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Background— The progression of compensated hypertrophy to heart failure (HF) is still debated. We investigated patients with isolated valvular aortic stenosis and differing degrees of left ventricular (LV) systolic dysfunction to test the hypothesis that structural remodeling, as well as cell death, contributes to the transition to HF. Methods and Results— Structural alterations were studied in LV myectomies from 3 groups of patients (group 1: ejection fraction [EF] >50%, n=12; group 2: EF 30% to 50%, n=12; group 3: EF 1 were upregulated correlating with fibrosis, which increased 2.3-, 2.2-, and 3.2-fold over control in the 3 groups. Myocyte degeneration increased 10, 22, and 32 times over control. A significant correlation exists between EF and myocyte degeneration or fibrosis. Ubiquitin-related autophagic cell death was 0.5‰ in control and group 1, 1.05 in group 2, and 6.05‰ in group 3. Death by oncosis was 0‰ in control, 3‰ in group 1, and increased to 5‰ (groups 2 and 3). Apoptosis was not detectable in control and group 3, but it was present at 0.02‰ in group 1 and 0.01‰ in group 2. Cardiomyocyte mitosis was never observed. Conclusions— These structure-function correlations confirm the hypothesis that transition to HF occurs by fibrosis and myocyte degeneration partially compensated by hypertrophy involving DNA synthesis and transcription. Cell loss, mainly by autophagy and oncosis, contributes significantly to the progression of LV systolic dysfunction.

Left ventricular (LV) enlargement is the most important independent determinant of adverse outcome in patients (pts) after AMI. Depressed LV ejection fraction (LVEF) despite successful reperfusion therapy is the single most powerful predictor of progressive LV enlargement after AMI. Therefore, we investigated whether the intracoronary (i.c.) administration of bone marrow-derived progenitor cells (BMC) alters the association between LVEF within 7 days after successful reperfusion therapy for AMI and enddiastolic (EDV) and endsystolic (ESV) volume expansion at 4 months. In the REPAIR-AMI trial paired quantitative LV angiographic data at baseline (4.3 ± 1 days after AMI reperfusion) and at 4 months follow-up were available in 187 pts. 95 pts received i.c. BMC (4.4±1 days post AMI reperfusion therapy), whereas 92 pts received placebo at 4.3 ± 1 days after reperfusion. Baseline LVEF were similar in the BMC (47±10%) and in the placebo group (48±9 %, p = n.s.). At 4 months, ESV increased in the placebo (+6±22ml), but not in the BMC group (−0.6±19ml, p = 0.04 vs. placebo). Baseline LVEF was inversely correlated with ESV expansion at 4 months in the placebo, but not in the BMC group (figure ). Likewise, EDV expansion was closely correlated with baseline LVEF in the placebo (r=−0.36, p Conclusion: I.c. administration of BMC eliminates the correlation between depressed LVEF after reperfusion therapy and LV expansion during follow-up and thereby abrogates progressive LV enlargement after AMI. Change in endsystolic volume (baseline to 4 months , ml)

Background: The paradigm that the heart is a terminally differentiated organ has recently been challenged since some studies reported the ability of bone marrow (BM) derived cells to transdifferentiate into cardiomyocytes after myocardial damage. However, the physiological role of bone marrow derived cells during the lifespan of an undamaged heart is widely unknown. We therefore examined the quantity and phenotype of bone marrow derived cells in aged murine hearts. Methods: 12-week-old mice (n=20) were sublethally irradiated and BM from enhanced green fluorescent-transgenic (eGFP) littermates was transplanted. After 1 month 5 mice were sacrificed and served as control. The remaining mice were sacrificed after 18.2±1.1 months. Immunohistochemistry was performed in 10 hearts using titin antibodies to identify cardiomyocytes, vimentin for fibroblasts, sMemb for myofibroblasts, α-smooth muscle actin for smooth muscle cells, F4/80 for macrophages, BS-1 and CD31 for endothelial cells. Additionally, anti-eGFP immunostaining was used to exclude autofluorescence. Sections were analyzed using fluorescence and confocal laser microscopy. The remaining 5 hearts were digested with collagenase and cell sorting was performed for a quantification of BM-derived cells in relation to eGFP negative cells. Results: BM transplantation was successful as FACS analysis showed 92±5% eGFP expressing leukocytes after 1 month and 78±6% after 18 months. In the juvenile hearts only few eGFP-positive cells were detected ( Conclusion: The present study demonstrates for the first time a substantial recruitment and accumulation of BM derived cells in the ageing myocardium suggesting their contribution in cell turnover of the heart during the lifespan of mice.

Eighteen days after having received conservative treatment for a myocardial infarction, a 65-year-old patient developed acute right heart failure caused by a ventricular septal rupture. Progressive multiorgan failure contraindicated open heart surgery. Therefore, we implanted a ventricular septal defect occluder via a venous approach as an emergency intervention, thereby achieving stabilization of the patient within 24 hours. After another 6 weeks, an aneurysmectomy was planned because a remarkable aneurysm of the anterior wall, including the part of the septum in which the occluder was located, was detected by echocardiography and magnetic resonance imaging. During open heart surgery, the occluder was …

Background We tested the hypothesis that hibernating myocardium represents an incomplete adaptation to a reduced myocardial oxygen supply. Methods and Results In 38 patients, areas of hibernating myocardium were identified by angiography, multigated radionuclide ventriculography, thallium scintigraphy with reinjection, and low-dose dobutamine echocardiography. Biopsies removed at cardiac surgery showed structural degeneration characterized by a reduced protein and mRNA expression and disorganization of the contractile and cytoskeletal proteins myosin, actin, desmin, titin, α-actinin, and vinculin by electron microscopy, immunohistochemistry, and in situ hybridization. Additionally, an increased amount of extracellular matrix proteins resulting in a significant degree of reparative fibrosis was present. Dedifferentiation, ie, expression of fetal proteins, was absent. Apoptosis indicating suicidal cell death was found by the terminal deoxynucleotidyl transferase end-labeling method and electron microscopy. Radionuclide ventriculography showed improvement of regional function at 3 months postoperatively compared with preoperative values (mean values, 23.5% and 48%, respectively), and the echocardiographic wall-motion score index decreased from 3.4 to 1.8. The degree of severity of the morphological changes (three stages) correlated well with the extent of postoperative functional recovery: more advanced clinical improvement was observed in patients with slight and moderate morphological degeneration (stages 1 and 2), but recovery was only partial in severe degeneration (stage 3). Conclusions Cellular degeneration rather than adaptation is present in hibernating myocardium. The consequence is progressive diminution of the chance for complete structural and functional recovery after restoration of blood flow. The practical consequence from this study should be early revascularization in patients showing areas of hibernating myocardium.