[Despite medication, overdrive pacing is required to stabilize the electrical storm associated with acute coronary syndrome: a case report].

A 75-year-old female complained of severe chest pain and was emergently admitted to our hospital because of anterior acute myocardial infarction. Emergent coronary angiography was performed and revealed occlusion in segment 7, so a stent was implanted. Lidocaine, carvedilol, amiodarone, magnesium, and nifekalant were administered successively because non-sustained ventricular tachycardia (NSVT) frequently appeared like an electrical storm. After nifekalant administration, QTc was significantly prolonged and torsades de pointes was induced. Overdrive pacing was performed and finally the NSVT was completely controlled. If fatal arrhythmias such as NSVT show resistance to medication, overdrive pacing should be considered to stabilize the arrhythmia associated with acute coronary syndrome.

[Coronary ectasia resulting in thrombotic coronary occlusion after warfarin interruption: a case report].

A 68-year-old man taking aspirin and warfarin for ectatic right coronary artery complained of chest pain and was admitted to our hospital with acute myocardial infarction. He had discontinued taking warfarin due to nail bleeding for a month. Coronary angiography revealed total occlusion at segment 3 of the ectatic right coronary artery with massive thrombus. Because of unsuccessful reperfusion by an aspiration device, a 5F straight catheter was inserted into the ectatic right coronary artery to aspirate the massive thrombus, and Thrombolysis in Myocardial Infarction grade 3 flow reperfusion was obtained. Intravascular ultrasonography showed "moyamoya" vessels in the ectatic right coronary artery, suggesting an abnormal coronary flow pattern, but there was no evidence of unstable plaque. Warfarization should be considered to treat ectatic coronary artery.

Bone marrow cell-seeded biodegradable polymeric scaffold enhances angiogenesis and improves function of the infarcted heart.

BACKGROUND: The present study examined whether a bioengineered polyglycolic acid cloth (PGAC) impregnated with bone marrow cells (BMC) improved the function and angiogenesis of the infarcted heart. METHODS AND RESULTS: The coronary artery was ligated in Lewis rats and the infarcted area was covered with a PGAC in group 1 (n=8), with a PGAC containing basic-fibroblast growth factor (b-FGF) in group 2 (n=11) and a PGAC containing b-FGF and freshly isolated BMC in group 3 (n=10). In addition, BMC derived from transgenic mice expressing green fluorescent protein (GFP)-BMC were seeded into a PGAC, which was sutured over the infarcted area of C57BL/6 mice (n=5). In the rat study, developed and systolic pressures, dp/dt max and dp/dt min) were the highest in group 3, as were the capillary density in the PGAC and infarcted area. In the mouse study, there were few GFP-BMC in the PGAC, but none in the infarcted area. CONCLUSIONS: A PGAC with BMC improved cardiac function by inducing angiogenesis without migration of BMC. Freshly isolated BMC work as angiogenic inducers and a PGAC is useful as a "drug delivery system".

[Coronary artery embolism from ruptured plaque in the left main trunks with difficulty in detection of culprit lesion: a case report].

A 60-year-old man complained of severe chest pain and was emergently admitted to our hospital with a dignosis of anterior acute myocardial infarction. Emergent coronary angiography revealed significant stenosis in segment 7 and filling defect in segment 11 without flow delay. Haziness was observed in segment 5. Coronary thromboembolism was suspected, but the embolic source or culprit lesion was hard to detect. Intravascular ultrasonography detected ruptured plaque with lipid pooling in segment 5. Stent implantation for segment 5 was performed successfully and the patient had an excellent clinical course. Coronary thromboembolism is rare and intravascular ultrasonography may be useful to detect the culprit lesion.

Endogenous bone-marrow-derived stem cells contribute only a small proportion of regenerated myocardium in the acute infarction model.

BACKGROUND: Our recent study showed that granulocyte-colony stimulating factor (G-CSF) promoted bone-marrow cells (BMC) to migrate into the infarcted heart and that they differentiated into cardiomyocytes. However, we still do not know to what degree bone-marrow-derived cardiomyocytes contribute to myocardial regeneration after injury. In this study, we verified the proportional contribution of cells from bone marrow (BM) and from non-bone marrow (n-BM) in regenerating neomyocardium after myocardial infarction. METHODS: Eight C57BL/6 mice were irradiated (900 cGy), and green fluorescent protein (GFP) mouse-derived BMCs (GFP-BMC, 1 x 10(6) cells) were injected. Four weeks later, the left descending coronary artery was ligated. Recombinant human G-CSF (200 microg/kg/day, 8 days) was injected. At 4 weeks after ligation, hearts were fixed for histology. We calculated the proportions of cardiomyocytes derived from BM and n-BM after taking the chimeric rate into consideration. RESULTS: The chimeric rate was 54.6% +/- 5.9%. At the infarcted border area, the total cell number was 1000.3 +/- 56.5/mm(2), and mobilized BM-derived GFP-BMC was 103.3 +/- 13.1/mm(2). After compensation with the chimeric rate, we found BM-derived troponin I-positive cells at 23.9 +/- 4.1/mm(2), nestin-positive cells at 12.9 +/- 2.6/mm(2), and Ki67-positive cells at 18.3 +/- 2.6/mm(2), respectively. We found significant differences in the contribution of troponin I-(6.7% +/- 1.7% vs 93.3% +/- 1.7%), nestin- (2.4 +/- 0.5 vs 97.6 +/- 0.5), and Ki67-positive (3.9 +/- 1.0 vs 96.1 +/- 1.0) cells derived from BM and n-BM. CONCLUSIONS: Bone marrow was one of the origins of regenerated cardiomyocytes; however, the contribution of cells from BM was very small compared with those of n-BM origin in the infarction model.

Granulocyte-colony stimulating factor enhanced the recruitment of bone marrow cells into the heart: time course evaluation of phenotypic differentiation in the doxorubicin-induced cardiomyopathic model.

OBJECTIVE: We traced and evaluated bone marrow-derived cells after granulocyte-colony stimulating factor (G-CSF) treatment in the doxorubicin-induced cardiomyopathic heart in the time course. METHODS: C57BL/6 male mice received doxorubicin (15 mg/kg, i.p.). At 1 week after administration of doxorubicin, the mice were irradiated (900 cGy) followed by transplantation of bone marrow cells (BMT) derived from transgenic mice expressing green fluorescent protein (GFP) (1 x 10(6)) via a tail vein (BMT). G-group (n = 22) received G-CSF (50 microg/kg/day x 8 days, s.c.) after BMT, while C-group (n = 17) received saline. At 4 and 7 weeks after BMT, heart sections were fixed to evaluate bone marrow-derived GFP cells (BMD-GFP) with immunostaining for Troponin I (TnI), atrial-natriuretic peptide (ANP), connexin 43, von Willebrand factor, and Ki67. RESULT: There were migrated BMD-GFP in the whole heart of all animals. In the time course, migrated BMD-GFP increased in G-group. At 7 weeks the number of migrated BMD-GFP in G-group (56.2 +/- 15.6/HPF) was larger than that in C-group (18.9 +/- 10.7/HPF) (p < 0.05). TnI- and connexin 43-positive BMD-GFP were spindle-shaped. Von Willebrand factor-positive BMD-GFP showed thinner-shape. ANP- and Ki67-positive BMD-GFP showed oval-shape. The numbers of these positive cells derived from BMD-GFP, not different between the 2 groups, did not change from 4 to 7 weeks. CONCLUSION: The migration of BMD-GFP into the heart increased from 4 to 7 weeks after BMT by G-CSF. However, cardiomyocytes and endothelial cells originating from BMD-GFP were very few and neither increased nor changed in their shapes and numbers in the short term.

Bone marrow is a source of regenerated cardiomyocytes in doxorubicin-induced cardiomyopathy and granulocyte colony-stimulating factor enhances migration of bone marrow cells and attenuates cardiotoxicity of doxorubicin under electron microscopy.

BACKGROUND: It has been reported previously that granulocyte colony-stimulating factor (GCSF) injection improves infarcted heart function, but the mechanism remains unclear. In this study we sought to determine whether GCSF-mobilized bone marrow cells could regenerate neo-myocardium and repair doxorubicin-induced cardiomyopathy. METHODS: C57BL/6 mice were irradiated and bone marrow cells (BMC; 1 x 10(6)) from green fluorescent protein (GFP) mice (GFP-BMC) were transplanted intravenously, followed by splenectomy. Doxorubicin (2.5 mg/kg, 6 times for 2 weeks) was administered intraperitoneally 2 weeks later. GCSF (50 microg/kg/day for 8 days) was administered sub-cutaneously after doxorubicin injection (Group I, n = 11) and 3 weeks later (Group II, n = 8), and saline was injected in Group III animals (n = 8). Eight weeks after doxorubicin injection, the excised hearts were studied immunologically and electron microscopically. RESULTS: Survival rates were 81.8% in Group I, 50.0% in Group II and 62.5% in Group III. The number of GFP-BMC in Group I (15.4 +/- 7.4 per high-power field) was highest (p < 0.05). In all groups, cardiac troponin I-positive cells derived from GFP-BMC were observed in the hearts. GFP-BMC in hearts stained positively against cardiac troponin I (4.3 +/- 2.5%), myosin heavy chain (5.0 +/- 4.3%), atrial natriuretic peptide (ANP; 3.9 +/- 2.4%) and connexin 43 (11.9 +/- 7.3%) in Group I. Myofibrils, mitochondria and fundamental architecture were almost all preserved in Group I, whereas hearts were severely damaged in Groups II and III. CONCLUSIONS: Bone marrow was shown to be one of the sources of regenerated cardiomyocytes in the doxorubicin-induced cardiomyopathic heart. Early administration of GCSF enhanced the migration of bone marrow cells into the heart, and attenuated the cardiotoxicity of doxorubicin.

Bone marrow mononuclear cell transplantation had beneficial effects on doxorubicin-induced cardiomyopathy.

BACKGROUND: Cell transplantation is a promising therapy for treating end-stage heart failure. Bone marrow mononuclear cells (BMMNC) have been used to enhance angiogenesis in ischemic heart disease. However, the effect of BMMNC transplantation in non-ischemic dilated cardiomyopathy is unknown. In this study, we evaluated the efficacy of BMMNC transplantation in doxorubicin-induced cardiomyopathy in a rat model. METHODS: Doxorubicin (15 mg/kg, IP) was introduced into 52 Lewis rats. They were divided into 3 groups at 4 weeks after injection: transplant group (TX, BMMNC [1 x 10(6)] implantation, n = 18), control group (CN, saline injection, n = 18), and sham group (SH, thoracotomy, n = 16). At 4 weeks after surgery, we used echocardiography to measure systolic left ventricular diameter (LVDs), diastolic left ventricular diameter (LVDd), fractional shortening (FS), and left ventricular wall thickness/LVDs. We used a Langendorff apparatus to measure systolic, diastolic, and developed pressures. We used radioimmunoassay to measure circulating atrial natriuretic peptide concentration, and we performed histologic study, including electron-microscopic study. RESULTS: Left ventricular wall thickness/LVDs in the TX group was the largest of all groups (p < 0.05). Systolic and developed pressures in the TX group were the greatest (p < 0.005). Systolic left ventricular diameter, FS, and end-diastolic pressure in the TX group were smaller than in the SH group (p < 0.05). These cardiac parameters did not differ significantly between TX and CN groups, but secondary changes (decreased heart weight, developed ascites, and increased atrial natriuretic peptide concentration) caused by doxorubicin-induced heart failure were most attenuated in the TX group. In the TX group, vascular density was greatest (p < 0.05) in the left ventricular free wall and in the septum. In addition, electron microscopy showed that myocardium in the TX group was most maintained. CONCLUSION: Bone marrow mononuclear cell transplantation had beneficial effects in doxorubicin-induced cardiomyopathy.

A novel application of myocardial contrast echocardiography to evaluate angiogenesis by autologous bone marrow cell transplantation in chronic ischemic pig model.

OBJECTIVES: We investigated the feasibility of myocardial contrast echocardiography (MCE) to evaluate regional perfusion after bone marrow cell transplantation. BACKGROUND: The myocardial microvessels improved by cell transplantation are too small to visualize with conventional angiography. METHODS: Fourteen mini-pigs from the Nippon Institute for Biological Science were used. The proximal left anterior descending coronary artery was ligated. One month later, nine pigs survived. Six pigs received autologous cell transplantation into the left ventricular anterior wall: bone marrow mononuclear cells (BMMNCs) (n = 3) and bone marrow stromal cells (BMSCs) (n = 3). The other three pigs received saline (control group, n = 3). The pigs were sacrificed one month later. Myocardial contrast intensity (MCI) with a contrast agent was measured using the SONOS 5500 system (Philips). Capillary density (CD) and MCI were measured at four areas: anteroseptum (nontransplanted infarct area), anterior wall (transplanted infarct area), septum (border zone), and lateral wall (normal). We compared the anteroseptum with the anterior wall by MCI and CD. RESULTS: In the BMMNC and BMSC subsets, the CD of the anterior wall was higher than that of the anteroseptum (p < 0.001). There was a linear relation between MCI and CD (acoustic unit [AU2] = 0.234 CD + 0.010, r = 0.92, p < 0.001). At one month after cell transplantation, MCI of the anterior wall increased in the BMMNC and BMSC subsets (p < 0.05), although it did not change in the control group. The ratio of wall thickness (systole/diastole) in the transplanted infarct area was larger than that in the nontransplanted infarct area (p < 0.01). CONCLUSIONS: Myocardial contrast echocardiography is useful to evaluate regional perfusion, which was enhanced by bone marrow cell transplantation.

G-CSF promotes bone marrow cells to migrate into infarcted mice heart, and differentiate into cardiomyocytes.

A recent study showed that granulocyte-colony stimulating factor (G-CSF) treatment improved the infarcted cardiac function. Although mobilized stem cells may affect it, the mechanism is unclear. In this study, we investigated the origins of stem cells and phenotypic changes of the migrated cells, and evaluated the efficacy of G-CSF. Eighteen C57BL/6 mice were irradiated (900 cGy) and GFP mouse-derived bone marrow cells (GFP-BMC: 10(6) cells) were injected via a tail vein followed by splenectomy 4 weeks later. Ligation of the left descending coronary artery was performed 2 weeks later. Recombinant human G-CSF (200 microg/kg/day) was injected for 3 days before and 5 days after ligation (group 1, n = 10). Saline was injected in group 2 (n = 8). Four weeks after infarction, hearts and other organs were fixed for histology. The survival rate after postoperative day 3 in group 1 was 100%, while that in group 2 was 50% (p = 0.03). Bone marrow-derived GFP cells (BMD-GFP) in group 1 (103.3+/-71.9/mm2) were located at the infarcted border area significantly more than those in group 2 (43.6+/-23.7/mm2) (p < 0.0001). BMD-GFP cells were positive for troponin I (16.6%), myosin heavy chain-slow (16.7%), and nestin (8.8%) in group 1. Ki-67-positive BMD-GFP in group 1 (10.0+/-7.0/mm2) were significantly more than those in group 2 (4.8+/-6.1/mm2) (p = 0.01). G-CSF increased the survival rate after infarction. G-CSF promoted BMC to migrate into the infarcted border area. Bone marrow was one of the origins of regenerated cardiomyocytes.

Direct cell-cell interaction of cardiomyocytes is key for bone marrow stromal cells to go into cardiac lineage in vitro.

OBJECTIVES: Cardiac environmental factors are thought to be powerful inducers in cardiomyogenic differentiation. In this study we simulated the cardiac environment using coculture and evaluated the cardiomyogenic differentiation in bone marrow stromal cells. METHODS: In group 1 only bone marrow stromal cells derived from transgenic mice expressing green fluorescent protein (GFP-BMCs) were cultured (n = 5). In group 2 cardiomyocytes from neonatal rats were grown on inserts, which we applied to culture dishes seeded with GFP-BMCs (n = 5). In group 3 GFP-BMCs were cocultured with cardiomyocytes on the same dishes (n = 5). We cultured these cells for 7 days and evaluated the synchronous contraction and the cardiomyogenic differentiation of GFP-BMCs by means of immunostaining. RESULTS: In groups 1 and 2 GFP-BMCs protein did not show any myogenic phenotypes for 7 days. In contrast, in group 3 some GFP-BMCs were incorporated in parallel with cardiomyocytes and revealed myotube-like formation on day 1. On day 2, some GFP-BMCs started to contract synchronously with cardiomyocytes. Myosin heavy chain-positive GFP-BMCs were recognized in 2.49% +/- 0.87% of the total GFP-BMCs on day 5 (P <.0001). Cardiac-specific troponin I-positive GFP-BMCs were in 1.86% +/- 0.53% of the total cells on day 5 (P <.0001). Atrial natriuretic peptide was also seen in GFP-BMCs, and connexin 43 was detected between GFP-BMCs and cardiomyocytes. CONCLUSIONS: Direct cell-cell interaction with cardiomyocytes was important for bone marrow stromal cells to differentiate into cardiomyocytes. This coculture was useful for simulating the cardiac environment in vitro for the research of cell transplantation in the heart.

Bone marrow stromal cells contract synchronously with cardiomyocytes in a coculture system.

OBJECTIVES: Cell transplantation is a promising therapy for improving damaged heart function. Cardiac environmental factors are thought to be powerful differentiation inducers, but their effects are not well understood because of their in vivo nature. We simulated the cardiac environment using coculture and evaluated cardiomyogenic differentiation in bone marrow stromal cells and synchronous contraction with other cardiomyocytes. METHODS: Experiment 1. We evaluated the labeling efficiency, intensity, and pattern of green fluorescence in the transgenic mouse expressing green fluorescent protein-derived bone marrow stromal cells (GFP-BMCs) from initial plating through 8 weeks under fluorescent microscopy. Experiment 2. GFP-BMCs (10(5) cells) were cocultured with neonatal rat cardiomyocytes (10(5) cells). We also evaluated the incorporation, myogenic differentiation, and synchronous contraction of GFP-BMCs for 1 week under the same microscopy with a digital video camera. RESULTS: Experiment 1. All GFP-BMCs but red blood cells maintained green fluorescence from initial plating through 8 weeks. Experiment 2. Some GFP-BMCs were incorporated in parallel with cardiomyocytes and showed myotube-like formation on day 1. On day 2, GFP-BMCs started to contract synchronously with cardiomyocytes. GFP-BMCs formed colonies and maintained synchronous contraction on day 7. CONCLUSIONS: Direct cell-to-cell interaction with cardiomyocytes is essential for myogenic differentiation and synchronous contraction of bone marrow cells. This coculture is a simple tool for simulating the cardiac environment and evaluating phenotypic changes in vitro.

Effects of continuous IV prostacyclin in a patient with pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease (PVOD) is a rare but life-threatening disease. Although prostacyclin (PGI(2)) attenuates pulmonary hypertension and improves the prognosis in patients with primary pulmonary hypertension, little information is available regarding the effect of PGI(2) on patients with PVOD. This report describes a patient with severe PVOD who showed marked improvement in exercise capacity and pulmonary hemodynamics with continuous IV PGI(2) treatment. Furthermore, he experienced no clinical events for 12 months and survived for 25 months after the initiation of PGI(2) therapy. These results suggest that continuous IV PGI(2) therapy may serve as a bridge to transplantation in some cases of PVOD.