[Pulmonary hypertension in adults with congenital heart disease in light of the 2022-ESC-PAH guidelines - Part II: Supportive therapy, special situations (pregnancy, contraception, non-cardiac surgery), targeted pharmacotherapy, organ transplantation, special management (shunt lesions, left ventricular disorders, univentricular hearts), interventions, intensive care, follow-up, future perspectives]. / Pulmonale Hypertonie bei Erwachsenen mit angeborenen Herzfehlern im Lichte der 2022-ESC-PAH-Leitlinien.

The number of adults with congenital heart defects (CHD) is steadily rising and amounts to approximately 360,000 in Germany. CHD is often associated with pulmonary hypertension (PH), which may develop early in untreated CHD. Despite timely treatment of CHD, PH not infrequently persists or recurs in older age and is associated with significant morbidity and mortality.The revised European Society of Cardiology/European Respiratory Society 2022 guidelines for the diagnosis and treatment of PH represent a significant contribution to the optimized care of those affected. However, the topic of "adults with congenital heart disease" is addressed only relatively superficial in these guidelines. Therefore, in the present article, this topic is commented in detail from the perspective of congenital cardiology.

Continuous Long-Term Assessment of Heart Rate Variability in Adults with Cyanotic Congenital Heart Disease after Surgical Repair.

Background: Heart rate variability (HRV) is an established, non-invasive parameter for the assessment of cardiac autonomic nervous activity and the health status in general cardiology. However, there are few studies on HRV in adults with congenital heart defects (CHDs). The aim of the present study was to evaluate the use of long-term continuous HRV measurement for the assessment of global health status in adults with cyanotic CHD. Methods: This prospective study included 45 adults (40% female, mean age = 35.2 ± 9.2 [range: 19-58] years) after cardiac surgical repair. HRV parameters were calculated from continuous 24 h measurements using a Bittium Faros 180 sensor (Bittium Corp., Oulu, Finland). Results: Postoperative patients with transposition of the great arteries (TGA) (n = 18) achieved significantly higher values of standard deviation of NN intervals (SDNN) (175.4 ± 59.9 ms vs. 133.5 ± 40.6 ms; p = 0.013) compared with patients with other conotruncal anomalies (n = 22). Comparing patients with TGA after a Senning-Brom or Mustard operation (n = 13) with all other heart surgery patients (n = 32), significantly higher HRV parameters were found after atrial switch (root mean square of successive RR interval differences: 53.6 ± 20.7 ms vs. 38.4 ± 18.3 ms; p = 0.019; SDNN: 183.5 ± 58.4 ms vs. 136.3 ± 45.3 ms; p = 0.006). A higher SDNN was also measured after Senning-Brom or Mustard operations than after a Rastelli operations (n = 2) (SDNN: 183.5 ± 58.4 ms vs. 84.5 ± 5.2 ms; p = 0.037). When comparing atrial switch operations (n = 3) with Rastelli operations, the SDNN value was significantly shorter in the Rastelli group (p = 0.004). Conclusions: Our results suggest that continuous HRV monitoring may serve as a marker of cardiac autonomic dysfunction in adults with cyanotic CHD after surgical repair. Impaired cardiac autonomic nervous activity may be associated with an increased risk of adverse reactions in patients with repaired CHD. Therefore, a longitudinal assessment of HRV patterns and trends may provide a deeper insight into dynamic changes in their autonomic regulation and disease progression, lifestyle changes, or treatments. As each person has individual variability in heart rate, HRV may be useful in assessing intra-individual disease progression and may help to improve personalized medicine. Further studies are needed to better understand the underlying mechanisms and to explore the full potential of HRV analysis to optimize medical care for ACHDs.

PATHFINDER-CHD: prospective registry on adults with congenital heart disease, abnormal ventricular function, and/or heart failure as a foundation for establishing rehabilitative, prehabilitative, preventive, and health-promoting measures: rationale, aims, design and methods.

BACKGROUND: Adults with congenital heart defects (ACHD) globally constitute a notably medically underserved patient population. Despite therapeutic advancements, these individuals often confront substantial physical and psychosocial residua or sequelae, requiring specialized, integrative cardiological care throughout their lifespan. Heart failure (HF) is a critical challenge in this population, markedly impacting morbidity and mortality. AIMS: The primary aim of this study is to establish a comprehensive, prospective registry to enhance understanding and management of HF in ACHD. Named PATHFINDER-CHD, this registry aims to establish foundational data for treatment strategies as well as the development of rehabilitative, prehabilitative, preventive, and health-promoting interventions, ultimately aiming to mitigate the elevated morbidity and mortality rates associated with congenital heart defects (CHD). METHODS: This multicenter survey will be conducted across various German university facilities with expertise in ACHD. Data collection will encompass real-world treatment scenarios and clinical trajectories in ACHD with manifest HF or at risk for its development, including those undergoing medical or interventional cardiac therapies, cardiac surgery, inclusive of pacemaker or ICD implantation, resynchronization therapy, assist devices, and those on solid organ transplantation. DESIGN: The study adopts an observational, exploratory design, prospectively gathering data from participating centers, with a focus on patient management and outcomes. The study is non-confirmatory, aiming to accumulate a broad spectrum of data to inform future hypotheses and studies. PROCESSES: Regular follow-ups will be conducted, systematically collecting data during routine clinical visits or hospital admissions, encompassing alterations in therapy or CHD-related complications, with visit schedules tailored to individual clinical needs. ASSESSMENTS: Baseline assessments and regular follow-ups will entail comprehensive assessments of medical history, ongoing treatments, and outcomes, with a focus on HF symptoms, cardiac function, and overall health status. DISCUSSION OF THE DESIGN: The design of the PATHFINDER-CHD Registry is tailored to capture a wide range of data, prioritizing real-world HF management in ACHD. Its prospective nature facilitates longitudinal data acquisition, pivotal for comprehending for disease progression and treatment impacts. CONCLUSION: The PATHFINDER-CHD Registry is poised to offer valuable insights into HF management in ACHD, bridging current knowledge gaps, enhancing patient care, and shaping future research endeavors in this domain.

[Pulmonary arterial hypertension in congenital heart disease - Part I]. / Pulmonale arterielle Hypertonie bei Erwachsenen mit angeborenen Herzfehlern ­ Teil I.

The number of adults with congenital heart disease (CHD) is steadily rising and amounts to approximately 360,000 in Germany. CHD is often associated with pulmonary arterial hypertension (PAH), which may develop early in untreated CHD. Despite timely treatment of CHD, PAH often persists or recurs in older age and is associated with significant morbidity and mortality.The revised European Society of Cardiology/European Respiratory Society 2022 guidelines for the diagnosis and treatment of PH represent a significant contribution to the optimized care of those affected. However, the topic of "adults with congenital heart defects" is addressed only relatively superficially in these guidelines. Therefore, this article addresses the perspective of congenital cardiology in greater depth.

Long-term course of pulmonary arterial hypertension in adults with congenital heart disease under targeted therapy: a retrospective analysis of a single tertiary center.

Background: Pulmonary arterial hypertension (PAH), a common complication in adults with congenital heart disease (CHD), leads to significant morbidity and mortality. Targeted PAH medication is available, but PAH-CHD patient data are limited. Several questions regarding indication, treatment escalation, and combination therapy remain unanswered. The aim of this study was therefore to evaluate PAH-specific treatment in adults with PAH-CHD to better understand PAH-specific therapy management. Methods: In this cross-sectional study we retrospectively examined clinical, demographic, and cardiac-catheterization data and medical management for PAH-CHD, and analyzed clinical course and midterm outcome. Results: Over up to 14 years (median, 6.2 years), 103 PAH-CHD patients (66% female) receiving targeted PAH-therapy for pre-tricuspid-shunt (15.5%), post-tricuspid-shunt (32.0%), and complex CHD (52.4%) were followed. Based on modified clinical European Society of Cardiology (ESC) classification, patients were assigned to the following subgroups: Eisenmenger syndrome (ES) (45.6%), severe pulmonary vascular disease (PVD) in complex CHD (20.4%), post-repair patients (19.4%), prevalent systemic-to-pulmonary shunt (3.9%), coincidental/small defects (0%), and Fontan circulation (10.7%). Changes in targeted PAH therapy were observed 249 times, with up to 6 (median, 2) therapy changes over a median period of 1.3 years. Over the study course, the medical treatment strategy changed towards combination therapy (baseline, 13.6%; study-end, 41%), resulting mostly in stabilized functional class or even improvement in cases of prevalent systemic-to-pulmonary shunt, ES, and patients with repaired CHD. Functional class deterioration, however, was seen in patients with severe PVD due to complex CHD, and Fontan patients. Of the 103 patients in the study, 25 died (24.3%). Patients with repaired CHD and patients with systemic-to-pulmonary shunt or ES showed the best survival rates. Mortality was remarkably higher in patients with severe PVD in complex CHD and Fontan patients. Conclusions: Many patients with PAH-CHD benefited from targeted PAH therapy over a median period of 6.2 years. Treatment decisions after targeted PAH-medication initiation were based mainly on clinical assessment. To counteract disease progression, an escalation towards combination therapy was observed during the study course. We consider survival rates under targeted PAH medication to be favorable, particularly in the ES subgroup. Nevertheless, further research is needed to optimize the use of PAH medication, especially in patients with complex CHD.

Left Ventricular Strain Analysis During Submaximal Semisupine Bicycle Exercise Stress Echocardiography in Childhood Cancer Survivors.

Background Childhood cancer survivors (CCSs) show relevant cardiac morbidity and mortality throughout life. Early detection is key for optimal support of patients at risk. The aim of this study was to evaluate 2-dimensional speckle-tracking echocardiography strain analysis during semisupine exercise stress in CCSs for detection of subclinical left ventricular dysfunction after cancer treatment. Methods and Results Seventy-seven CCSs ≥1-year postchemotherapy were prospectively examined at rest, low, and submaximal stress level and compared with a cohort of healthy adolescents and young adults (n=50). Global longitudinal strain (GLS), short axis circumferential strain, and corresponding strain rates were analyzed using vendor-independent software. CCSs at median 7.8 years postchemotherapy showed comparable left ventricular GLS, circumferential strain, and strain rate values at all stress stages to healthy controls. Yet, prevalence of abnormal GLS (defined as <2 SD of controls reference) in CCSs was 1.3% at rest, 2.7% at low, and 8.6% at submaximal stress. In CCSs, relative change of circumferential strain from rest to submaximal stress was lower than in healthy controls, median 16.9 (interquartile range [IQR], 3.4; 28.8) % versus 23.3 (IQR, 11.3; 33.3) %, P=0.03, most apparent in the subgroups of CCSs after high-dose anthracycline treatment and cancer diagnosis before the age of 5 years. Conclusions In this prospective 2-dimensional speckle tracking echocardiography strain study, prevalence of abnormal left ventricular GLS increased with stress level reflecting impaired cardiac adaptation to exercise stress in some CCSs. However, relatively early after last chemotherapy, this did not result in significant differences of mean GLS-, circumferential strain-, and strain rate values between CCSs and controls at any stress level.

Quality of life in adults with congenital heart disease with and without pulmonary hypertension: a comparative study.

Background: Pulmonary vascular disease and pulmonary hypertension (PH) belong to the most relevant complications of congenital heart disease (CHD) in the long-term course. Although PH might lead to a severely impaired quality of life (QOL), there are no current studies comparing QOL in adults with CHD (ACHD) with and without PH. Therefore, this study aimed to systematically examine QOL in ACHD with and without PH in order to generate a more differentiated understanding of their overall health-status and to employ newly gained findings into general care of this particular patient population. Methods: In this comparative cross-sectional study, a representative sample of 803 adults with various forms of CHD with or without PH was analyzed. Data collection took place between September 2017 until February 2018 in a tertiary care center for ACHD. Medical data was retrieved from medical records. QOL was assessed using the EQ-5D-5L questionnaire. Descriptive methods, chi-square and t-tests were used to compare QOL of patients with and without PH. Results: Of 803 patients, 752 patients had no PH [93.6%; 47.3% female; mean age: 34.9±11.83 (range, 18-86) years], 51 were identified with manifest PH [6.4%; 55.8% female; mean age: 41.9±12.17 (range, 21-69) years]. PH patients showed significantly worse overall QOL [mean no PH: 86.78±13.30 (8.2-100) vs. mean PH: 81.79±12.77 (43.6-100); 95% confidence interval (CI): 1.43 to 9.46; P=0.013], worse crosswalk index [mean no PH: 93.29±12.86 (-11, 100) vs. mean PH: 89.73±11.77 (47-100); 95% CI: 0.08 to 7.56; P=0.043], and worse VAS [mean no PH: 80.12±16.50 (15-100) vs. mean PH: 72.56±16.80 (40-100); 95% CI: 3.29 to 12.17; P=0.004]. However, after adjusting for age, only the VAS stayed significant (P=0.039). The QOL within the dimensions mobility (P<0.001), self-care (P=0.002), and usual activities (P=0.007), were significantly decreased in PH patients. Overall, anxiety and depression (11.08%) as well as pain and discomfort (11.03%) were the most impaired dimensions in both patient groups. Conclusions: Since QOL is a significant predictor of outcome, PH-CHD patients need an early provision of psychosocial, health promoting support in addition to dedicated care and targeted PH treatment. It is therefore pivotal to timely identify unique psychosocial impairments in order to enhance quantity and QOL in this particularly vulnerable patient population.

Healthcare status of adults with pulmonary hypertension due to congenital heart disease.

Background: In the long-term course of treated and untreated congenital heart defects (CHD), pulmonary hypertension (PH) is one of the most relevant complications. Since PH carries a high risk for mortality and morbidity, it is important to improve the status of healthcare and medical knowledge regarding the affected patients. Therefore, this study aimed to determine the current medical care status, health-related knowledge, and specific counseling needs of adults with various forms of CHD (ACHD) who are at increased risk of developing PH, as well as those with manifest PH. Methods: In this retrospective cross-sectional study, a representative sample of 803 ACHD were analyzed. Patients were split into three groups based on CHD: low risk for PH, at risk for pre- or post-capillary PH, and manifest PH. Data collection took place between September 2017 until February 2018 in a tertiary care center for ACHD. Healthcare status and specific needs for information or advice were analyzed using a questionnaire designed by our group. The state of knowledge of the patients was assessed by comparing this questionnaire and the corresponding medical records. Results: Both patients with manifest PH (n=51) and patients at risk to develop PH (n=629) were insufficiently informed about their health status, specific care structures available to them, and patient organizations. About 50% of the patients had specific counseling needs, especially regarding physical capability and sports, daily stress, rehabilitation measures, and pregnancy. Only 47.8% of patients with manifest PH were aware of suffering from PH (P<0.001). In particular, the patients had large knowledge deficits regarding comorbidities related to their health condition. Conclusions: PH is a quantitatively and qualitatively underestimated residuum or sequela of CHD that significantly affects outcome and prognosis in ACHD. Multidisciplinary, structured, and specific counseling of affected individuals with corresponding risk constellations is urgently needed. A prerequisite for this is closer collaboration between primary care physicians (PCPs), such as general practitioners, family physicians, internists, or general cardiologists, and ACHD specialists. Targeted patient counseling and care could have a positive impact on the level of awareness of those affected and favorably influence their prognosis.

Systematic assessment of health care perception in adults with congenital heart disease in Germany.

BACKGROUND: The number of adults with congenital heart disease (ACHD) is steadily rising due to increased survival rate and improved medical resources. Accordingly, more than 330,000 ACHD are currently living in Germany. Almost all of them require lifelong specialized medical follow-up for their chronic heart disease, often accompanied by residua, sequelae, or comorbidities. Primary care physicians (PCPs) are a crucial factor in directing patients to ACHD specialists or specialized institutions, but despite all efforts, the number of ACHD under specialized care is low, the lost-to-follow-up rate is high, and the morbidity and mortality is substantial. The present cross-sectional study was designed to systematically characterize the health care of ACHD from a patient perspective, including (I) use of medical care by ACHD, (II) medical counselling needs, and (III) perceived satisfaction with health care. METHODS: The German-wide analysis was based on a 25-item questionnaire designed to address different aspects of medical status and health issues of ACHD from their own perspective, performed between May of 2017 and July of 2020. RESULTS: A total of 4,008 ACHD (52% female; mean age 41.9±17.2 years) completed the questionnaire. The majority of ACHD (3,524, 87.9%) reported, that they consulted their PCP for non-cardiac health problems, and 49.7% (n=1,991) consulted their PCP also for medical problems associated with the underlying CHD. Almost all ACHD reported a need for medical advice concerning exercise capacity and daily life activities, occupational skills, pregnancy, rehabilitation, genetic counselling, insurance, and retirement. A total of 1,840 (45.9%) patients were not aware of the existence of certified ACHD specialists or centers. Moreover, 2,552 (67.6%) of those surveyed were uninformed about patient organizations for ACHD. CONCLUSIONS: The present study demonstrates that ACHD are largely uninformed about the ACHD care structures available nationwide, although the patients have a great need for specialized follow-up, advice, and care.

Left Ventricular Strain and Strain Rate during Submaximal Semisupine Bicycle Exercise Stress Echocardiography in Healthy Adolescents and Young Adults: Systematic Protocol and Reference Values.

OBJECTIVE: Combining stress echocardiography with strain analysis is a promising approach for early detection of subclinical cardiac dysfunction not apparent at rest. Data on normal myocardial strain and strain rate (SR) response to exercise in adolescents and young adults are contradictory and limited. The aim of this study was to propose a standardized protocol for semisupine bicycle stress echocardiography and to provide corresponding reference values of left ventricular (LV) two-dimensional speckle-tracking echocardiography (2D STE) strain and SR in adolescents and young adults. METHODS: Fifty healthy adolescents and young adults (mean age, 17.8 ± 3.2 years, 44% female) were prospectively assessed. Images were acquired at rest, low stress, submaximal stress, and during recovery. Optimal image quality for offline strain analysis was pursued, and image quality was rated. Global longitudinal strain and SR from apical four-/two-/three-chamber views and short-axis circumferential strain and SR were analyzed using vendor-independent software. Interobserver variability was assessed. RESULTS: Strain and SR increased during progressive exercise stress. Mean LV global longitudinal strain was -20.4% ± 1.3%, SR -1.1 ± 0.15/sec at rest (heart rate, 79.4 ± 12.0 beats/minute), increasing to -22.6% ± 1.6% and -1.5 ± 0.16/sec at low stress level (heart rate, 117.1 ± 8.7 beats/minute) and -23.7% ± 1.1% and -1.9 ± 0.29/sec at submaximal stress level (heart rate, 154.2 ± 7.0 beats/minute), respectively, returning to -20.6% ± 1.4% and -1.2 ± 0.16/sec postexercise (heart rate, 90.1 ± 9.4 beats/minute). Restriction on submaximal stress level ensured adequate image quality for 2D STE strain analysis. Interobserver variability for strain was acceptable even during submaximal stress. CONCLUSIONS: This study provides a systematic, standardized protocol and corresponding reference data for 2D LV STE-derived strain and SR during semisupine bicycle exercise testing in adolescents and young adults. According to our results, global longitudinal strain and SR appear to be the most comprehensible parameters for cross-sectional studies.

Heart Rate Response During Treadmill Exercise Test in Children and Adolescents With Congenital Heart Disease.

Background: Impaired exercise capacity is a common feature of congenital heart disease (CHD). In adults with CHD, it has been shown that impaired heart rate response during exercise may contribute to exercise limitation. Systematic data in children and adolescents on this topic is limited. We therefore purposed to assess heart rate response during treadmill exercise testing in children and adolescents with CHD compared to healthy controls. Methods: One hundred and sixty three children and adolescents (103 with CHD, median age 15 years and 60 age-matched controls) performed cardiopulmonary exercise testing and were included in this study. Beyond peak oxygen consumption, increase in heart rate from resting level to peak exercise (heart rate reserve) and decrease of heart rate after peak exercise (heart rate recovery) were measured. Chronotropic index was defined as percentage of age predicted maximal heart rate reserve. According to data from adults on bicycle exercise, chronotropic incompetence was assumed for chronotropic index below 0.8. Results: While resting heart rate was similar between both groups, peak heart rate, heart rate reserve as well as chronotropic index were lower in the CHD group than in controls. Chronotropic index was lowest in patients with single ventricle hemodynamics and correlated with peak oxygen consumption. Heart rate recovery was impaired in the CHD group 1 and 2 min after peak exercise compared to controls and correlated with peak oxygen consumption. Chronotropic index below 0.8 was a relatively frequent finding even in the control group suggesting that the threshold of 0.8 appears inadequate for the identification of chronotropic incompetence using treadmill exercise testing in children. After normalizing to the 2.5th chronotropic index percentile of the control group we obtained a chronotropic incompetence threshold of 0.69. Conclusion: As an adjunct to measurement of peak oxygen consumption, heart rate response to exercise appears to be a physiologically important diagnostic parameter in children and adolescents with CHD. However, interpretation of heart rate response needs to consider specific age characteristics and the mode of exercise test. Our data may help future studies on chronotropic incompetence using treadmill ergometer protocols in children and adolescents.

Impact of the Right Ventricular Sokolow-Lyon Index in Children with Idiopathic Pulmonary Arterial Hypertension.

Right ventricular (RV) hypertrophy is regarded as the adaptation on chronic RV pressure load in pulmonary hypertension. As the RV Sokolow-Lyon index (RVSLI) is an electrocardiographic marker of RV hypertrophy, we hypothesized that RVSLI might be able to reflect RV pressure load. Therefore, the purpose of this study was to characterize the diagnostic impact of the RVSLI in children with idiopathic pulmonary arterial hypertension (IPAH) in order to assess disease severity and to evaluate its value for the prediction of worse outcome. Forty-two children (aged 3-17 years) with IPAH were included in this retrospective study. The follow-up after baseline examination was 59 ± 17 months. Receiver-operating characteristic (ROC) curves and Kaplan-Meier analysis were used to discriminate a cut-off value of RVSLI and to assess its predictive value regarding morbidity and mortality. In 12/42 patients (29%) severe cardiovascular events (defined as death, lung transplantation, or Potts shunt) were observed (time to event 20 ± 22 months). Patients with an event showed higher RVSLI values (3.6 ± 1.2 mV vs. 2.6 ± 1.6 mV; p < 0.05). ROC analysis discriminated an RVSLI of 2.1 as the best cut-off value (area under the ROC curve: 0.79, sensitivity: 0.91, specificity: 0.70, p < 0.05) to detect patients with high-risk PAH (mPAP/mSAP ratio > 0.75). Relative risk for a severe event with an index > 2.1 mV was 1.76 (95% CI 1.21-3.20). Relative risk for death with RVSLI > 2.1 mV was 2.01 (95% CI 1.61-4.80). Our study demonstrates a strong relationship between RVSLI and disease severity in children with IPAH. An RVSLI > 2.1 mV at the time of first diagnosis is a predictor for patients at risk for cardiac events. As an adjunct to the usual diagnostic assessment this parameter may therefore contribute to the initial prognostic estimation.

Impact of cell number and microvascular obstruction in patients with bone-marrow derived cell therapy: final results from the randomized, double-blind, placebo controlled intracoronary Stem Cell therapy in patients with Acute Myocardial Infarction (SCAMI) trial.

BACKGROUND: In patients with acute myocardial infarction (AMI), the number of transplanted autologous bone-marrow cells (BMC) has been linked to improvement in left ventricular ejection fraction (LVEF). Complete obstruction of myocardial microvasculature is indicated by microvascular obstruction (MO) in cardiac magnetic resonance imaging (CMR). We analyzed whether the number of transplanted cells and presence of MO were associated with improved LVEF in the double-blind, placebo-controlled, randomized intracoronary Stem Cell therapy in patients with Acute Myocardial Infarction (SCAMI) trial. METHODS AND RESULTS: Patients (N = 42) received study therapy mean 7 days after AMI. Median number of transplanted BMC was 324 × 10(6). CMR was performed prior to study therapy and annually up to 3 years and revealed no difference between BMC and placebo population. Patients treated with a cell number above the median experienced a significant improvement in LVEF compared with patients with cell number below the median 3.6 ± 3.4 versus -0.5 ± 6.4 % (difference 4.1, 95 % CI 0.2 to 8.1 %, p = 0.04) at 6 months. The difference in LVEF change between the groups remained with 3.8 % (p = 0.12) at 12 months, 4.5 % (p = 0.07) at 24 months and 5.6 % (p = 0.03) at 36 months. BMC treated patients without MO experienced a better improvement in LVEF compared with patients with MO at 6, 12, 24 and 36 months with 3.5, 5.3, 6.4 and 3.2 %. CONCLUSIONS: In the randomized, placebo-controlled double-blind SCAMI trial improvement in LVEF up to 3 years was higher in BMC patients treated with a high cell number or without MO.

Results of intracoronary stem cell therapy after acute myocardial infarction.

To assess the effect of autologous bone-marrow cell (BMC) therapy in patients with acute myocardial infarction in a rigorous double-blind, randomized, placebo-controlled trial. Patients with reperfusion >6 hours after symptom onset were randomly assigned in a 2:1 ratio to receive intracoronary BMC or placebo therapy 5 to 7 days after symptom onset. The patients were stratified according to age, acute myocardial infarction localization, and left ventricular (LV) function. Rigorous double-blinding was ensured using autologous erythrocytes for the placebo preparation that was visually indistinguishable from the active treatment. Serial cardiac magnetic resonance imaging studies were performed before study therapy and after 1, 3, and 6 months. The primary end point was the difference in the LV ejection fraction from baseline to 6 months. The secondary end points included changes in the LV end-diastolic and end-systolic volume indexes and infarct size. A total of 42 patients were enrolled (29 in the BMC group and 13 in the placebo group) in the integrated pilot phase. A mean of 381 x 10(6) mononuclear BMCs were administered. The baseline clinical and cardiac magnetic resonance imaging parameters did not differ. Compared to baseline, the difference in LV ejection fraction for the placebo group versus BMC group was 1.7 +/- 6.4% versus -0.9 +/- 5.5% at 1 month, 3.1 +/- 6.0% versus 1.9 +/- 4.3% at 3 months, and 5.7 +/- 8.4% versus 1.8 +/- 5.3% at 6 months (primary end point; not significant). No difference was found in the secondary end points between the 2 groups, including changes in infarct size or LV end-diastolic and end-systolic volume indexes. In conclusion, in this rigorous double-blind, randomized, placebo-controlled trial, we did not observe an evidence for a positive effect for intracoronary BMC versus placebo therapy with respect to LV ejection fraction, LV volume indexes, or infarct size.