A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial.

AIMS: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. METHODS AND RESULTS: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. CONCLUSIONS: This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

Outcomes of Patients Undergoing Transcatheter Aortic Valve Implantation With Incidentally Discovered Masses on Computed Tomography.

Routine preprocedural chest and abdomen computed tomography is done prior to transcatheter aortic valve implantation (TAVI), which, in turn, have led to the discovery of radiographic potentially malignant incidental masses (pMIM). It is largely unknown whether pMIM impact the outcomes of patients undergoing TAVI. In this retrospective cohort study from a single center, 1,081 patients underwent TAVI from 2012 to 2016, who had available computed tomographies, survived the index hospitalization, and also had 1 year follow-up data for review. Machine learning (backward propagation neural network)-augmented multivariable regression for mortality by pMIM was conducted. In this cohort of 1,081 patients, the mean age was 79.1 (± 9.0), 48.8% were females, 16.8% had a history of prior malignancy, and 21.1% had pMIM. One-year mortality for the entire cohort was 12.6%. The most common prior malignancies were prostate, breast, and lymphoma and the most common pMIM were present in the lung, kidneys, and thyroid. In a fully adjusted regression analysis, neither prior malignancy nor pMIM increased mortality odds. However, having both was associated with a higher 1-year mortality (odds ratio 4.02, 95% confidence interval 1.50 to 10.73, p = 0.006). In conclusion, presence of pMIM alone was not associated with an increased 1-year mortality among patients undergoing TAVI. However, the presence of pMIM and a history of prior malignancy was associated with a significant increase in 1-year mortality.

Pseudo-Acute Myocardial Infarction in a Young COVID-19 Patient.

A 29-year-old man tested positive for COVID-19 and developed acute respiratory distress syndrome. While mechanically ventilated, his electrocardiogram showed inferior ST-segment elevations, with normal serial cardiac troponin I and transthoracic echocardiograms. He was treated conservatively, with complete clinical recovery and resolution of his electrocardiographic abnormalities. (Level of Difficulty: Beginner.).

Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients: The CCTRN SENECA Trial.

BACKGROUND: Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure (HF) treatment. OBJECTIVES: SENECA (Stem Cell Injection in Cancer Survivors) was a phase 1 study of allo-MSCs in AIC. METHODS: Cancer survivors with chronic AIC (mean age 56.6 years; 68% women; NT-proBNP 1,426 pg/ml; 6 enrolled in an open-label, lead-in phase and 31 subjects randomized 1:1) received 1 × 108 allo-MSCs or vehicle transendocardially. Primary objectives were safety and feasibility. Secondary efficacy measures included cardiac function and structure measured by cardiac magnetic resonance imaging (CMR), functional capacity, quality of life (Minnesota Living with Heart Failure Questionnaire), and biomarkers. RESULTS: A total of 97% of subjects underwent successful study product injections; all allo-MSC-assigned subjects received the target dose of cells. Follow-up visits were well-attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-CMR compatible devices, CMR endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes. Secondary measures included 6-min walk test (p = 0.056) and Minnesota Living with Heart Failure Questionnaire score (p = 0.048), which tended to favor the allo-MSC group. CONCLUSIONS: In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible, and CMR was successfully performed in the majority of the HF patients with devices. This study lays the groundwork for phase 2 trials aimed at assessing efficacy of cell therapy in patients with AIC.

National 10-year trends and outcomes of isolated and concomitant tricuspid valve surgery.

BACKGROUND: The data on the trends and comparative outcomes after isolated and concomitant tricuspid valve repair/replacement (TVR) is scarce. METHODS: The International Classification of Diseases - 9th version was used to identify the patients who underwent TVR, using the National Inpatient Sample. Outcomes were evaluated using the analysis of variance and Chi-square test, and trends across the years were tested via Cochran-Armitage Test. RESULTS: Of 6868 patients who underwent TVR between 2005-14, 1601 (23%) were isolated. Over the 10-years period, the number of total and isolated TVR has steadily increased (P<0.001). The proportion of patients undergoing repair has increased compared to replacement. Overall in-hospital mortality was 8.5% and 7.7% (p=0.28), permanent pacemaker requirement was 11.24% and 10.69% (P=0.53), blood transfusion rates were 32.6% and 37.9% (P<0.001), and the post-procedure length of stay (LOS) was 14.1±0.44 and 12.5±0.17 days (P<0.001) after isolated and concomitant TVR respectively. High (26.25%) number of patients were discharged to skilled facility. The operative mortality associated with TV repair was lower than with replacement (6.8% versus 11.15%, P<0.001), but the mortality trend over the 10-years has stayed relatively stable. Independent predictors of mortality were age >50 years, heart failure, cerebrovascular accident, end-stage renal disease, peripheral vascular disease, liver disease, and TV replacement. CONCLUSIONS: Both isolated and concomitant TVR has increased over the last 10 years, however is associated with high mortality, complications, need for skilled facility placement, and longer LOS. The mortality after TV replacement was significantly higher than that after repair.

Role of imaging in novel mitral technologies-echocardiography and computed tomography.

As minimally invasive cardiovascular procedures gain popularity, novel transcatheter mitral valve repair devices continue to emerge. The success of these technologies is critically dependent on high quality imaging performed at all stages: patient selection, intervention planning, intraprocedural guidance, monitoring complications and follow-up. We present an overview of specific imaging requirements and challenges applicable to mitral valve interventional techniques. Modern valve imaging is multimodal and primarily combines echocardiography and computed tomography (CT). Echocardiography remains the gold standard for detailed anatomic imaging, complete hemodynamic characterization and real-time guidance and evaluation of procedural success. CT is indispensable for mitral annulus (MA) imaging and in predicting left ventricular outflow tract (LVOT) obstruction post transcutaneous mitral valve replacement (TMVR). 3D modeling, fusion imaging and automated image analysis may further contribute to the evolutionary transformation of valvular heart imaging.

Minimally Invasive Versus Transcatheter and Surgical Aortic Valve Replacement: A Propensity Matched Study.

BACKGROUND: An increasing number of options exist for the treatment of severe symptomatic aortic stenosis. The study aim was to compare short-term outcomes in patients undergoing surgical aortic valve replacement (SAVR), minimally invasive aortic valve replacement (MIAVR), and transcatheter aortic valve replacement (TAVR). METHODS: A multi-institutional retrospective review of 2,571 patients undergoing SAVR (n = 842), MIAVR via right anterior thoracotomy (n = 699) and TAVR (n = 1,030) between 2011 and 2014 was conducted. TAVR patients were further stratified as either transfemoral (TF) or transapical (TA). Propensity matching was performed between MIAVR and SAVR (384 pairs), MIAVR and TA-TAVR (115 pairs), and MIAVR and TF-TAVR (247 pairs). RESULTS: Total numbers of AVR increased between 2011 and 2014. When stratified by procedure type, MIAVR and TF-TAVR accounted for most of the growth, while TA-TAVR and SAVR each experienced a decreased volume. Propensity matched comparisons of SAVR, TF-TAVR, and TA-TAVR versus MIAVR revealed no difference in 30-day mortality. TF-TAVR versus MIAVR revealed that MIAVR had a decreased rate of stroke (0.4% versus 3.6%, p = 0.02) and increased atrial fibrillation (AF; 19.4% versus 4%, p <0.01). When compared to SAVR, MIAVR had a lower incidence of AF (19% versus 32.6%, p <0.01). MIAVR exhibited decreased ventilation time (27.2 versus 134 h, p = 0.03) and intensive care unit time (63.7 versus 92.7 h, p = 0.02) compared to TA-TAVR. CONCLUSIONS: During recent years, MIAVR and TFTAVR have experienced significant growth in volume with near-comparable short-term outcomes, while SAVR and TA-TAVR volumes have declined. These results underscore the importance of surgeons adopting MIAVR and TF-TAVR techniques in order to offer patients optimal outcomes.

Traditional Sternotomy Versus Minimally Invasive Aortic Valve Replacement in Patients Stratified by Ejection Fraction.

OBJECTIVE: Low ejection fraction (EF < 40%) portends adverse outcomes in patients undergoing valvular heart surgery. The role of traditional median sternotomy aortic valve replacement (SAVR) compared with minimally invasive aortic valve replacement (MIAVR) in this cohort remains incompletely understood. METHODS: A multi-institutional retrospective review of 1503 patients who underwent SAVR (n = 815) and MIAVR via right anterior thoracotomy (n = 688) from 2011 to 2014 was performed. Patients were stratified into two groups: EF of less than 40% and EF of 40% or more. In each EF group, SAVR and MIAVR patients were propensity matched by age, sex, body mass index, race, diabetes, hypertension, dyslipidemia, dialysis, cerebrovascular disease, cardiovascular disease, cerebrovascular accident, peripheral vascular disease, last creatinine level, EF, previous MI and cardiogenic shock, and the Society for Thoracic Surgeons (STS) score. RESULTS: Among patients with an EF of 40% or more (377 pairs), patients who underwent MIAVR compared with SAVR had decreased intensive care unit hours (56.8% vs 84.6%, P < 0.001), postoperative length of stay (7.1 vs 7.9 days, P = 0.04), incidence of atrial fibrillation (18.8% vs 38.7%, P < 0.001), bleeding (0.8% vs 3.2%, P = 0.04), and a trend toward decreased 30-day mortality (0.3% vs 1.3%, P = 0.22). The STS scores were largely equivalent in patients undergoing MIAVR compared with SAVR (2.4% vs 2.6%, P = 0.09). In patients with an EF of less than 40% (35 pairs), there was no difference in intensive care unit hours (69% vs 72.6%, P = 0.80), postoperative length of stay (10.3 vs 7.2 days, P = 0.13), 30-day mortality (3.8% vs 0.8%, P = 0.50), or the STS score (3.3% vs 3.2%, P = 0.68). CONCLUSIONS: Minimally invasive aortic valve replacement in patients with preserved EF was associated with improved short-term outcomes compared with SAVR. In patients with left ventricular dysfunction, short-term outcomes between MIAVR and SAVR are largely equivalent.

Comparison of 30-day mortality and myocardial scar indices for patients treated with prehospital reduced dose fibrinolytic followed by percutaneous coronary intervention versus percutaneous coronary intervention alone for treatment of ST-elevation myocardial infarction.

OBJECTIVES: We investigated whether prehospital, reduced dose fibrinolysis coupled with urgent percutaneous coronary intervention (FAST-PCI) reduces mortality and cardiac magnetic resonance (CMR) measures of infarct size, compared with primary percutaneous coronary intervention (PPCI), in patients with ST-elevation myocardial infarction (STEMI). BACKGROUND: Current standard therapy for STEMI is PPCI. However, FAST-PCI may shorten ischemic time (IT) and improve outcomes. METHODS: Eligible STEMI patients received prehospital, reduced dose fibrinolysis along with standard therapy, and were transported for urgent percutaneous coronary intervention, or else they received usual treatment without prehospital fibrinolysis. Patients were divided retrospectively into four groups based on IT (<120, 120-179, 180-239 min, ≥240) for a mortality analysis cohort, and into three groups (<120, 120-179, ≥180 min) for a CMR analysis cohort. Within each IT group, patients were compared by FAST-PCI vs. PPCI strategy. RESULTS: Between 1/2007 and 2/2014, 1,112 STEMI patients were treated. FAST-PCI was employed in 551 and PPCI in 561. Of these, 357 (32.1%) underwent CMR. The treatment groups were well matched. In STEMI patients with short IT (<120 and 120-179 min groups), those treated by FAST-PCI had lower 30-day mortality and myocardial scar sizes compared with PPCI treatment. For IT ≥180 min, the mortalities and myocardial scar sizes were equivalent for both groups. CONCLUSIONS: In STEMI patients with IT <180 min, FAST-PCI may reduce 30-day mortality and myocardial scar size compared with PPCI. This suggests that infarct interventions must be instituted within 3 hr of symptom onset in order to detect an optimal beneficial effect both clinically and by CMR measurement. © 2016 Wiley Periodicals, Inc.

Ischemic time is a better predictor than door-to-balloon time for mortality and infarct size in ST-elevation myocardial infarction.

BACKGROUND: Current guidelines for ST-elevation myocardial infarction (STEMI) recommend early revascularization with optimal ischemic time (IT) < 120 min and door-to-balloon (D2B) time < 90 min. The focus of most studies has been D2B time, while IT is not frequently reported. We tested the hypothesis that total IT is a better predictor than D2B time for mortality and infarct size. METHODS AND RESULTS: Between December 2008 and April 2013, 786 patients with STEMI were treated in our STEMI center, and 262 of these had cardiac magnetic resonance imaging 3-5 days after the index event. Total IT was defined as time from symptom onset to device activation, while D2B time was defined as hospital arrival to device activation. Patients were divided into three groups according to IT (<120, 120-239, ≥240 min) and into four groups according to D2B time (<30, 30-59, 60-89, ≥90 min). Baseline demographics including age, cardiac risk factors, and LAD infarct location were similar between groups. The 30-day mortality rate significantly increased across IT groups but did not correlate with D2B time groups. Similarly, infarct size significantly increased across IT groups but did not correlate with D2B time groups. CONCLUSIONS: In STEMI patients, IT was a better predictor than D2B time for 30-day mortality and infarct size. Our findings suggest that the focus of STEMI care should be directed at early initiation of therapy and minimizing IT rather than on D2B time alone. The potential impact of IT reporting in current STEMI registries merits further consideration. © 2015 Wiley Periodicals, Inc.

Lambl's excrescence, migrainous headaches, and "tiger stripes": puzzling findings in one patient.

Lambl's excrescences are mobile, thin, filiform structures that occur at sites of valve closure. Even though many clinicians consider them to be part of the normal aging process, evidence suggests an association between Lambl's excrescences and ischemic stroke, migrainous headaches, and acute coronary syndromes. As a thin filamentous structure, a Lambl's excrescence is better detected and characterized with transesophageal than with transthoracic echocardiography. Intracardiac oscillatory structures can also be seen as "tiger stripes" on spectral pulsed Doppler echocardiographic recordings. Herein, we present the case of a 68-year-old woman who had 3 concurrent enigmatic findings with unclear correlation: migrainous headaches, Lambl's excrescences, and the uncommon finding of "tiger stripes" on spectral Doppler echocardiography. We discuss the possible correlation between these 3 findings and review the available literature on Lambl's excrescences and tiger stripes.

Outcome of pulmonary vein isolation ablation for paroxysmal atrial fibrillation: predictive role of left atrial mechanical dyssynchrony by speckle tracking echocardiography.

INTRODUCTION: Although few clinical variables have been associated with recurrence of atrial fibrillation (AF) after pulmonary vein isolation (PVI) the role of left atrial (LA) mechanical function in the outcome of catheter ablation of AF is not adequately defined. The aim of our study was to determine whether LA mechanical dyssynchrony as evaluated by speckle tracking echocardiography can predict outcome of PVI ablation procedure in patients with paroxysmal AF. METHODS: Twenty-five patients (age 58 ± 11 years, [mean ± standard deviation], 17 males) with paroxysmal AF who met specific enrollment criteria pertaining to clinical presentation and follow-up, assessment of LA mechanical dyssynchrony, and strategy of catheter ablation procedure were enrolled. For LA mechanical dyssynchrony assessment, the time to peak longitudinal strain (TPk) in opposing walls in the midportion of the LA walls at peak atrial contraction in standard two- and four-chamber echocardiographic views by vector velocity imaging (VVI) was measured. Outcome of PVI procedure, whether no recurrence (NR) or AF recurrence (AFR) after 3 months of post-procedural blanking period, was evaluated based on AF-related symptoms and documentation of AF by electrocardiogram, continuous 24-h Holter, and intermittent event monitor recordings. RESULTS: During a follow-up period of 20.3 ± 8.6 months, 18 out of 25 (72 %) patients had no recurrence (NR group), and 7 out of 25 (28 %) patients had recurrence of AF (AFR group). Significant gender difference was observed in terms of outcome such that all AFR patients were men and no woman had recurrence of AF. Between the NR and AFR groups, neither the left atrial diameter, 4.0 ± 0.3 and 4.2 ± 0.2 cm, respectively (p = 0.2), nor the left atrial volume indexes, 45 ± 15 and 48 ± 20 ml/m(2), respectively (p = 0.56), were statistically significantly different. For LA mechanical function, compared to the patients in NR group who had maximum opposing wall TPk delay of 39.9 ± 12.0 ms, those in the AFR group demonstrated significantly more LA mechanical dyssynchrony with maximum opposing wall TPk delay of 64.4 ± 17.0 ms prior to ablation (p = 0.007). Using receiver operative characteristic analyses of the data that had an area under the curve of 0.865, we identified a maximum opposing wall delay cutoff value of 51 ms which predicted AF recurrence with sensitivity and specificity values of 89 and 72 %, respectively (p = 0.005). CONCLUSIONS: Speckle tracking strain analysis echocardiography can evaluate the LA mechanical dyssynchrony quantitatively. The severity of LA mechanical dyssynchrony by VVI can predict the outcome of PVI catheter ablation for paroxysmal AF.

Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial.

CONTEXT: While the delivery of cell therapy after ST-segment elevation myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular function has not been analyzed. OBJECTIVES: To determine the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery after STEMI on recovery of global and regional left ventricular function and whether timing of BMC delivery (3 days vs 7 days after reperfusion) influences this effect. DESIGN, SETTING, AND PATIENTS: A randomized, 2 × 2 factorial, double-blind, placebo-controlled trial, Timing In Myocardial infarction Evaluation (TIME) enrolled 120 patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤ 45%) after successful primary percutaneous coronary intervention (PCI) of anterior STEMI between July 17, 2008, and November 15, 2011, as part of the Cardiovascular Cell Therapy Research Network sponsored by the National Heart, Lung, and Blood Institute. INTERVENTIONS: Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1) within 12 hours of aspiration and cell processing administered at day 3 or day 7 (randomized 1:1) after treatment with PCI. MAIN OUTCOME MEASURES: The primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and change in left ventricular function as affected by timing of treatment on day 3 vs day 7. The secondary end points included major adverse cardiovascular events as well as changes in left ventricular volumes and infarct size. RESULTS: The mean (SD) patient age was 56.9 (10.9) years and 87.5% of participants were male. At 6 months, there was no significant increase in LVEF for the BMC group (45.2% [95% CI, 42.8% to 47.6%] to 48.3% [95% CI, 45.3% to 51.3%) vs the placebo group (44.5% [95% CI, 41.0% to 48.0%] to 47.8% [95% CI, 43.4% to 52.2%]) (P = .96). There was no significant treatment effect on regional left ventricular function observed in either infarct or border zones. There were no significant differences in change in global left ventricular function for patients treated at day 3 (−0.9% [95% CI, −6.6% to 4.9%], P = .76) or day 7 (1.1% [95% CI, −4.7% to 6.9%], P = .70). The timing of treatment had no significant effect on regional left ventricular function recovery. Major adverse events were rare among all treatment groups. CONCLUSION: Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00684021.

Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial.

CONTEXT: Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. OBJECTIVE: To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina. DESIGN, SETTING, AND PATIENTS: A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011. INTERVENTION: Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group). MAIN OUTCOME MEASURES: Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory. RESULTS: Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement. CONCLUSION: Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00824005.

Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial.

CONTEXT: Clinical trial results suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first week following myocardial infarction (MI). However, because a substantial number of patients may not present for early cell delivery, the efficacy of autologous BMC delivery 2 to 3 weeks post-MI warrants investigation. OBJECTIVE: To determine if intracoronary delivery of autologous BMCs improves global and regional LV function when delivered 2 to 3 weeks following first MI. DESIGN, SETTING, AND PATIENTS: A randomized, double-blind, placebo-controlled trial (LateTIME) of the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network of 87 patients with significant LV dysfunction (LV ejection fraction [LVEF] ≤45%) following successful primary percutaneous coronary intervention (PCI) between July 8, 2008, and February 28, 2011. INTERVENTIONS: Intracoronary infusion of 150 × 10(6) autologous BMCs (total nucleated cells) or placebo (BMC:placebo, 2:1) was performed within 12 hours of bone marrow aspiration after local automated cell processing. MAIN OUTCOME MEASURES: Changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone between baseline and 6 months, measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volumes and infarct size. RESULTS: A total of 87 patients were randomized (mean [SD] age, 57 [11] years; 83% men). Harvesting, processing, and intracoronary delivery of BMCs in this setting was feasible. Change between baseline and 6 months in the BMC group vs placebo for mean LVEF (48.7% to 49.2% vs 45.3% to 48.8%; between-group mean difference, -3.00; 95% CI, -7.05 to 0.95), wall motion in the infarct zone (6.2 to 6.5 mm vs 4.9 to 5.9 mm; between-group mean difference, -0.70; 95% CI, -2.78 to 1.34), and wall motion in the border zone (16.0 to 16.6 mm vs 16.1 to 19.3 mm; between-group mean difference, -2.60; 95% CI, -6.03 to 0.77) were not statistically significant. No significant change in LV volumes and infarct volumes was observed; both groups decreased by a similar amount at 6 months vs baseline. CONCLUSION: Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs vs intracoronary placebo infusion, 2 to 3 weeks after PCI, did not improve global or regional function at 6 months. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00684060.

Quantification of myocardial segmental function in acute and chronic ischemic heart disease and implications for cardiovascular cell therapy trials: a review from the NHLBI-Cardiovascular Cell Therapy Research Network.

Global left ventricular (LV) ejection fraction (LVEF) has been used as a measure of improvement in LV function following cell therapy. Although the impact of cell therapy on LVEF in short- and long-term follow-up has been generally positive, there is concern that research evaluating regional therapeutics (e.g., cell or gene therapy) may require analysis of regional LV function localized to the site of intervention. Regional LV assessment is traditionally performed with qualitative or quantitative analysis of wall thickening within 16 myocardial segments, but advances in noninvasive imaging permit an increasingly more detailed and accurate evaluation of LV function. Wall-thickness measurements can now include evaluation of over 1,000 myocardial segments. In addition to higher resolution measures of wall thickening, automated assessments of myocardial segment deformation, such as strain imaging, exist. Strain imaging allows for direct evaluation of the mechanical properties that may improve following regional therapeutic intervention. Improvements in regional LV function may also be assessed by determining regional ejection fraction (EF). Regional EF offers the advantage of summarizing the end result of all of the complex deformations in the adjacent myocardial segments. Although regional EF and strain imaging, as compared with wall thickening, enhance detection of improvement in complex measures of regional myocardial function, it remains unclear whether such measures are better able to predict meaningful improvement in clinical outcomes.

Percutaneous repair or surgery for mitral regurgitation.

BACKGROUND: Mitral-valve repair can be accomplished with an investigational procedure that involves the percutaneous implantation of a clip that grasps and approximates the edges of the mitral leaflets at the origin of the regurgitant jet. METHODS: We randomly assigned 279 patients with moderately severe or severe (grade 3+ or 4+) mitral regurgitation in a 2:1 ratio to undergo either percutaneous repair or conventional surgery for repair or replacement of the mitral valve. The primary composite end point for efficacy was freedom from death, from surgery for mitral-valve dysfunction, and from grade 3+ or 4+ mitral regurgitation at 12 months. The primary safety end point was a composite of major adverse events within 30 days. RESULTS: At 12 months, the rates of the primary end point for efficacy were 55% in the percutaneous-repair group and 73% in the surgery group (P=0.007). The respective rates of the components of the primary end point were as follows: death, 6% in each group; surgery for mitral-valve dysfunction, 20% versus 2%; and grade 3+ or 4+ mitral regurgitation, 21% versus 20%. Major adverse events occurred in 15% of patients in the percutaneous-repair group and 48% of patients in the surgery group at 30 days (P<0.001). At 12 months, both groups had improved left ventricular size, New York Heart Association functional class, and quality-of-life measures, as compared with baseline. CONCLUSIONS: Although percutaneous repair was less effective at reducing mitral regurgitation than conventional surgery, the procedure was associated with superior safety and similar improvements in clinical outcomes. (Funded by Abbott Vascular; EVEREST II ClinicalTrials.gov number, NCT00209274.).

Effect of percutaneous mitral repair with the MitraClip device on mitral valve area and gradient.

AIMS: Percutaneous repair of mitral regurgitation (MR) by leaflet apposition using a clip deployed via transseptal catheterisation is undergoing evaluation. METHODS AND RESULTS: In order to detect the potential for clinically significant left ventricular inflow obstruction after percutaneous repair, we measured mitral valve area (MVA) and mean transmitral gradient (MVG) echocardiographically in 96 patients implanted with a clip followed for up to 24 months. By planimetry, the mean MVA decreased from 6.0 +/- 1.3 cm2 to 3.6 +/- 1.2 cm2 (p < 0.05) (range 1.9 to 7.6 cm2) after clip placement, and remained unchanged after 24 months of follow-up (3.5 +/- 0.8 cm2). The mean MVG increased after clip placement from 1.7 +/- 0.9 mmHg to 4.1 +/- 2.2 mmHg (p < 0.05), and did not increase further to 24 months (3.8 +/- 1.9 mmHg). There were no differences in MVA or MVG between patients who received 1-clip (69%) and those receiving 2-clips (31%). Patients with functional MR (23%) had a slightly smaller MVA, both at baseline and after clip placement, but did not differ from degenerative MR patients at later follow-up. After 2 years of follow-up, no patient required surgery for LV inflow obstruction. CONCLUSIONS: Mitral repair with the MitraClip device for MR decreases MVA without significant mitral obstruction. After 2 years of follow-up, no patient required surgery for LV inflow obstruction, and these results were not influenced by the use of more than 1 clip or the aetiology of MR.