group (from easy to very difficult) was 95%, 88%, 57%, and 22%, respectively. Areas under receiver-operator characteristic curves for the CT-RECTOR and J-CTO scores were 0.83 and 0.71, respectively (p < 0.001). Both the original model fit and 10-fold cross-validation correctly classified 77.3% of lesions. CONCLUSIONS The CT-RECTOR score represents a simple and accurate noninvasive tool for predicting time-efficient GW crossing that may aid in grading CTO difficulty before PCI. (Computed Tomography Angiography Prediction Score for Percutaneous Revascularization for Chronic Total Occlusions [CT-RECTOR]; NCT02022878).

Radiation Dose Exposure of Computed Tomography Coronary Angiography - Comparison of Dual Source -, 16 – slice and 64 – slice - CT

Background: Dual-source CT (DSCT) promises a significant reduction of radiation dose exposure for coronary CT angiography (CTA). Large studies on radiation dose estimates are rare. Objective: To compare radiation dose estimates of DSCT with 16- and 64-slice multidetector CT (MDCT) for non-invasive coronary angiography. Patients and design: Retrospective data analysis was performed on 292 patients: 56 patients were examined with 16-slice MDCT, 38 patients with 64-slice MDCT and 202 patients using DSCT. The effective dose (ED) estimates were calculated for all patients from the dose–length product and the conversion factor k (0.017 mSv/mGy/cm), as recommended by current guidelines. Results: The mean (SD) ED for patients examined by 16-slice MDCT was 9.8 (1.8) mSv, for 64-slice MDCT 8.6 (2.8) mSv and for DSCT 11.4 (7.2) mSv. With a protocol of 100 kV tube voltage and 110 ms ECG pulsing window the mean (SD) ED was 3.8 (1.7) mSv for DSCT scanning. When DSCT with a tube voltage of 100 kV was used, a significant inverse correlation between heart rate and radiation dose exposure was found. Conclusions: When standard protocols for coronary CTA with 16-, 64-slice MDCT and DSCT scanners are used, the radiation dose is still high. However, using optimised and individually adjusted protocols low estimated radiation doses can be achieved.

Ischemia triggers BNP expression in the human myocardium independent from mechanical stress

BACKGROUND It is unknown whether the increased B-type natriuretic peptide (BNP) values found in ischemic heart disease are triggered directly by ischemia or whether they are caused indirectly by ischemia through diastolic contractures or regional wall motion abnormalities. Therefore, we investigated the BNP expression in isolated human muscle strips under conditions of ischemia with and without mechanical stress. METHODS Muscle strips (n=90) were isolated from human right atria (n=46). Contractures were induced by oxygen and glucose withdrawal. In 18 muscle strips contractures were prevented by means of butanedione monoxime (BDM). Sarcomere lengths were measured by electron microscopy (n=12). The gene expression and protein amount of BNP were determined and compared to control muscle strips contracting under physiological conditions. RESULTS Hypoxia significantly decreased systolic force and induced diastolic contractures. This mechanical stress could be prevented in the group treated with BDM as evidenced by electron microscopy. Ischemia significantly increased BNP expression in both groups as evidenced by Northern blot analysis and immunohistochemistry. This increase was independent from mechanical stress. CONCLUSION Our results indicate that ischemia is a potent mechanism for the expression of BNP. The increase in BNP expression under ischemic conditions is independent from concomitant mechanical alterations.