Gustavo Lopera

Transendocardial Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells for Ischemic Cardiomyopathy: The TAC-HFT Randomized Trial

IMPORTANCE Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial. OBJECTIVE To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy. DESIGN, SETTING, AND PATIENTS A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than 50% (September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n = 11) and BMCs (n = 19) with placebo (n = 10), with 1 year of follow-up. INTERVENTIONS Injections in 10 LV sites with an infusion catheter. MAIN OUTCOMES AND MEASURES Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias. RESULTS No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6% (95% CI, 12.6% to 56.6%) for MSCs, 31.6% (95% CI, 12.6%-56.6%) for BMCs, and 38.1% (95% CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95% CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95% CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95% CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P = .03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9%; 95% CI, -30.4 to -7.4; within-group, P = .004) but not by BMCs (-7.0%; 95% CI, -15.7% to 1.7%; within-group, P = .11) or placebo (-5.2%; 95% CI, -16.8% to 6.5%; within-group, P = .36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95% CI, -13.3 to 3.5; within-group repeated measures, P = .03) but not BMCs (-2.1; 95% CI, -5.5 to 1.3; P = .21) or placebo (-0.03; 95% CI, -1.9 to 1.9; P = .14). Left ventricular chamber volume and ejection fraction did not change. CONCLUSIONS AND RELEVANCE Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00768066.

Intramyocardial Stem Cell Injection in Patients With Ischemic Cardiomyopathy Functional Recovery and Reverse Remodeling

Rationale: Transcatheter, intramyocardial injections of bone marrow–derived cell therapy produces reverse remodeling in large animal models of ischemic cardiomyopathy. Objective: We used cardiac MRI (CMR) in patients with left ventricular (LV) dysfunction related to remote myocardial infarction (MI) to test the hypothesis that bone marrow progenitor cell injection causes functional recovery of scarred myocardium and reverse remodeling. Methods and Results: Eight patients (aged 57.2±13.3 years) received transendocardial, intramyocardial injection of autologous bone marrow progenitor cells (mononuclear or mesenchymal stem cells) in LV scar and border zone. All patients tolerated the procedure with no serious adverse events. CMR at 1 year demonstrated a decrease in end diastolic volume (208.7±20.4 versus 167.4±7.32 mL; P=0.03), a trend toward decreased end systolic volume (142.4±16.5 versus 107.6±7.4 mL; P=0.06), decreased infarct size (P<0.05), and improved regional LV function by peak Eulerian circumferential strain in the treated infarct zone (−8.1±1.0 versus −11.4±1.3; P=0.04). Improvements in regional function were evident at 3 months, whereas the changes in chamber dimensions were not significant until 6 months. Improved regional function in the infarct zone strongly correlated with reduction of end diastolic volume (r2=0.69, P=0.04) and end systolic volume (r2=0.83, P=0.01). Conclusions: These data suggest that transcatheter, intramyocardial injections of autologous bone marrow progenitor cells improve regional contractility of a chronic myocardial scar, and these changes predict subsequent reverse remodeling. The findings support the potential clinical benefits of this new treatment strategy and ongoing randomized clinical trials.

Intramyocardial Stem Cell Injection in Patients With Ischemic Cardiomyopathy

Rationale: Transcatheter, intramyocardial injections of bone marrow–derived cell therapy produces reverse remodeling in large animal models of ischemic cardiomyopathy. Objective: We used cardiac MRI (CMR) in patients with left ventricular (LV) dysfunction related to remote myocardial infarction (MI) to test the hypothesis that bone marrow progenitor cell injection causes functional recovery of scarred myocardium and reverse remodeling. Methods and Results: Eight patients (aged 57.2±13.3 years) received transendocardial, intramyocardial injection of autologous bone marrow progenitor cells (mononuclear or mesenchymal stem cells) in LV scar and border zone. All patients tolerated the procedure with no serious adverse events. CMR at 1 year demonstrated a decrease in end diastolic volume (208.7±20.4 versus 167.4±7.32 mL; P=0.03), a trend toward decreased end systolic volume (142.4±16.5 versus 107.6±7.4 mL; P=0.06), decreased infarct size (P<0.05), and improved regional LV function by peak Eulerian circumferential strain in the treated infarct zone (−8.1±1.0 versus −11.4±1.3; P=0.04). Improvements in regional function were evident at 3 months, whereas the changes in chamber dimensions were not significant until 6 months. Improved regional function in the infarct zone strongly correlated with reduction of end diastolic volume (r2=0.69, P=0.04) and end systolic volume (r2=0.83, P=0.01). Conclusions: These data suggest that transcatheter, intramyocardial injections of autologous bone marrow progenitor cells improve regional contractility of a chronic myocardial scar, and these changes predict subsequent reverse remodeling. The findings support the potential clinical benefits of this new treatment strategy and ongoing randomized clinical trials.

Safety of serial MRI in patients with implantable cardioverter defibrillators

Objective While patients with cardiac implantable electronic devices could benefit from magnetic resonance (MR) imaging, the presence of such devices has been designated as an absolute contraindication to MR. Although scanning algorithms are proposed for cardiac implantable electronic devices, their safety remains uncertain. To address this issue, the safety of serial cardiac MR scans was evaluated in patients with implantable cardioverter defibrillators (ICDs). Methods Three serial cardiac MR scans were prospectively performed at 1.5 T on 10 patients (9 men) of median age 56 years (range 51–68) with ICDs. ICD interrogation was performed before and after the MR scan and at a follow-up of median 370 days (range 274–723). Image quality was also assessed. Results In all patients MR scanning occurred without complications. There were no differences between pre- and post-MR pacing capture threshold, pacing lead or high voltage lead impedance, or battery voltage values. During follow-up there were no occurrences of ICD dysfunction. Although most patients had image artifacts, the studies were generally diagnostic regarding left ventricular function and wall motion. Delayed enhancement imaging was of good quality for inferior wall and inferolateral infarcts, but ICD artifacts often affected the imaging of anterior wall infarcts. Conclusion Serial MR scans at 1.5 T in patients with ICDs, when carefully performed in a monitored setting, have no adverse effects on either patient or device. When required, single or multiple MR scans at 1.5 T may therefore be considered for clinical diagnostic purposes in these patients.

Patency rates for angioplasty in the treatment of pacemaker-induced central venous stenosis in hemodialysis patients: results of a multi-center study.

While hemodialysis access ligation has been used to manage pacemaker (PM) and implantable cardioverter‐defibrillator (ICD) lead‐induced central venous stenosis (CVS), percutaneous transluminal balloon angioplasty (PTA) has also been employed to manage this complication. The advantages of PTA include minimal invasiveness and preservation of arteriovenous access for hemodialysis therapy. In this multi‐center study we report the patency rates for PTA to manage lead‐induced CVS. Consecutive PM/ICD chronic hemodialysis patients with an arteriovenous access referred for signs and symptoms of CVS due to lead‐induced CVS were included in this analysis. PTA was performed using the standard technique. Technical and clinical success was examined. Technical success was defined as the ability to successfully perform the procedure. Clinical success was defined as the ability to achieve amelioration of the signs and symptoms of CVS. Both primary and secondary patency rates were also analyzed. Twenty‐eight consecutive patients underwent PTA procedure. Technical success was 95%. Postprocedure clinical success was achieved in 100% of the cases where the procedure was successful. The primary patency rates were 18% and 9% at 6 and 12 months, respectively. The secondary patency rates were 95%, 86%, and 73% at 6, 12, and 24 months, respectively. On average, 2.1 procedures/year were required to maintain secondary patency. There were no procedure‐related complications. This study finds PTA to be a viable option in the management of PM/ICD lead‐induced CVS. Additional studies with appropriate design and sample size are required to conclusively establish the role of PTA in the management of this problem.

Deep Myocardial Ablation Lesions Can Be Created with a Retractable Needle-Tipped Catheter

RF catheter ablation of ventricular tachycardia is sometimes limited by inadequate lesion depth. This study investigated the use of a retractable needle‐tipped catheter to create deep RF lesions in vivo in porcine myocardium. An 8 Fr electrode catheter with an extendable 27‐gauge needle at the tip was modified for RF ablation by embedding a thermocouple and attaching a pin connector. In three swine (32–58 kg) the left ventricle was entered via the femoral artery and endocardial contact was made. The needle was advanced 10 mm and 13 RF applications were made under a controlled temperature (90°C × 120 s). Nine control lesions were made using a standard 4‐mm tip catheter (60°C × 120 s). The lesions were fixed, serially sectioned from the endocardium, digitally imaged, and quantified. Needle ablation lesions were deeper (10.15 ± 0.77 vs 5.67 ± 0.37 mm, P < 0.001) and more likely to be transmural (77 vs 11%, P = 0.008) than control lesions. The volume of control lesions, however, was larger (358.4 ± 56.2 vs 174.7 ± 18.6 mm3, P = 0.002) due to a significantly larger cross‐sectional area at the endocardium (0.548 ± 0.04 vs 0.151 ± 0.01 cm2, P < 0.001). At depths > 6 mm, the needle electrode lesions had a greater cross‐sectional area (0.136 ± 0.01 vs 0.005 ± 0.004 cm2, P < 0.001). Catheter‐based needle ablation is feasible and allows creation of deeper lesions that can be transmural. Although deep, the lesions had a small cross‐sectional area such that precise targeting would be required for success. (PACE 2004; 27:594–599)

Spontaneous paroxysmal atrioventricular block in patients with positive tilt tests and negative electrophysiologic studies

A subgroup of patients with neurocardiogenic syncope and negative electrophysiologic studies and adenosine tests (in 5 of 6 cases), who developed symptomatic paroxysmal atrioventricular block in the natural, ambulatory state, had positive tilt tests without advanced block. Lack of concordance between electrocardiographic changes may have reflected differential effects of the autonomic nervous system in the sinus and atrioventricular nodes, occurring in diverse circumstances and less likely because of the protocol used for tilt testing.

Epicardial Cardiac Rhythm Devices for Dialysis Patients: Minimizing the Risk of Infection and Preserving Central Veins

Transvenous leads of cardiac rhythm devices (CRDs) are known to cause central stenosis and are vulnerable to contamination during hemodialysis access‐related bacteremia. In this retrospective study, nine consecutive chronic hemodialysis patients with transvenous CRD infection due to dialysis access‐related bacteremia and recurrent central stenosis are presented. Four patients with tunneled hemodialysis catheters (TDCs) and three with arteriovenous grafts experienced access‐related bacteremia that spread to the transvenous CRD. Two patients required repeated angioplasty procedures (less than 3 months apart) for central venous stenosis. Transvenous CRD was removed and replaced with an epicardial system in all. One patient with TDC switched to peritoneal dialysis and did not experience infection of the epicardial system despite two episodes of peritonitis. The remaining TDC (n = 3) and graft patients (n = 3) received a new TDC after the resolution of bacteremia. While all six experienced on average 1.5 episodes of catheter‐related bacteremia (average follow‐up = 14.5 months), none developed infection of the epicardial system. The patients with central stenosis have required only one angioplasty each for the past 8 and 6 months. To the best of our knowledge this is the first study to suggest that an epicardial approach might be a preferred method over transvenous leads for chronic hemodialysis patients.

Heart rate dynamics before the spontaneous onset of ventricular tachyarrhythmias in Chagas' heart disease.

A lterations in the spectral analysis of heart rate (HR) have been documented in patients with Chagas’ disease, which can be interpreted as markers of an impaired cardiac neural regulatory mechanism.1,2 The aim of this study was to determine whether cardiac autonomic regulation plays a role in the onset of life-threatening arrhythmias in patients with Chagas’ disease by analyzing the HR dynamics before the onset of ventricular tachyarrhythmia events in patients with Chagas’ heart disease who experienced spontaneous ventricular tachycardia (VT) or ventricular fibrillation (VF) events after receiving an implantable cardioverter-defibrillator. • • • The study group consisted of 17 subjects with a diagnosis of Chagas’ heart disease seen at the Fundacion Cardiovascular del Oriente Colombiano, Bucaramanga, Colombia, who experienced spontaneous episodes of sustained VT and VF during a 1-year period after receiving an implantable cardioverter-defibrillator. Chagas’ heart disease was defined by a combination of epidemiologic, serologic, and clinical criteria. These included a history of residence in an endemic area, 2 positive serologic test (enzyme-linked immunosorbent assay, hemaglutination test) for Trypanosoma cruzi, a clinical syndrome compatible with Chagas’ heart disease and no evidence of another cardiac disorder to which the findings could be attributed. Two-dimensional echocardiographic and electrophysiologic studies were performed in all patients. All patients had clinical VT or VF and fulfilled generally accepted indications for implantation of a cardiac defibrillator.3 RR intervals preceding the arrhythmic episodes, including 1,000 RR intervals before the onset of VT or VF, were stored in the defibrillator’s memory. Most episodes were interrogated within the first 48 hours after the defibrillator had delivered therapy, and a similar period of RR intervals was also recorded during the control clinical visit 48 hours to 1 month after each VT or VF event. Data were downloaded from the defibrillator memory and transferred to a computer for further analysis of HR variability. The memory-retrieved right ventricular electrograms were visually analyzed to differentiate between VT and VF according to the regularity, morphology, and rate of the RR intervals. After the data were transferred to the computer, the RR intervals were edited manually and artifacts as well as ectopic beats were deleted. The details of this analytic technique have been described previously.4 The mean cycle length of all RR intervals and the SD of all RR intervals (SDNN) were computed as time domain measures from the entire recording period. The power spectra were quantified by measuring the area in 2 frequency bands: 0.04 to 0.15 Hz (low frequency) and 0.15 to 0.4 Hz (high frequency).4,5 To quantify fractal correlation properties of HR, the detrended fluctuation analysis technique was used. The method has been validated for time series data and quantifies the presence or absence of fractal correlation properties.6,7 In this method the root-meansquare fluctuation of integrated and detrended time series is measured at each observation window and plotted against the size of the observation window on a log-log scale. The signal with 1/f spectrum results in an exponent value 1.0. White Gaussian noise (random signal) results in an exponent value of 0.5 and the Brownian noise signal (1/f signal spectrum) and an exponent value of 1.5. In this study, HR correlation properties were defined separately for short-term (,11 beats, a1) and for intermediate-term (.11 beats, a2) correlations of RR interval data (shortand intermediate-term scaling exponents).6,7 The results are expressed as means 6 SD unless otherwise indicated. Repeated measurements analysis of variance followed by post hoc comparisons between the groups were used to compare clinical control visit and arrhythmic events (SPSS for Windows release 9.0, Chicago, Illinois). A p value ,0.05 was considered significant. In the light of KolmogorovSmirnov tests (z value .1.0), a logarithmic transforFrom the Division of Cardiology, Department of Medicine, University of Miami School of Medicine, Miami, Florida; Division of Cardiology, Department of Medicine, University of Oulu, Oulu, Finland; and Department of Cardiology and Cardiovascular Sciences, Fundacion Cardiovascular del Oriente Colombiano, Bucaramanga, Colombia. This study was supported in part by Grant 6566–04–788–98 provided by COLCIENCIAS (Colombian Institute for the Advancement of Science and Technology) to Dr. Morillo, by funds provided by the Cardiovascular Research Center at the Fundacion Cardiovascular del Oriente Colombiano-Instituto del Corazon, Bucaramanga, Colombia, and by grants from the Medical Council of Academic of Finland, the Finnish Foundation for Cardiovascular Research and Finnish Medical Foundation, Helsinki, Finland. Dr. Morillo’s address is: Department of Cardiology and Cardiovascular Sciences, Fundacion Cardiovascular del Oriente Colombiano, Calle 155 A No. 23-58, Bucaramanga, Colombia. E-mail: cmorillo@fcv.org. Manuscript received August 1, 2000; revised manuscript received and accepted December 5, 2000.

Transvenous Cardiac Implantable Electronic Devices and Hemodialysis Catheters: Recommendations to Curtail a Potentially Lethal Combination

Abnormal renal function is an independent risk factor for cardiac implantable electronic device (CIED) infection. The risk of CIED infection increases as the degree of renal dysfunction worsens with the highest risk observed in patients with stage V chronic kidney disease. A significant portion of these patients use a tunneled hemodialysis catheter (TDC) for dialysis therapy. These devices are associated with very high rates of catheter‐related bacteremia (1.6–5.5 episodes of bacteremia per 1000 catheter days), and have been known to cause infection of CIED indwelling in the bloodstream. In this context, the cardiac device is exposed to the risk of infection due to the presence of renal failure and episodes of bacteremia related to TDCs. Both increase the risk of CIED infection. Once infected, a cardiac rhythm device carries a marked increase in morbidity and mortality. In this context, the combination of a TDC and a CIED indwelling in the bloodstream becomes a potentially deadly combination. Recent data have emphasized that epicardial CIED implantation reduces cardiac device infection in TDC patients. This report highlights the risk of CIED infection in renal patients, presents TDC’s contribution to the cardiac device infection, and suggests recommendations to minimize the risk of CIED infection in chronic hemodialysis patients dialyzing with a TDC.