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 (r(2)=0.69, P=0.04) and end systolic volume (r(2)=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.

A novel and practical technique to facilitate lead insertion at the His bundle region.

BACKGROUND: His bundle (HB) pacing techniques are challenging and time-consuming. This is primarily due to the limitations in locating the relatively small area of the HB body for pacing. METHODS: Permanent HB pacing was performed in 133 consecutive patients with symptomatic bradycardia. A right atrial septo-gram (RAS) was performed in all patients to locate the HB. Briefly, 8-10 cc of contrast was injected through the Medtronic C315HIS delivery sheath while fluoroscopy cine runs were obtained in the RAO 15-20° projection. The images obtained provided the visualization of an approximately 90° angle composed by the medial aspect of the tricuspid valve annulus (TVA) anteriorly and the superior aspect of the interatrial septum superiorly. The apex of this angle coincides with the tip of the triangle of Koch (TK), where the HB body is usually located. A Medtronic SelectSecure™ MRI SureScan™ Model 3830 lead was then advanced and directed towards this area. The HB was mapped using pace mapping and unipolar recordings from the lead tip. RESULTS: Localization of the apex of the TK/HB body with the RAS was successful in all patients. The overall acute success of inserting the lead at the HB was 95%. CONCLUSION: This study demonstrated that our method of utilizing a RAS to facilitate the localization the HB body proved to be safe and efficient in achieving permanent HB pacing with a success rate higher than previously reported.

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.

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.

Representation of the His Bundle Cloud on a Three-dimensional Electroanatomical Map and Its Implications for His Bundle Pacing.

His bundle pacing has been proposed as a more physiologic approach to chronic ventricular stimulation, yet the achievement of permanent His bundle pacing can be challenging.

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.

Interatrial septal aneurysm and patent foramen ovale: diagnosis and dynamic evaluation with electrocardiogram-gated multidetector-row computed tomography imaging.

We describe an elderly woman with paroxysmal atrial fibrillation who was evaluated by electrocardiogram-gated multidetector-row computed tomography (MDCT) prior to left atrial radiofrequency ablation therapy to rule out coronary artery disease and to obtain a 3-dimensional anatomical map of the left atrium and pulmonary veins. MDCT documented the dynamic bidirectional motion of an interatrial septal aneurysm associated with a patent foramen ovale. MDCT findings correlated well with transesophageal and intracardiac echocardiograms.

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.

Risk stratification for sudden cardiac death: current approaches and predictive value.

Sudden cardiac death (SCD) is a serious public health problem; the annual incidence of out-of-hospital cardiac arrest in North America is approximately 166,200. Identifying patients at risk is a difficult proposition. At the present time, left ventricular ejection fraction (LVEF) remains the single most important marker for risk stratification. According to current guidelines, most patients with LVEF <35% could benefit from prophylactic ICD implantation, particularly in the setting of symptomatic heart failure. Current risk stratification strategies fail to identify patients at risk of SCD in larger population groups encompassing a greater number of potential SCD victims. However, the best approach to identifying patients and the value of various risk stratification tools is not entirely clear. The goal of this review is to discuss the problem of SCD and the value of the different risk stratification markers and their potential clinical use either alone or in combination with other risk stratification markers.

Chronic inappropriate sinus tachycardia in elderly females.

BACKGROUND: The vast majority of reports of inappropriate sinus tachycardia (IST) had included predominantly young females with ages ranging between 15 and 46 years. In contrast, the present study presents the findings in four elderly females (aged 61-71 years) with long-standing symptoms of palpitations, more than 15 years, in whom IST was diagnosed in their 6th or 7th decade. METHODS: Clinical and laboratory examinations including electrocardiograms, echocardiograms, and heart rate variability studies were retrospectively reviewed in four of the nine elderly female patients with long-standing cardiac symptoms. Indices of heart rate variability were compared to four age-matched asymptomatic elderly females with no structural heart disease. RESULTS: The resting electrocardiograms were normal but one had voltage criteria for left ventricular hypertrophy. All traditional time- and frequency-domain indices were significantly decreased in the symptomatic elderly females as compared to the controls. Echocardiograms showed normal ejection fraction, and in three patients evidence of diastolic dysfunction and mild left ventricular hypertrophy. Blood pressures were elevated, with systolic blood pressure ranging from 170 to 190 and diastolic blood pressure ranging from 94 to 106. Anxiety disorders were diagnosed in all patients. CONCLUSIONS: This study demonstrates that IST can be present in a wide spectrum of patient populations, including elderly populations. It seems that some cases of IST can become chronic if not treated adequately. Apparently, earlier identification and treatment could have improved the quality of life of the patients. Traditional HRV indices may not be valuable to support either a sympathetic or parasympathetic mechanism. Therefore, further studies should consider the potential usefulness of the nonlinear method such as, for example, approximate entropy and detrended fluctuation analysis.

Effects of carvedilol on heart rate dynamics in patients with congestive heart failure.

BACKGROUND: Patients with congestive heart failure (CHF) have alterations in the traditional and nonlinear indices of heart rate (HR) dynamics, which have been associated with an increased risk of mortality. This study was designed to test the effects of carvedilol, a nonselective beta-blocker with alpha-1 blocking properties, on HR dynamics in patients with CHF. METHODS: We studied 15 patients with CHF secondary to ischemic or idiopathic cardiomyopathy who met the following inclusion criteria: NYHA functional class II-III, optimal conventional medical therapy, normal sinus rhythm, left ventricular ejection fraction (LVEF) of < 40%, and resting systolic blood pressure greater than 100 mmHg. The 6-minute corridor walk test, estimation of LVEF, and 24-hour Holter recording were performed at baseline and after 12 weeks of therapy with carvedilol. Traditional time and frequency domain measures and short-term fractal scaling exponent of HR dynamics were analyzed. RESULTS: After 12 weeks of therapy with carvedilol, the mean LVEF improved significantly (from 0.27 +/- 0.08 to 0.38 +/- 0.08, P < 0.001). The average HR decreased significantly (from 86 +/- 11 to 70 +/- 8 beats/min, P < 0.001). The mean distance traveled in the 6-minute walk test increased significantly (from 177 +/- 44 to 273 +/- 55 m, P < 0.01). The frequency-domain indices (HF and LF), the time domain indices (rMSSD and PNN5 ), and the short-term fractal scaling exponent increased significantly. The scaling exponent increased particularly among the patients with the lowest initial values (< 1.0), and the change in the fractal scaling exponent correlated with the change in ejection fraction (r = 0.63, P < 0.01). CONCLUSION: Carvedilol improves time and frequency domain indices of HR variability and corrects the altered scaling properties of HR dynamics in patients with CHF. It also improves LVEF and functional capacity. These specific changes in HR behavior caused by carvedilol treatment may reflect the normalization of impaired cardiovascular neural regulation of patients with CHF.

Identification and ablation of three types of ventricular tachycardia involving the his-purkinje system in patients with heart disease.

INTRODUCTION: Ventricular tachycardia (VT) with involvement of the His-Purkinje system (HPS) can be difficult to recognize in patients with heart disease, but it may be particularly susceptible to ablation targeting the HPS. This study defines the incidence and types of HPS involvement in VT. METHODS AND RESULTS: Involvement of the HPS was sought during electrophysiologic study with catheter mapping in 234 consecutive patients referred for catheter ablation of recurrent VT associated with heart disease. HPS VT was observed in 20 (8.5%) patients (mean ejection fraction 29%+/- 17%); in 9 (11%) of 81 patients with nonischemic heart disease and 11 (7.1%) of 153 patients with coronary artery disease (P = NS). Three types of HPS VT were observed: 16 patients (group 1) had typical bundle branch reentry, 2 patients (group 2) had bundle branch reentry and interfascicular reentry, and 2 patients (group 3) had VT consistent with a focal origin in the distal HPS. In all three groups, the VT QRS had morphologic similarity to the sinus rhythm QRS. Ablation of HPS VT was successful in all patients in whom it was attempted but produced high-degree AV block in 6 (30%). In 12 patients (60%), other VTs due to reentry through scar also were inducible. CONCLUSION: Involvement of the HPS in VT associated with heart disease has three distinct clinical forms, all of which are susceptible to ablation. Ablation often is not sufficient as the sole therapy due to other induced VT's and conduction abnormalities, requiring pacemaker and/or defibrillator implantation.

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 degrees C x 120 s). Nine control lesions were made using a standard 4-mm tip catheter (60 degrees C x 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 mm(3), P = 0.002) due to a significantly larger cross-sectional area at the endocardium (0.548 +/- 0.04 vs 0.151 +/- 0.01 cm(2), 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 cm(2), 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.