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Over the past 13 years bone marrow-derived mononuclear cells (BM-MNCs) have been widely investigated for clinical efficacy in patients following acute myocardial infarction (AMI). These early phase II trials have used various surrogate markers to judge efficacy and, although promising, the results have been inconsistent. The phase III BAMI trial has therefore been designed to demonstrate that intracoronary infusion of BM-MNCs is safe and will significantly reduce the time to first occurrence of all-cause death in patients with reduced left ventricular ejection fraction after successful reperfusion for ST-elevation AMI (powered with the aim of detecting a 25% reduction in all-cause mortality). This is a multinational, multicentre, randomized, open-label, controlled, parallel-group phase III study aiming to enrol approximately 3000 patients in 11 European countries with at least 17 sites. Eligible patients who have impaired left ventricular ejection (≤45%) following successful reperfusion for AMI will be randomized to treatment or control group in a 1:1 ratio. The treatment group will receive intracoronary infusion of BM-MNCs 2–8 days after successful reperfusion for AMI added on top of optimal standard of care. The control group will receive optimal standard of care. The primary endpoint is time from randomization to all-cause death. The BAMI trial is pivotal and the largest trial to date of BM-MNCs in patients with impaired left ventricular function following AMI. The aim of the trial is to provide a definitive answer as to whether BM-MNCs reduce all-cause mortality in this group of patients.

Rationale: Cell-based therapies are a promising option in patients with chronic postinfarction heart failure (ischemic cardiomyopathy [ICM]). However, the responses after intracoronary infusion of autologous bone marrow–derived mononuclear cells (BMCs) are heterogeneous, which may be related to impaired cell retention in patients with ICM. Ischemic injury is associated with upregulation of prototypical chemoattractant cytokines mediating retention and homing of circulating cells. The development of ultrasensitive tests to measure high-sensitive troponin T (hs-TnT) serum levels revealed the presence of ongoing minute myocardial injury even in patients with stable ICM. Objective: To test the hypothesis that serum levels of hs-TnT correlate with cell retention and determine the response to intracoronary BMC application in patients with ICM. Methods and Results: About 157 patients with stable ICM and no substantial impairment of kidney function received intracoronary BMC administration. Immediately prior to cell application, hs-TnT levels to measure myocardial injury and NT-proBNP levels as marker of left ventricular wall stress were determined. Patients with elevated hs-TnT were older and had more severe heart failure. Importantly, only patients with elevated baseline hs-TnT≥15.19 pg/mL (upper tertile) demonstrated a significant ( P =0.04) reduction in NT-proBNP serum levels (−250 [−1465; 33] pg/mL; relative reduction −24%) 4 months after BMC administration, whereas NT-proBNP levels remained unchanged in patients in the 2 lower hs-TnT tertiles. The absolute decrease in NT-proBNP at 4 months was inversely correlated with baseline hs-TnT ( r =−0.27, P =0.001). Finally, retention of intracoronarily infused, 111 Indium-labeled cells within the heart was closely associated with hs-TnT levels in patients with chronic ischemic heart failure ( P =0.0008, n=10, triple measurements). Conclusions: The extent of ongoing myocardial injury as measured by serum levels of hs-TnT predicts the reduction of NT-proBNP serum levels at 4 months after intracoronary BMC administration in patients with ICM, suggesting that the beneficial effects of BMC application on LV remodeling and wall stress are confined to patients with ongoing minute myocardial injury. Clinical Trial Registration: URL: www.clinicaltrials.gov . Unique identifier: NCT00962364.

Sudden cardiac death (SCD) is reported to account for two-thirds of deaths due to cardiovascular causes in the United States, taking half a million lives every year ([1][1]). In cohort studies on SCD, women accounted for only 25% of the patient populations and less often had coronary artery disease

Somatic mutations in hematopoietic stem cells can lead to the expansion of mutated blood cells, known as clonal hematopoiesis (CH). Mutations in the most prevalent genes DNMT3A and TET2 with a variant allele frequency (VAF)≥2% (CHIP) have been associated with atherosclerosis and chronic heart failure (CHF). However, the mutational landscape in CHF and the effects in CH-driver genes other than DNMT3A and TET2 with low VAF≤2% on CHF are still unknown. Therefore we analyzed bone marrow and blood cells from 399 CHF patients by deep error-corrected targeted sequencing of 56 genes and associated mutations with the long-term mortality (3.95 years median follow-up). We detected 1113 mutations with a VAF≥0.5% in 347 patients (87%). Despite a high prevalence of mutations in the most frequently mutated genes DNMT3A and TET2, mutations in the genes CBL, CEBPA, EZH2, GNB1, PHF6, SMC1A and SRSF2 were associated with increased death compared to the average death rate of all patients (20%). To avoid confounding effects caused by the presence of DNMT3A and TET2 CHIP mutations, we excluded patients with CHIP-related mutations (VAF≥2%) for further analyses. Kaplan-Meier survival analyses revealed a significantly higher mortality in patients with mutations in the seven genes (53 patients), combined as the CH risk gene set for CHF. These patients showed no significant differences in any parameter including patient age, confounding diseases or blood parameters except for a reduced number of platelets. However, carrying a mutation in any of the risk genes remained significant after multivariate cox regression analysis (HR, 3.1; 95% CI, 1.8-5.4; p Somatic mutations with low VAF in these risk genes are prevalent in young CHF patients and comprise an independent risk factor for the outcome, potentially providing a novel tool for risk assessment in CHF.

Background Resuming activity following a new diagnosis of dilated cardiomyopathy (DCM) or myocardial infarction (MI) is important for improvements in morbidity and mortality. Activity is also associated with an improved ejection fraction (EF) and lower risk of reinfarction. Patient management could benefit from having normative values and expected gains in activity early following diagnosis of DCM or MI. Purpose Assess the change in activity among women for the first 30 days after hospital discharge following a new DCM diagnosis or MI. Methods Female adult patients prescribed a wearable cardioverter defibrillator (WCD) for a diagnosis of DCM (n=3550) or MI (n=1422) with low EF were included. Step count was measured by WCD accelerometer. Change in activity over time was analyzed, including weekly percentage gains. Results Women with DCM were significantly younger (64, SD = 13) than women post-MI (67, SD = 12). Median daily step count across the entire 30-day period was 4093 (IQR: 2123–6609). Women with DCM demonstrated a higher step count compared to women post-MI, 4405 (IQR: 2348–6986) and 3352 (IQR: 1644–5709), respectively, even after correcting for the difference in age between the groups. The greatest increases in activity for all occurred from week 1 to week 2. Women with DCM or post-MI had a 15.4% and 19.1% increase, respectively. Incremental increases in activity continued throughout the month. Conclusion Physical activity among women with newly diagnosed DCM or MI and a low EF increased within the first 30 days. The most significant increase occurred from week 1 to week 2. This data can be used as a benchmark to develop and assess prescriptive activity programs for women.

Background Previous studies highlighted the importance of adequate heart rate control in heart failure patients, and suggested under-treatment with beta-blockers especially in women. However, data on women achieving effective heart rate control during beta-blocker therapy optimization are lacking. Methods The wearable cardioverter defibrillator (WCD) allows continuous monitoring of heart rate (HR) trends during WCD use. In the current study, we assessed resting HR trends (nighttime: midnight-7am) in women, both at the beginning of WCD use and at the end of WCD use to assess the adequacy of beta-blockade following a typical 3 months of therapy optimization with beta-blockers. An adequate heart rate control was defined as having a nighttime HR Results There were a total of 21,453 women with at least 30 days of WCD use (>140 hours WCD use on the first and last week). The mean age was 67 years (IQR 58–75). The mean nighttime heart rate was 72 bpm (IQR 65–81) at the beginning of WCD use, that decreased to 68 bpm (IQR 61–76) at the end of WCD use with therapy optimization. Women had an insufficient heart rate control with resting heart rate ≥70 bpm in 59% at the beginning of WCD use that decreased to 44% at the end of WCD use, but still remained surprisingly high. Interestingly, there were 21% of the women starting with HR ≥70 bpm at the beginning of use (BOU) who achieved adequate heart rate control by the end of use (EOU). Interestingly, 6% of women with adequate heart rate control at the start of therapy optimization ended up having higher heart rates >70 bpm at the end of the therapy optimization time period (Figure). Figure 1 Conclusions A significant proportion of women with heart failure and low ejection fraction do not reach an adequate heart rate control during the time of beta blocker initiation/titration. The wearble cardioverter defibrillator is a monitoring device that has been demonstrated in this study to appropriately identify patients with inadequate heart rate control at the end of the therapy optimization period. The WCD could be utilized to improve management of beta-blocker therapy in women and improve the achievement of adequate heart rate control in women.

Background Monocytes and macrophages have distinct roles in cardiovascular health where they may contribute to beneficial processes like wound healing and cardiac conductance or to pathological processes like inflammation, remodeling and fibrosis. Despite their importance, the specific signatures of circulating monocytes are missing. Single cell RNA sequencing (scRNA-seq) provides a novel opportunity to define subsets of monocytes mediating inflammation in humans. Purpose To detect and study the inflammatory burden driven by subsets of monocytes in healthy individuals and subjects with chronic ischemic heart failure (CHF) using scRNA-seq. Methods and results Circulating CD31+ cells of CHF patients (n=11) along with aged matched (n=3) and young healthy controls (n=5) were sorted and scRNA-seq then performed. Unsupervised clustering of present sequencing data revealed these cells to be comprised of 19 subpopulations (primarily monocytes). Many subpopulations of cells were comprised chiefly or solely by CHF subjects. Dysregulated genes in CHF subjects, relative to healthy controls included interleukin-1b, thrombospondin-1, S100A8 and matrix metalloprotease-1, which were confirmed by FACS and qRT-PCR in a validation cohort. Given the expanded, divergent and highly inflammatory transcriptional populations of monocytes in patients with CHF, we assessed whether occurrence of somatic mutations associated with clonal hematopoiesis of indeterminate potential (CHIP), recently shown to be increased in subjects with atherosclerosis and heart failure, might occur in these subjects. Indeed, we identified patients who revealed mutations in the DNA methyltransferase DNMT3A and other CHIP-driver genes. DNMT3A mutations were associated with changes in known DNMT3A target genes such as the pro-inflammatory genes CXCL1, CXCL2 and IL6 in circulating monocytic cells. Moreover, cell fate trajectory analysis showed shared fates of cells driven by pseudotime-dependent variables from subjects harboring DNMT3A mutations. Regulated genes in this fate were associated with cell survival, migration and inflammation, appropriate for this disease phenotype. Conclusions This is the first study to show scRNA-seq profiles of monocytes in patients with CHF. Healthy subjects displayed remarkable homogeneity in their transcriptional profiles. CHF subjects show changes in inflammatory gene expression. CHF subjects with clonal hematopoiesis share signature gene expression profiles driving similar cell fates. Subjects with CHF of ischemic origin harboring DNMT3A mutations have a worse prognosis than non-CHIP carrier CHF controls. Identification of early alterations in immune cell subsets recognized by single cell sequencing and genetic testing of CHIP mutations may detect subjects with a high risk and allow for a precision treatment of the immune disorders. Acknowledgement/Funding SFB834

Introduction Inflammation plays a crucial role in many aspects of cardiovascular disease. Particularly, acquired mutations of hematopoietic stem cells (HSC) leading to clonal expansion of inflammatory cells (CHIP) are increased with age and are associated with an enhanced risk of cardiovascular disease. The bone marrow (BM) vascular niche plays a crucial role in maintenance and regulation of HSC functions. Previous studies in mice showed the reduction of a specific Endomucin-high (H-type) endothelial cells (EC) subpopulation by aging. However, the impact of cardiovascular disease is unclear. Therefore, we aimed to investigate the effects of age and heart failure (HF) on the vascular BM cell composition in mice and humans. Methods and results Aging mice showed an age-dependent decrease of type H (Emcn-high) BM ECs (p=0.004), whereas the BM frequencies of type L (Emcn-low) ECs did not significantly differ (P=0.18). Importantly, we also observed a marked reduction of type H EC in chronic ischemic mice (P=0.016 vs. sham) indicating that chronic ischemic HF induces similar alterations of the vascular stem cell niche. Importantly, type H ECs were also significantly reduced in ischemic HF patients (n=16) compared with control subjects (n=8; P=0.0003). To gain insights into the mechanisms underlying the changes in the vascular niche, we performed single cells RNA sequencing of human BM ECs. These studies confirmed the decrease in Emcn-expressing ECs in ischemic HF patients, which was accompanied by significantly increased expression of inflammatory genes, including IL1b (P Conclusions Our data show for the first time an impact of chronic heart failure on the bone marrow vascular niche in humans. These changes seem to be strongly associated with increased inflammatory response and bone matrix remodeling in CHF. Specifically, the induction of the inflammatory cytokine IL1b may contribute to the disturbed phenotype suggesting that inhibition of IL1b (e.g. by canakinumab) may be used as a novel strategy to prevent or reverse the deterioration of the vascular BM niche.

Background The Wearable Cardioverter Defibrillator (WCD) is an effective therapy for treating ventricular arrhythmias (VT/VF) in at-risk patients, while providing continuous heart rate (HR) monitoring. Because women are under-represented in defibrillator trials, we chose to specifically focus on HR control in women prior to VT/VF events. Purpose To evaluate HR profiles preceding sustained VT/VF in women fitted with a WCD. Methods Data from women fitted with WCD (≥30 days use) from 2015 to 2018 were obtained from the manufacturer's database. HR is expressed as a weekly resting nighttime median (midnight to 7 am). Men (random sample) with the same inclusion criteria served as a control. Results A total of 21,440 women, age 67±15 years, were included for analysis. Over a median WCD use of 90 days (59–116 days), 118 women (0.6%) and 133 men (0.8%) received shocks for VT/VF (p=0.01). Resting HR one-week preceding VT/VF was above the target of 70bpm in 55% of shocked women (65 of 118) versus 44% of non-shocked women (9,272 of 21,322, p=0.01) (figure). HR one week before WCD shock was similar in women and men (71 bpm vs. 72 bpm; p=0.60). Younger women (≤50 years) had higher HR prior to shock than older women (HR 80 bpm vs. 70 bpm p=0.003). Among shocked patients, 24-hour-survival was 89% in women and 88% in men. During three-month follow-up, the same percentage of men and women died after receiving adequate WCD shock therapy (18%). Heart rate profiles Conclusions Women with adequate heart rate control experienced significantly less spontaneous VT/VF than those with higher heart rates. The WCD can be utilized as a diagnostic tool to monitor HR in at-risk women in addition to treating sustained VT/VF.

Summary: Clonal hematopoiesis of indeterminate potential (CHIP) is caused by recurrent somatic mutations leading to clonal blood cell expansion. However, direct evidence of the fitness of CHIP-mutated human hematopoietic stem cells (HSCs) in blood reconstitution is lacking. Because myeloablative treatment and transplantation enforce stress on HSCs, we followed 81 patients with solid tumors or lymphoid diseases undergoing autologous stem cell transplantation (ASCT) for the development of CHIP. We found a high incidence of CHIP (22%) after ASCT with a high mean variant allele frequency (VAF) of 10.7%. Most mutations were already present in the graft, albeit at lower VAFs, demonstrating a selective reconstitution advantage of mutated HSCs after ASCT. However, patients with CHIP mutations in DNA-damage response genes showed delayed neutrophil reconstitution. Thus, CHIP-mutated stem and progenitor cells largely gain on clone size upon ASCT-related blood reconstitution, leading to an increased future risk of CHIP-associated complications. : With age, human hematopoiesis becomes affected by blood cell clones with recurrent acquired mutations, resulting in clonal hematopoiesis (CHIP). Ortmann et al. show that hematopoietic stress caused by autologous stem cell transplantation and cytotoxic therapy promotes both size and number of mutant clones in 81 myeloma and lymphoma patients. Keywords: clonal hematopoiesis, CHIP, autologous stem cell transplantation, ASCT, hematopoietic stress, hematopoietic stem cells, clonal dominance, chemotherapy, somatic mutations, leukemia

Einleitung Patienten mit fortgeschrittener Herzinsuffizienz leiden unter wiederholten Hospitalisierungen. Nichtinvasives hamodynamisches Telemonitoring zur Bestimmung des ventrikularen Fullungsdrucks kann Hospitalisierungen reduzieren. Die Autoren berichten uber den rechtsventrikularen (RV), den pulmonalarteriellen (PA) und den linksatrialen (LA) Drucksensor zur nichtinvasiven Abschatzung des ventrikularen Fullungsdrucks.

Administration of bone marrow-derived mononuclear cells (BMC) may increase cardiac function after myocardial ischemia. However, the functional capacity of BMC derived from chronic heart failure (CHF) patients is significantly impaired. As modulation of the energy metabolism allows cells to match the divergent demands of the environment, we examined the regulation of energy metabolism in BMC from patients and healthy controls (HC). The glycolytic capacity of CHF-derived BMC is reduced compared to HC, whereas BMC of metabolically activated bone marrow after acute myocardial infarction reveal increased metabolism. The correlation of metabolic pathways with the functional activity of cells indicates an influence of metabolism on cell function. Reducing glycolysis without profoundly affecting ATP-production reversibly reduces invasion as well as colony forming capacity and abolishes proliferation of CD34+CD38− lin− hematopoietic stem and progenitor cells (HSPC). Ex vivo inhibition of glycolysis further reduced the pro-angiogenic activity of transplanted cells in a hind limb ischemia model in vivo. In contrast, inhibition of respiration, without affecting total ATP production, leads to a compensatory increase in glycolytic capacity correlating with increased colony forming capacity. Isolated CD34+, CXCR4+, and CD14+ cells showed higher glycolytic activity compared to their negative counterparts. Metabolic activity was profoundly modulated by the composition of media used to store or culture BMC. This study provides first evidence that metabolic alterations influence the functional activity of human HSPC and BMC independent of ATP production. Changing the balance between respiration and glycolysis might be useful to improve patient-derived cells for clinical cardiac cell therapy.

Parachute mitral valve (PMV) is a congenital heart anomaly which consists of a unifocal attachment of the mitral valve chordae into a single or dominant papillary muscle. This morphological anomaly determines the impairment of mitral leaflet motion, resulting in different grades of mitral stenosis. Due to its frequent association with other congenital cardiac defects requiring surgical correction, the therapy of a relevant stenotic PMV is usually represented by surgical commissurotomy. Herein is reported the case of a PMV treated by surgery in infancy, which showed a severe restenosis after 34 years and was successfully treated by percutaneous valvuloplasty with the additional creation of a restrictive atrial communication.

Cardiovascular diseases (CVD) are one of the leading causes of death. Beside established risk factors, clonal hematopoiesis of indeterminate potential (CHIP) is associated with a higher risk of CVD. CHIP is defined as the expansion of a blood cell clone by somatic mutations in individuals without hematologic diseases. Our studies focused on the questions, whether there is a different disease progression in chronic ischemic heart failure (CHF) patients with CHIP and what the consequences on blood cell lineages and hematopoietic stem and progenitor cells (HSPC) are. Therefore, we investigated a clinically well-characterized cohort of CHF patients and correlated disease progression with CHIP-mutations and investigated alterations of peripheral blood (PB) and bone marrow (BM) cells. The most recurrent mutations occurred in DNMT3A and TET2, which both epigenetically control gene expression and regulate inflammation. We demonstrated a significant association of poor prognosis in CHF and CHIP-mutations in these genes. They may causally contribute to disease progression since there was a striking dose-response between the variant allele fraction and clinical outcome. By analyzing PB and BM in CHF patients, we detected an increase of HSPCs and BM leukocyte numbers without a bias in the distribution of leukocyte lineages in the BM of CHIP carriers. In patients harboring TET2 mutations. Surprisingly, we did not determine any alterations in HSPCs in patients with a DNMT3A mutation, which contrasts the results in knock-out mouse models, showing an increased stem cell self-renewal. Whether non-mutated HSPCs are also affected in individuals with TET2 mutations in a paracrine, cell-extrinsic fashion, caused by an inflammatory milieu due to altered cytokine production, requires further investigation.

Background Previous studies highlighted the importance of adequate heart rate control in heart failure patients, and suggested under-treatment with beta-blockers especially in women. However, data on women achieving effective heart rate control during beta-blocker therapy optimization are lacking. Methods The wearable cardioverter defibrillator (WCD) allows continuous monitoring of heart rate (HR) trends during WCD use. In the current study, we assessed resting HR trends (nighttime: midnight-7am) in women, both at the beginning of WCD use and at the end of WCD use to assess the adequacy of beta-blockade following a typical 3 months of therapy optimization with beta-blockers. An adequate heart rate control was defined as having a nighttime HR Results There were a total of 21,453 women with at least 30 days of WCD use (>140 hours WCD use on the first and last week). The mean age was 67 years (IQR 58-75). The mean nighttime heart rate was 72 bpm (IQR 65-81) at the beginning of WCD use that decreased to 68 bpm (IQR 61-76) at the end of WCD use with therapy optimization. Women had an insufficient heart rate control with resting heart rate ≥ 70 bpm in 59% at the beginning of WCD use that decreased to 44% at the end of WCD use, but still remained surprisingly high. Interestingly, there were 21% of the women starting with HR ≥ 70 bpm at the beginning of use (BOU) who achieved adequate heart rate control by the end of use (EOU). Interestingly, 6% of women with adequate heart rate control at the start of therapy optimization ended up having higher heart rates >70 bpm at the end of the therapy optimization time period (Figure). Conclusions A significant proportion of women with heart failure and low ejection fraction do not reach an adequate heart rate control during the time of beta blocker initiation/titration. The wearble cardioverter defibrillator is a monitoring device that has been demonstrated in this study to appropriately identify patients with inadequate heart rate control at the end of the therapy optimization period. The WCD could be utilized to improve management of beta-blocker therapy in women and improve the achievement of adequate heart rate control in women.

Aims Regenerative therapies have evolved as a promising new option in the treatment of post-infarction heart failure. A major limitation of intracoronary application of autologous bone marrow-derived mononuclear cells (BM-MNCs) is that homing of the applied cells is profoundly reduced in patients with post-infarction heart failure compared with patients with acute myocardial infarction. However, early pilot and also randomized controlled trials have demonstrated significant improvements in overall cardiac function. The aim of the present analysis was to quantify a potential mortality risk reduction and reduced hospitalization in order to provide data for a prospective outcome trial. Methods and results The results of an ongoing single-centre registry including 297 post-infarction heart failure patients suggest that repeated intracoronary application of autologous bone marrow-derived cells is associated with a significant better 2-year survival compared with a single BM-MNC application (2-year survival 93.6 vs. 84.0%, P = 0.03). Likewise, mortality is significantly lower at 2-year follow-up compared with the mortality estimated by the use of the Seattle Heart Failure Model (SHFM) in patients receiving repeated BM-MNC application (observed mortality 6.4%, predicted mortality 16.2%, P = 0.02). Although the trend persisted at 3-year follow-up, the mortality reduction was no longer statistically significant between single and repeated treatment (mortality 21.9 vs. 13.7%, P = 0.06). Conclusion Repeated intracoronary administration of BM-MNC appears to be associated with improved clinical outcome compared with single treatment at 2 years. This registry provides the rationale for the design of the multicentre randomized, controlled, open-label REPEAT trial, which prospectively compares the effects of single vs. repeated intracoronary application of autologous BM-MNC on total and SHFM-predicted mortality in patients with chronic post-infarction heart failure.

Background In the REPAIR-AMI trial, intracoronary infusion of bone marrow-derived cells (BMCs) was associated with a significantly greater recovery of contractile function in patients with acute myocardial infarction (AMI) at 4-month follow-up than placebo infusion. The current analysis investigates clinical outcome and predictors of event-free survival at 5 years. Methods and results In the multicentre, placebo-controlled, double-blind REPAIR-AMI trial, 204 patients received intracoronary infusion of BMCs ( n = 101) or placebo ( n = 103) into the infarct vessel 3–7 days following successful percutaneous coronary intervention. Fifteen patients died in the placebo group compared with seven patients in the BMC group ( P = 0.08). Nine placebo-treated patients and five BMC-treated patients required rehospitalization for chronic heart failure ( P = 0.23). The combined endpoint cardiac/cardiovascular/unknown death or rehospitalisation for heart failure was more frequent in the placebo compared with the BMC group (18 vs. 10 events; P = 0.10). Univariate predictors of adverse outcomes were age, the CADILLAC risk score, aldosterone antagonist and diuretic treatment, changes in left ventricular ejection fraction, left ventricular end-systolic volume, and N-terminal pro-Brain Natriuretic Peptide (all P < 0.01) at 4 months in the entire cohort and in the placebo group. In contrast, in the BMC group, only the basal ( P = 0.02) and the stromal cell-derived factor-1-induced ( P = 0.05) migratory capacity of the administered BMC were associated with improved clinical outcome. Conclusion In patients of the REPAIR-AMI trial, established clinical parameters are associated with adverse outcome at 5 years exclusively in the placebo group, whereas the migratory capacity of the administered BMC determines event-free survival in the BMC-treated patients. These data disclose a potency–effect relationship between cell therapy and long-term outcome in patients with AMI.

Women at risk for sudden cardiac death (SCD) are often underrepresented in defibrillator trials and outcomes surrounding ventricular arrhythmias (VA) are therefore not well studied. The wearable-cardioverter defibrillator (WCD) is an effective short-term therapy and serves as a diagnostic tool to

Key Points Question What is the clinical significance of clonal hematopoiesis of indeterminate potential (CHIP) for chronic heart failure (CHF) owing to ischemic origin? Findings In this cohort study, CHIP had a high prevalence in 200 investigated patients with CHF. While no clinical baseline characteristics associated with CHF were different between CHIP carriers and non-CHIP carriers, except for the mean age, harboring mutations in the most prevalent driver genes associated with CHIP, namely DNMT3A and TET2, was associated with a significant and profound increase in death and rehospitalization for heart failure. Meaning Clonal hematopoiesis of indeterminate potential is presented as a newly identified risk factor for impaired long-term survival and increased disease progression in patients with CHF that may be well targetable as a valuable approach to precision medicine in patients with CHF carrying specific mutations encoding for clonal hematopoiesis., Importance Somatic mutations causing clonal expansion of hematopoietic cells (clonal hematopoiesis of indeterminate potential [CHIP]) are increased with age and associated with atherosclerosis and inflammation. Age and inflammation are the major risk factors for heart failure, yet the association of CHIP with heart failure in humans is unknown. Objective To assess the potential prognostic significance of CHIP in patients with chronic heart failure (CHF) owing to ischemic origin. Design, Setting, and Participants We analyzed bone marrow–derived mononuclear cells from 200 patients with CHF by deep targeted amplicon sequencing to detect the presence of CHIP and associated such with long-term prognosis in patients with CHF at University Hospital Frankfurt, Frankfurt, Germany. Data were analyzed between October 2017 and April 2018. Results Median age of the patients was 65 years. Forty-seven mutations with a variant allele fraction (VAF) of at least 0.02 were found in 38 of 200 patients with CHF (18.5%). The somatic mutations most commonly occurred in the genes DNMT3A (14 patients), TET2 (9 patients), KDM6A (4 patients), and BCOR (3 patients). Patients with CHIP were older and more frequently had a history of hypertension. During a median follow-up of 4.4 years, a total of 53 patients died, and 23 patients required hospitalization for heart failure. There was a significantly worse long-term clinical outcome for patients with either DNMT3A or TET2 mutations compared with non-CHIP carriers. By multivariable Cox proportional regression analysis, the presence of somatic mutations within TET2 or DNMT3A (HR, 2.1; 95% CI, 1.1-4.0; P = .02, for death combined with heart failure hospitalization) and age (HR, 1.04; 95% CI, 1.01-1.07 per year; P = .005) but not a history of hypertension remained independently associated with adverse outcome. Importantly, there was a significant dose-response association between VAF and clinical outcome. Conclusions and Relevance Our data suggest that somatic mutations in hematopoietic cells, specifically in the most commonly mutated CHIP driver genes TET2 and DNMT3A, may be significantly associated with the progression and poor prognosis of CHF. Future studies will have to validate our findings in larger cohorts and address whether targeting specific inflammatory pathways may be valuable for precision medicine in patients with CHF carrying specific mutations encoding for CHIP., This study assesses the potential prognostic significance of clonal hematopoiesis of indeterminate potential in patients with chronic heart failure owing to ischemic origin.

Aortic regurgitation was found to develop in a considerable share of patients supported with continuous flow left ventricular assist devices (LVADs). The resulting circulatory loop renders LVAD operation inefficient so that symptoms of heart failure develop in spite of high LVAD flows. In patients with a high reoperative risk, transcatheter aortic valve implantation may be considered as an alternative to reoperative valve surgical procedures. We report a case of percutaneous transcatheter aortic valve implantation using the SAPIEN S3 (Edwards Lifesciences, Inc, Irvine, CA) valve for post-LVAD aortic regurgitation.

We present the case of a 69-year-old female surviving an extensive dissecting thoracic aortic aneurysm. Due to the initial presentation with angina and epigastric pain the first working diagnosis was acute coronary syndrome. However, on transthoracic and transesophageal echocardiography (TEE), the dissecting aneurysm (type Stanford A) could be detected. Our article stresses the importance of imaging for the rapid and accurate diagnosis of thoracic aortic aneurysms with dissection. In our case, TEE detected the intimal flap separating true and false lumen, and the consecutive hemodynamically relevant aortic valve regurgitation, in addition to the aneurysm extent. The patient underwent surgical repair with aortic arch replacement and recovered without sequelae.

Defining responders to cell treatment based on functional measurements in cardiac stem cell trials has been troublesome, and it may be considered as the Holy Grail. The functional recovery after myocardial infarction (MI) can range from only mild impairments and recovery to progression into heart failure at the next clinical visit regardless of the therapy given. In a clinical trial with adequate randomization, this will not pose an issue on the overall outcome of the trial. However, subgroup analyses become difficult, as the whimsical course of the disease influences the end result on top of the effect of the cell treatment. In other words, even patients who have suffered significant loss of functional cardiac capacity may still have benefited from cell therapy compared with the potential reference point of the same patient in the placebo group. Among other reasons, this can make subgroup analyses hard to interpret and potentially less informative. Proper subgroup analyses are ideally addressing true response, based on (pre)clinical hints, and are prospectively declared. Furthermore, the power needed to show specific responding groups might be beyond the number of participants included in hitherto conducted cell therapy trials. Meta-analyses including all randomized controlled studies have consistently shown significant positive effects of treatment with bone marrow mononuclear cells (BMMNCs) after MI. Stratified subgroup meta-analyses hint toward different effects with increasing age and specific functional parameters.1 Researchers have questioned the availability and quality of autologous cells harvested from patients with multiple risk factors.2 The negative effects of endogenous risk factors on bone marrow and circulating progenitor cells have been confirmed with regard to age, smoking, heart failure, diabetes mellitus, and general risk factor profiles.2 To date, it is not known if the negative effect of clinical risk factors on BMMNC function …

Rationale: Cell therapy is a promising option for the treatment of acute or chronic myocardial ischemia. The intracoronary infusion of cells imposes the potential risk of cell clotting, which may be prevented by the addition of anticoagulants. However, a comprehensive analysis of the effects of anticoagulants on the function of the cells is missing. Objective: Here, we investigated the effects of heparin and the thrombin inhibitor bivalirudin on bone marrow–derived mononuclear cell (BMC) functional activity and homing capacity. Methods and Results: Heparin, but not bivalirudin profoundly and dose-dependently inhibited basal and stromal cell–derived factor 1 (SDF-1)–induced BMC migration. Incubation of BMCs with 20 U/mL heparin for 30 minutes abrogated SDF-1–induced BMC invasion (16±8% of control; P P Conclusions: Heparin blocks SDF-1/CXCR4 signaling by binding to the ligand as well as the receptor, thereby interfering with migration and homing of BMCs. In contrast, the thrombin inhibitor bivalirudin did not interfere with BMC homing or SDF-1/CXCR4 signaling. These findings suggest that bivalirudin but not heparin might be recommended as an anticoagulant for intracoronary infusion of BMCs for cell therapy after cardiac ischemia.

Aims We aimed to characterize the influence of acute myocardial infarction (AMI) on the metabolic activity of the bone marrow (BM) and on the composition and functional activity of BM-derived mononuclear cells (BMC). Acute ischaemia or other stressors induce the mobilization of progenitor cells from the BM stem cell niche. The effect of AMI on the numbers and functional activity of cells within the BM is unknown. Methods and results In patients of the REPAIR-AMI trial as well as in mice, the number and functionality of BMC was compared with respect to the time interval from AMI. Activation of Wnt signalling was assessed after AMI induction in TOP-GAL transgenic reporter mice, carrying a β-galactosidase gene driven by an LEF/TCF/β-catenin responsive promoter. The metabolic activity of the BM, as determined by F-18-fluorodeoxyglucose-positron emission tomography, was significantly higher in patients with AMI compared with patients with chronic post-ischaemic heart failure. Moreover, the number of haematopoietic CD34+ ( P < 0.05) and CD133+ ( P < 0.05) cells in the BM aspirates was significantly increased in patients within 7 days after AMI. In order to confirm these clinical data, we induced AMI in mice, which time-dependently increased the number of c-kit + Sca-1 + lin- cells and colony-forming units in the BM. Activation of the BM by AMI induced a significant increase in Wnt signalling, which is known to induce proliferation of haematopoietic stem cells, and demonstrated increased levels of the Wnt target Axin-2 in BM-derived cells on Day 7 ( P < 0.01 vs. control). Conclusion Acute myocardial infarction is associated with an increased metabolic activity and increased levels of progenitor cells within days after AMI. These findings document an activation of the stem cell niche within the BM following AMI, which may have important implications for the optimal timing of cell aspirations used for therapeutic application in patients with AMI.

Ischemia-induced left ventricular (LV) diastolic dysfunction (DD) is increasingly recognized as a therapeutic challenge. While DD during acute myocardial infarction (AMI) determines patients' prognosis, it is unknown how LV remodeling after AMI affects the development of DD. Therefore, we aimed to identify AMI characteristics, which determine diastolic function after 5 years.41 patients with reperfused AMI and intracoronary infusion of progenitor cells were included into the present analysis of the TOPCARE-AMI trial. At 5-year follow-up, we determined LV diastolic function including LV-filling index (E/E') by echocardiography. Diastolic function was normal in 21 patients (DD class 0), impaired in 14 patients (DD class 1) and pseudonormal in 6 patients (DD class 2). E/E' increased from DD class 0 to 2 (6.6 ± 1.3 vs. 9.0 ± 2.4 vs. 12.1 ± 6.2; p 0.01). E/E' correlated with the maximal creatine kinase activity during AMI (CKMB(max) r = 0.73, p 0.01), the change in end-diastolic or end-systolic LV volumes between AMI and 4 months (∆LVEDV r = 0.67, p 0.01; ∆LVESV r = 0.58, p 0.01), ejection fraction at 5 years (r = -0.47, p 0.01) and NT-proBNP serum levels at 5 years (r = 0.37, p 0.05). Multivariate analysis revealed CKMB(max) (β = 0.56, p 0.01) and ∆LVEDV (β = 0.38, p 0.01) as independent predictors for E/E' 5 years after AMI.Adverse early remodeling processes (reflected by LV dilatation between infarction and 4 months) determine long-term diastolic function in patients after reperfused AMI and progenitor cell therapy.

In the aftermath of myocardial infarction, increased loading conditions will trigger hypertrophy of viable myocardium. This in turn causes deterioration of regional contractility. Cardiac magnetic resonance imaging (cMRI) allows the exact differentiation of viable and infarcted myocardium and therefore the measurement of regional wall thickness and function. Bone marrow-derived stem cell (BMC) transfer has been shown to improve global function and remodeling. The present study examines the effect of BMC transfer on regional remodeling and function after myocardial infarction by cMRI. Fifty-four patients of the MR substudy of the REPAIR-AMI trial have been studied at baseline and 12-month follow-up. Enddiastolic wall thickness (EDWT) and wall thickening (WT%) have been measured on SSFP cine sequences. Enddiastolic wall thickness decreased in both placebo and BMC groups in viable as well as infarcted segments. The effect was largest in the pre-specified subgroup of patients below the median EF of 48.9% (infarcted segments −1.14 mm Placebo vs. −1.91 mm BMC, p for interaction 0.01, remote segments −0.19 mm Placebo vs. −0.94 mm BMC, p for interaction 0.00001). Corrected for baseline values BMC therapy yielded smaller EDWT at 12 months in infarcted and remote segments (infarcted 7.58 mm Placebo vs. 6.13 mm BMC p = 0.0001, remote 8.76 mm Placebo vs. 7.32 mm BMC, p = 0.0001). This was associated with better contractility within the infarcted segments among BMC patients (WT% 24.17% Placebo vs. 49.31% BMC, p = 0.0001). The WT% was inversely correlated with EDWT (r = −0.37, p = 0.0001). Bone marrow-derived stem cell therapy yields smaller EDWT when compared with placebo patients suggesting a positive effect on maladaptive hypertrophy of viable myocardium. This notion is supported by the enhanced regional contractility within the BMC group which is inversely correlated with EDWT.

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 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.

Aims Depressed left ventricular ejection fraction (LVEF) despite successful reperfusion therapy is the single most powerful predictor of progressive LV enlargement after acute myocardial infarction (AMI) and independently determines adverse outcome in these patients. Methods and results We investigated the effect of intracoronary administration of bone marrow-derived mononuclear cells (BMC) within 7 days after successful reperfusion therapy for AMI, on early (within 4 months) LV remodelling processes assessed by quantitative LV angiography. Overall, 95 patients received BMC and 92 patients received placebo. Remodelling was assessed as the changes in either LVEF and end-systolic volume (ESV) or stroke volume and end-diastolic volume (EDV) at 4 months, respectively. Baseline LVEF was inversely correlated with ESV expansion at 4 months in the placebo group, but not in the BMC group. Likewise, EDV expansion was significantly correlated with baseline LVEF in the placebo (r = −0.36, P < 0.001), but not in the BMC group (r = −0.17, P = 1.0). Analysing the interaction between convalescent LV contractile function and LV volumes revealed that the increase in LVEF or stroke volume did not occur at the expense of increases in ESV or EDV, respectively, in the BMC group. Conclusion Intracoronary administration of BMC eliminates the correlation between depressed LVEF after reperfusion therapy and LV expansion during follow-up and, thereby, abrogates early LV remodelling after AMI.

Background— Intracoronary administration of bone marrow–derived progenitor cells (BMC) was shown to improve coronary microvascular function in ischemic heart disease. Because coronary microvascular dysfunction is implicated in the pathogenesis and prognosis of nonischemic dilated cardiomyopathy (DCM), we investigated the effects of intracoronary BMC administration in patients with DCM. Methods and Results— Intracoronary infusion of BMC was performed in 33 patients with DCM by using an over-the-wire balloon catheter. Left ventricular contractility at baseline and after 3 months was assessed by analysis of left ventricular angiograms. Coronary hemodynamics were determined by intracoronary Doppler wire measurements. After 3 months, regional wall motion of the target area (contractility from −1.08�0.39 to −0.97�0.47 SD/chord, P =0.029) and global left ventricular ejection fraction (from 30.2�10.9 to 33.4�11.5%, P P =0.002, n=24), whereas no changes were observed in the reference vessel (from 1.60�0.45 to 1.49�0.45 mm Hg � s/cm; P =0.133, n=13). Twelve months after BMC infusion, N-terminal prohormone brain natriuretic peptide (NT-proBNP) serum levels were decreased, suggesting a beneficial effect on left ventricular remodeling processes (from 1610�993 to 1473�1147 pg/mL; P =0.038 for logNT-proBNP, n=26). Conclusions— Intracoronary administration of BMC seems to be associated with improvements in cardiac contractile and microvascular function in patients with DCM. Thus, randomized blinded studies are warranted to evaluate potential clinical benefits of intracoronary BMC administration in patients with DCM.

Objective— We have previously demonstrated that ischemic cardiomyopathy is associated with selective impairment of progenitor cell function in the bone marrow and in the peripheral blood, which may contribute to an unfavorable left ventricular remodeling process. Methods and Results— With this study, we intended to identify the influence of telomere length on bone marrow functionality in 50 patients with coronary artery disease (CAD) and previous myocardial infarction. Mean telomere length (mTL) was measured simultaneously in peripheral blood leukocytes and mononuclear bone marrow cells (BMC), using the flow-FISH method. Telomere erosion already occurred at the bone marrow level, whereby age (39 bp/yr, P =0.025) and the number of affected vessels (434 bp/vessel, P =0.029) were the only independent predictors. Lymphocytes demonstrated significant TL shortening between BMCs and peripheral blood in CAD patients (−1011±897 bp) as opposed to an increase in a young control group (+235±459 bp, P r =0.42, P P Conclusion— In patients with CAD, telomere shortening of BMCs is dependent on both age and the extent of CAD and correlates with bone marrow cell functionality.

Background— The Doppler Substudy of the randomized, double-blind, placebo-controlled Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial aimed to investigate the effects of intracoronary infusion of bone marrow–derived progenitor cells (BMCs) on coronary blood flow regulation in patients with reperfused acute myocardial infarction. Methods and Results— In a total of 58 patients (BMC group, n=30; placebo group, n=28), coronary flow reserve (CFR) in the infarct artery and a reference vessel was assessed by intracoronary Doppler at the time of study therapy (4.2±0.1 days after acute myocardial infarction) and at the 4-month follow-up. Initial CFR was reduced in the infarct artery compared with the reference vessel in both groups (BMC: 2.0±0.1 versus 2.9±0.2, P P P P =0.005 versus placebo) in BMC-treated patients, resulting in a normalization of CFR (3.8±0.2; P P P Conclusions— Intracoronary BMC therapy after acute myocardial infarction restores microvascular function of the infarct-related artery, which is associated with a significant improvement in maximal vascular conductance capacity. These data provide clinical proof of concept that progenitor cell transplantation promotes vascular repair.

Background: The bone marrow vascular niche is essential for hematopoietic regeneration. Patients with chronic heart failure are characterized by myelosuppresion and anemia. Therefore, in order to investigate whether chronic heart failure is associated with an impairment in the vascular niche of the bone marrow, we measured in bone marrow plasma levels of the prototypical angiogenic factor PlGF (placental growth factor), as well as, its soluble inhibitor, sFlt-1 (Fms-like tyrosine kinase 1), which acts as a decoy receptor for PlGF, as a measure of the functional integrity of the vascular bone marrow niche. Methods and Results: Bone marrow plasma levels of sFlt-1 and PlGF were determined by ELISA in 187 patients (mean age: 62.2±11.3years) with chronic heart failure, who were enrolled in the Frankfurt Bone Marrow-Derived Mononuclear Cell Therapy Registry. Fifty-one patients died within the 5-year follow-up period. Patients with increased bone marrow-derived sFlt-1/PlGF ratio had a 1.35-fold increased risk for death (95%CI: 1.08 to 1.68, p=0.007). This association was robust after adjustment for age, gender, left ventricular ejection fraction (LVEF), eGFR and NT-proBNP serum levels (HR:1.3, 95%CI: 1.014 to 1.678, p=0.038) or the Seattle Heart Failure score (HR:1.38, 95%CI: 1.112 to 1.723, p=0.004). Importantly, this association remained significant even after adjustment for colony-forming unit capacity (HR:1.33, 95%CI: 1.051 to 1.675, p=0.018) and SDF-1-induced migratory capacity of bone marrow-derived cells (HR:1.35, 95%CI: 1.087 to 1.678, p=0.007). Conclusions: The present study for the first time discloses that an impairment of the angiogenic potential of the bone marrow microenvironment, defined as increased sFlt-1 to PlGF ratio in the bone marrow plasma, is independently associated with mortality in patients with chronic heart failure. These data further corroborate the importance of the bone marrow-heart axis to predict clinical outcome in patients with chronic heart failure.

Background: Administration of autologous bone marrow-derived mononuclear cells (BM-MNC) resulted in favorable outcomes after myocardial infarction (MI) compared to placebo in the REPAIR-AMI trial. Pre-clinical studies have shown that individual risk factors negatively influence cell function. To date, it is not known how these risk factors modify treatment effect in clinical trials and if potential (non-)responders can be identified. Aim: To investigate the effect of individual risk factors on functional outcome after BM-MNC therapy and to establish a prediction model for treatment response in patients with MI. Methods: Data from the REPAIR-AMI trial were used, consisting of 186 patients who had complete baseline and follow-up measurements. We performed univariable and multivariable linear regression with 18 predefined baseline characteristics using the difference in baseline EF and after 4 months (ΔEF4) as primary outcome. Our main goal was to identify interaction terms of predictors with BM-MNC treatment; i.e. effect modifiers of treatment response. An individual estimate of treatment effect over placebo (ΔΔEF4) was created by extrapolating an ‘untreated’ reference value for ΔEF4, based on the placebo-arm and comparing it to the observed value after treatment. Treatment response was defined as a ΔΔEF4 of >5% (so 5% over a predicted placebo value). Discrimination was quantified by the area under the ROC-curve (AUC). Results: The predictors age, weight, baseline EF and ESV showed an interaction with cell treatment in multivariable analysis with backward selection. Subsequently, the prediction model for individual ΔΔEF4 included age (-0.18/year, p=0.008), weight (+0.16/kg, p=0.01), baseline EF (-0.46/%, p=0.0001) and ESV (-0.09/ml, p=0.06). The predictive capacity for response to therapy showed an AUC of 79.2% (95% CI 69.7-88.6), which retained 74.8% (95% CI 65.0-84.5) after shrinkage. Conclusion: Response to BM-MNC administration after MI is influenced by age, weight, and baseline cardiac parameters. Using these continuous predictors, potential treatment responders can be accurately identified. Interestingly, an adverse risk-factor profile was associated with greater response, with potential implications for future patient selection.

Device-related infections in recipients of left ventricular assist devices (LVAD) have been recognized as a major source of morbidity and mortality. They require a high level of diagnostic effort as part of the overall burden resulting from infectious complications in LVAD recipients. We present a multi-allergic patient who was treated for persistent sterile intrathoracic abscess formation and pericardial empyema following minimally invasive LVAD implantation including use of a sheet of e-polytetrafluoroethylene (ePTFE) membrane to restore pericardial integrity. Sterile abscess formation and pericardial empyema recurred after surgical removal until the ePTFE membrane was removed, suggesting that in disposed patients, ePTFE may be related to sterile abscess formation or sterile empyema.

Background Pilot studies suggest that intracoronary transplantation of progenitor cells derived from bone marrow (BMC) or circulating blood (CPC) may improve left ventricular function after acute myocardial infarction. The effects of cell transplantation in patients with healed myocardial infarction are unknown. Methods After an initial pilot trial involving 17 patients, we randomly assigned, in a controlled crossover study, 75 patients with stable ischemic heart disease who had had a myocardial infarction at least 3 months previously to receive either no cell infusion (23 patients) or infusion of CPC (24 patients) or BMC (28 patients) into the patent coronary artery supplying the most dyskinetic left ventricular area. The patients in the control group were subsequently randomly assigned to receive CPC or BMC, and the patients who initially received BMC or CPC crossed over to receive CPC or BMC, respectively, at 3 months’ follow-up. Results The absolute change in left ventricular ejection fraction was significantly greater among patients receiving BMC (+2.9 percentage points) than among those receiving CPC (−0.4 percentage point, P = 0.003) or no infusion (−1.2 percentage points, P

Background Pilot trials suggest that the intracoronary administration of autologous progenitor cells may improve left ventricular function after acute myocardial infarction. Methods In a multicenter trial, we randomly assigned 204 patients with acute myocardial infarction to receive an intracoronary infusion of progenitor cells derived from bone marrow (BMC) or placebo medium into the infarct artery 3 to 7 days after successful reperfusion therapy. Results At 4 months, the absolute improvement in the global left ventricular ejection fraction (LVEF) was significantly greater in the BMC group than in the placebo group (mean [±SD] increase, 5.5±7.3% vs. 3.0±6.5%; P = 0.01). Patients with a baseline LVEF at or below the median value of 48.9% derived the most benefit (absolute improvement in LVEF, 5.0%; 95% confidence interval, 2.0 to 8.1). At 1 year, intracoronary infusion of BMC was associated with a reduction in the prespecified combined clinical end point of death, recurrence of myocardial infarction, and any revascularization procedure (P = 0.01). Conclusions Intracoronary administration of BMC is associated with improved recovery of left ventricular contractile function in patients with acute myocardial infarction. Largescale studies are warranted to examine the potential effects of progenitor-cell administration on morbidity and mortality. (ClinicalTrials.gov number, NCT00279175.)

Aims Experimental and clinical pilot studies suggest that intracoronary progenitor cell infusion can improve left ventricular function and remodelling after acute myocardial infarction (AMI). Since progenitor cells are also known to be involved in restenosis development and atherosclerosis progression, an increased restenosis rate may be a risk of intracoronary cell therapy. Methods We performed a retrospective study to compare quantitative angiographic measurements of the infarct target vessel in 83 patients with AMI treated with bare metal stent PCI (matched control) and in 83 patients receiving additional intracoronary progenitor cell infusion at a mean of 5 days post-AMI stent PCI and after 4 months. Results The late loss as a measure of neointima formation was similar between the control and the cell-treated group at follow-up (0.9±0.8 vs. 0.9±0.7 mm, P =0.9). Moreover, restenosis rate was comparable in both groups (35% control vs. 27% cell-treated group, P =0.2). Multivariable analysis excluded cell therapy as an independent significant predictor of increased late loss ( P =0.4), whereas acute gain ( P =0.012) and diabetes mellitus ( P =0.002) were independent predictors of late loss. Finally, in the cell-treated group, target vessel revascularization rate remained at 28.9% during a median of >3 years of follow-up, thus excluding an effect on atherosclerotic disease progression. Conclusion In patients with AMI successfully treated with bare metal stent PCI, additional intracoronary progenitor cell infusion does not lead to an increased neointima formation within the implanted stent within 4 months or aggravation of atherosclerotic disease progression.

Coronary microvascular dysfunction contributes to infarct extension and poor prognosis after an acute myocardial infarction (AMI). Recently, progenitor cell application has been demonstrated to improve neovascularization and myocardial function after experimental myocardial infarction. Therefore, we investigate coronary blood flow regulation in patients after AMI treated with intracoronary progenitor cell therapy. In the TOPCARE-AMI trial, patients received either bone marrow-derived or circulating progenitor cells into the infarct-related artery 3–7 days after AMI. The present substudy investigates in 40 patients coronary blood flow regulation at the time of progenitor cell therapy and at 4-month follow-up by i.c. Doppler in the infarct artery as well as a reference vessel. At the initial measurement, coronary flow reserve (CFR) was reduced in the infarct artery compared to the reference vessel (median 2.5 vs. 3.4, p

The diagnosis of nonischemic dilated cardiomypathy (DCM) comprises a primary myocardial disease of various causes, which is characterized by left ventricular (LV) dilation and impaired myocardial contractility. Although a broad range of pharmacological and device therapies are available, morbidity and mortality remain high in patients with advanced DCM. Thus, there is an urgent need for novel therapies aiming at functional regeneration of myocardial contractility in DCM. Although regenerative therapies using administration of a variety of different cell types have emerged as a promising approach to improve heart function in patients with ischemic disease,1 only a few pilot studies have investigated intracoronary application of autologous bone marrow–derived cells (BMC) in patients with DCM. Seth et al2 performed intracoronary infusion of BMC in 24 patients with DCM and reported a modest 5% increase in LV ejection fraction in parallel with an increased ratio of capillaries to myocytes as evidenced by endomyocardial biopsies at 6 months. In the TOPCARE-DCM pilot study including 33 patients, the improvement in global and regional LV contractile function was rather heterogeneous but was also paralleled by improved microvascular function as assessed by measuring coronary flow reserve at 3 months after intracoronary infusion of BMC.3 Article, see p 165 In this issue of Circulation Research , Vrtovec et al4 now considerably extend these previous observations. The authors randomized 110 patients with DCM to either intracoronary …

Objectives The Transplantation of Progenitor Cells And Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trial investigates both safety, feasibility, and potential effects on parameters of myocardial function of intracoronary infusion of either circulating progenitor cells (CPC) or bone marrow-derived progenitor cells (BMC) in patients with acute myocardial infarction (AMI). Background In animal experiments, therapy with adult progenitor cells was shown to improve vascularization, left ventricular (LV) remodeling, and contractility after AMI. Methods A total of 59 patients with AMI were randomly assigned to receive either CPC (n = 30) or BMC (n = 29) into the infarct artery at 4.9 ± 1.5 days after AMI. Results Intracoronary progenitor cell application did not incur any measurable ischemic myocardial damage, but one patient experienced distal embolization before cell therapy. During hospital follow-up, one patient in each cell group developed myocardial infarction; one of these patients died of cardiogenic shock. No further cardiovascular events, including ventricular arrhythmias or syncope, occurred during one-year follow-up. By quantitative LV angiography at four months, LV ejection fraction (EF) significantly increased (50 ± 10% to 58 ± 10%; p Conclusions Intracoronary infusion of progenitor cells (either BMC or CPC) is safe and feasible in patients after AMI successfully revascularized by stent implantation. Both the excellent safety profile and the observed favorable effects on LV remodeling, provide the rationale for larger randomized double-blind trials.

PS analyses, the authors found that the results betweenthese two techniques were not materially different inmost of these studies. Even if the results were differentbetween the two approaches, one could not necessarilyassume that the PS analysis yielded the ‘true’ answer,at least not without specifying underlying assumptions.In general, the approach of using traditional multi-variate regression adjustment is preferable if the sam-ple size is sufficiently large and the outcome of interestis not rare. Only if the outcome is rare relative to thenumber of confounders and the number of studysubjects in the smaller exposure group is sufficientlylarge to warrant multivariable PS estimation, then thisstatistical technique has a legitimate role to potentiallyreduce bias and expand the possibilities in observa-tional outcomes research [6]. Only then, the use of PScan be regarded a substantial help, not just hype.

UNLABELLED The number of elderly patients with coronary heart disease is rapidly growing. Morbidity, related with PTCA is increased in elderly patients, presumably because of the more complex adverse baseline characteristics. However, it has not been firmly elucidated whether routine use of coronary stents is associated with a more favourable outcome in this population. Therefore, we investigated the influence of age on acute procedural success, rate of restenosis (quantitative coronary angiography) and major cardiovascular events (death/myocardial infarction [MI]) 6 months after intra-coronary stent implantation in 1306 patients. Patients were categorised into 75 years (n= 154). RESULTS Older patients had a higher amount of multivessel disease (p 75 years 7.8%, p = 0.02). However, by multivariate analysis age was no longer an independent predictor of adverse clinical events (p = 0.26), which were predominantly determined by coexisting impaired left ventricular function (p < 0.001). CONCLUSION After proper judgement of the clinical situation, coronary stent implantation should be considered in selected elderly patients. Thus, advanced age as a solely factor should not be regarded as a contraindication for coronary stent implantation.

Endothelial progenitor cells (EPCs) play an important role in postnatal neovascularization of ischemic tissue. Ex vivo expansion of EPCs might be useful for potential clinical cell therapy of myocardial ischemia. However, cultivation of primary cells leads to cellular aging (senescence), thereby severely limiting the proliferative capacity. Therefore, we investigated whether statins might be able to prevent senescence of EPCs. EPCs were isolated from peripheral blood and characterized. After ex vivo cultivation, EPCs became senescent as determined by acidic β-galactosidase staining. Atorvastatin or mevastatin dose-dependently inhibited the onset of EPC senescence in culture. Moreover, atorvastatin increased proliferation of EPCs as assessed by BrdU incorporation and colony-forming capacity. Whereas geranylgeranylpyrophosphate or farnesylpyrophosphate reduced the senescence inhibitory effect of atorvastatin, NO synthase inhibition, antioxidants, or Rho kinase inhibitors had no effect. To get further insights into the underlying downstream effects of statins, we measured telomerase activity and determined the expression of various cell cycle regulatory genes by using a microarray assay. Whereas telomerase activity did not change, atorvastatin modulated expression of cell cycle genes including upregulation of cyclins and downregulation of the cell cycle inhibitor p27 Kip1 . Taken together, statins inhibited senescence of EPCs independent of NO, reactive oxygen species, and Rho kinase, but dependent on geranylgeranylpyrophosphate. Atorvastatin-mediated prevention of EPC senescence appears to be mediated by the regulation of various cell cycle proteins. The inhibition of EPC senescence and induction of EPC proliferation by statins in vitro may importantly improve the functional activity of EPCs for potential cell therapy.

Angiotensin II (Ang II) is central to the pathobiology of atherosclerosis. In endothelial cells (EC), Ang II induces apoptosis. The MAP kinase ERK1/2 plays a key role in regulating cell survival. We therefore investigated the effect of Ang II on ERK1/2. Incubation of EC with Ang II led to the dephosphorylation of ERK1/2 (43 % of control). To characterize the phosphatase involved, we investigated the effect of Ang II on MAP kinase phosphatase expression. Ang II induced MAP kinase phosphatase-3 (MKP-3) mRNA levels to about 2-fold, whereas MKP-1 expression was not affected. Transfection with a dominant negative MKP-3 construct (dnMKP-3mt) prevented the Ang II-induced ERK1/2 dephosphorylation and apoptosis in EC (p < 0.001). ERK1/2 inactivation has been shown to result in the dephosphorylation and proteasomal degradation of the antiapoptotic protein Bcl-2. Ang II induced the degradation of Bcl-2 wild type, whereas the dephosphorylation-resistant Bcl-2 construct mimicking phosphorylation by ERK1/2 was resistant to Ang II stimulation. These results indicate that Ang II-induced apoptosis signaling in human EC is mediated via MKP-3-dependent dephosphorylation of ERK1/2, which in turn leads to the degradation of Bcl-2.

Cell therapy of acute myocardial infarction (AMI) with bone marrow-derived mononuclear cells (BMC) resulted in a modest improvement of cardiac function, but clinical trial results were heterogeneous. After isolation, BMC are maintained in medium supplemented with complements such as autologous serum to maintain optimal cell viability until administration. In the REPAIR-AMI trial, serum was prepared using tubes containing coagulation accelerators, but the regulatory agency recommended using additive-free tubes for the pivotal BAMI trial. Here, we show that serum obtained from patients with anti-thrombotic therapy in tubes without coagulation accelerators induces clotting, thereby rendering the cell product unsuitable for intra-coronary application. Specifically, systemic treatment of patients with low doses of heparin prevented efficient coagulation ex vivo, and the resulting partially clotted plasma induced cell aggregation within 1-18 h in the cell product. Utmost care has to be taken to test autologous components of cell products before clinical use. The development of media including the appropriate recombinant growth factors for maintaining cell functionality ex vivo may be warranted.

Aims The objective of the present analysis was to systematically examine the effect of intracoronary bone marrow cell (BMC) therapy on left ventricular (LV) function after ST-segment elevation myocardial infarction in various subgroups of patients by performing a collaborative meta-analysis of randomized controlled trials. Methods and results We identified all randomized controlled trials comparing intracoronary BMC infusion as treatment for ST-segment elevation myocardial infarction. We contacted the principal investigator for each participating trial to provide summary data with regard to different pre-specified subgroups [age, diabetes mellitus, time from symptoms to percutaneous coronary intervention, infarct-related artery, LV end-diastolic volume index (EDVI), LV ejection fraction (EF), infarct size, presence of microvascular obstruction, timing of cell infusion, and injected cell number] and three different endpoints [change in LVEF, LVEDVI, and LV end-systolic volume index (ESVI)]. Data from 16 studies were combined including 1641 patients (984 cell therapy, 657 controls). The absolute improvement in LVEF was greater among BMC-treated patients compared with controls: [2.55% increase, 95% confidence interval (CI) 1.83-3.26, P < 0.001]. Cell therapy significantly reduced LVEDVI and LVESVI (-3.17 mL/m(2), 95% CI: -4.86 to -1.47, P < 0.001; -2.60 mL/m(2), 95% CI -3.84 to -1.35, P < 0.001, respectively). Treatment benefit in terms of LVEF improvement was more pronounced in younger patients (age < 55, 3.38%, 95% CI: 2.36-4.39) compared with older patients (age >= 55 years, 1.77%, 95% CI: 0.80-2.74, P 0.03). This heterogeneity in treatment effect was also observed with respect to the reduction in LVEDVI and LVESVI. Moreover, patients with baseline LVEF, < 40% derived more benefit from intracoronary BMC therapy. LVEF improvement was 5.30%, 95% CI: 4.27-6.33 in patients with LVEF,40% compared with 1.45%, 95% CI: 0.60 to 2.31 in LVEF >= 40%, P < 0.001. Noclear interaction was observed between other subgroups and outcomes. Conclusion Intracoronary BMC infusion is associated with improvement of LV function and remodelling in patients after ST-segment elevation myocardial infarction. Younger patients and patients with a more severely depressed LVEF at baseline derived most benefit from this adjunctive therapy.

Heart failure is frequently called the new epidemic of the 21st century, since the prevalence of this malignant disease has remained high through the last decade,1 mostly driven by the increased survival of patients with large acute myocardial infarctions. Established therapies aim at reducing preload, afterload, and neurohumoral activation, as well as mineralocorticoid dysregulation. However, the underlying ongoing loss of cardiomyocytes, which is followed by fibrosis, is only marginally influenced. Article, see p 1361 Cell therapy offers the attractive toolkit to improve cardiac function and to reduce adverse left ventricular remodeling.2 The scientific approach of using cell therapy generates new understandings for disease pathology, progression, and endogenous repair capacity. As part of a landmark investigation, the annual cardiomyocyte turnover-rate was estimated to be 1% in young adults, which decreases to 0.5% in the elderly, suggesting that approximately half of the heart’s muscle cells are renewed during lifespan.3 However, this endogenous repair capacity is not sufficient to cope with the loss of cardiomyocytes after acute myocardial infarction or other heart diseases. Enhancement of endogenous repair processes, optimally within a preconditioned microenvironment, would therefore offer unprecedented tools to enhance regenerative capacity and to modify adverse left ventricular remodeling. Indeed, supported by preclinical studies, numerous phase I and phase II clinical trials have been initiated and completed for more than 10 years now, testing various cell types and application protocols in a huge heterogeneity of patient conditions.4 However, clinical progress in developing convincing and successful therapies was rather modest, which can in part be attributed to rather small, underpowered trials using surrogate endpoints and open-label treatment approaches carrying the risk of bias. In an effort to overcome some of the mentioned limitations …