Namho Lee

Malignant Tumor Formation after Transplantation of Short-Term Cultured Bone Marrow Mesenchymal Stem Cells in Experimental Myocardial Infarction and Diabetic Neuropathy

Rationale: Bone marrow (BM)–derived mesenchymal stem cells (MSCs) hold great promise for cardiovascular cell therapy owing to their multipotency and culture expandability. Objective: The aim of the study was to investigate whether MSCs can treat experimental acute myocardial infarction (MI) and diabetic neuropathy. Methods and Results: We isolated mononuclear cells from mouse BM and cultured MSCs in a conventional manner. Flow cytometry analyses of these cultured cells at passage 4 showed expression of typical MSC markers such as CD44 and CD29, but not hematopoietic markers such as c-kit, flk1, and CD34. To determine the therapeutic effects of MSCs, we injected MSCs into the peri-infarct area after ligation of the left anterior descending coronary arteries of mice and, as separate experiments, injected the same batch of MSCs into hindlimb muscles of mice with diabetic neuropathy. During the follow-up at 4 to 8 weeks after cell transplantation, growing tumors were observed in 30% of hearts in the MI model, and in 46% of hindlimbs in the diabetic neuropathy model. Histological examination of the tumors revealed hypercelluarity, pleomorphic nucleoli, cytological atypia and necrosis, and positive staining for &agr;-smooth muscle actin, indicative of malignant sarcoma with myogenic differentiation. Chromosomal analysis of these MSCs showed multiple chromosomal aberrations including fusion, fragmentation, and ring formation. Conclusions: Genetically unmodified MSCs can undergo chromosomal abnormalities even at early passages and form malignant tumors when transplanted in vivo. These results suggest that careful monitoring of chromosomal status is warranted when in vitro expanded MSCs are used for cell therapy such as for MI.

Efficacy of High-Dose Atorvastatin Loading Before Primary Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction: The STATIN STEMI Trial

OBJECTIVES This study sought to determine the efficacy of high-dose atorvastatin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). BACKGROUND Previous randomized trials have demonstrated that statin pre-treatment reduced major adverse cardiac events (MACEs) in patients with stable angina pectoris and acute coronary syndrome. However, no randomized studies have been carried out with STEMI patients in a primary PCI setting. METHODS A total 171 patients with STEMI were randomized to 80-mg atorvastatin (n = 86) or 10-mg atorvastatin (n = 85) arms for pre-treatment before PCI. All patients were prescribed clopidogrel (600 mg) before PCI. After PCI, both groups were treated with atorvastatin (10 mg). The primary end point was 30-day incidence of MACE including death, nonfatal MI, and target vessel revascularization. Secondary end points included corrected thrombolysis in myocardial infarction frame count, myocardial blush grade, and ST-segment resolution at 90 min after PCI. RESULTS MACE occurred in 5 (5.8%) and 9 (10.6%) patients in the 80-mg and 10-mg atorvastatin pre-treatment arms, respectively (p = 0.26). Corrected thrombolysis in myocardial infarction frame count was lower in the 80-mg atorvastatin arm (26.9 +/- 12.3 vs. 34.1 +/- 19.0, p = 0.01). Myocardial blush grade and ST-segment resolution were also higher in the 80-mg atorvastatin arm (2.2 +/- 0.8 vs. 1.9 +/- 0.8, p = 0.02 and 61.8 +/- 26.2 vs. 50.6 +/- 25.8%, p = 0.01). CONCLUSIONS High-dose atorvastatin pre-treatment before PCI did not show a significant reduction of MACEs compared with low-dose atorvastatin but did show improved immediate coronary flow after primary PCI. High-dose atorvastatin may produce an optimal result for STEMI patients undergoing PCI by improving microvascular myocardial perfusion. (Efficacy of High-Dose AtorvaSTATIN Loading Before Primary Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction [STATIN STEMI]; NCT00808717).

Dual Angiogenic and Neurotrophic Effects of Bone Marrow–Derived Endothelial Progenitor Cells on Diabetic Neuropathy

Background— Endothelial progenitor cells (EPCs) are known to promote neovascularization in ischemic diseases. Recent evidence suggested that diabetic neuropathy is causally related to impaired angiogenesis and deficient growth factors. Accordingly, we investigated whether diabetic neuropathy could be reversed by local transplantation of EPCs. Methods and Results— We found that motor and sensory nerve conduction velocities, blood flow, and capillary density were reduced in sciatic nerves of streptozotocin-induced diabetic mice but recovered to normal levels after hind-limb injection of bone marrow–derived EPCs. Injected EPCs were preferentially and durably engrafted in the sciatic nerves. A portion of engrafted EPCs were uniquely localized in close proximity to vasa nervorum, and a smaller portion of these EPCs were colocalized with endothelial cells. Multiple angiogenic and neurotrophic factors were significantly increased in the EPC-injected nerves. These dual angiogenic and neurotrophic effects of EPCs were confirmed by higher proliferation of Schwann cells and endothelial cells cultured in EPC-conditioned media. Conclusions— We demonstrate for the first time that bone marrow-derived EPCs could reverse various manifestations of diabetic neuropathy. These therapeutic effects were mediated by direct augmentation of neovascularization in peripheral nerves through long-term and preferential engraftment of EPCs in nerves and particularly vasa nervorum and their paracrine effects. These findings suggest that EPC transplantation could represent an innovative therapeutic option for treating diabetic neuropathy.

Repair of ischemic heart disease with novel bone marrow-derived multipotent stem cells

Congestive heart failure is a growing, worldwide epidemic. The major causes of heart failure are related to irreversible damage resulting from myocardial infarction (heart attack). The long-standing axiom has been that the myocardium has a limited capacity for self-repair or regeneration; and the irreversible loss of cardiac muscle and accompanying contraction and fibrosis of myocardial scar tissue, sets into play a series of events, namely, progressive ventricular remodeling of nonischemic myocardium that ultimately leads to progressive heart failure. The loss of cardiomyocyte survival cues is associated with diverse pathways for heart failure, underscoring the importance of maintaining the number of viable cardiomyocytes during heart failure progression. Currently, no medication or procedure used clinically has shown efficacy in replacing the myocardial scar with functioning contractile tissue. Therefore, given the major morbidity and mortality associated with myocardial infarction and heart failure, new approaches have been sought to address the principal pathophysiologic deficits responsible for these conditions, resulting from the loss of cardiomyocytes and viable blood vessels. Recently, the identification of stem cells from bone marrow capable of contributing to tissue regeneration has ignited significant interest in the possibility that cell therapy could be employed therapeutically for the repair of damaged myocardium. In this review, we will discuss the currently available bone marrow-derived stem progenitor cells for myocardial repair and focus on the advantages of using recently identified novel bone marrow-derived multipotent stem cells (BMSC)

Calreticulin inhibits the MEK1,2-ERK1,2 pathway in α1-adrenergic receptor/Gh-stimulated hypertrophy of neonatal rat cardiomyocytes

In cardiac myocytes, stimulation of alpha(1)-adrenoceptor (AR) leads to a hypertrophic phenotype. The G(h) protein (transglutaminase II, TGII) is tissue type transglutaminase and transmits the alpha(1B)-adrenoceptor signal with GTPase activity. Recently, it has been shown that the calreticulin (CRT) down-regulates both GTP binding and transglutaminase activities of TGII. To elucidate whether G(h) mediates norepinephrine-stimulated intracellular signal transductions leading to activation of extracellular signal-regulated kinases (ERKs) and neonatal rat cardiomyocyte hypertrophy, we examined the effects of G(h) on the activation of ERKs and inhibitory effects of CRT on alpha(1)-adrenoceptor/G(h) signaling. In neonatal rat cardiomyocytes, norepinephrine-induced ERKs activation was inhibited by an alpha(1)-adrenoceptor blocker (prazosin), but not by an beta-adrenoceptor blocker (propranolol). Overexpression of the G(h) protein stimulated norepinephrine-induced ERKs activation, which was inhibited by alpha-adrenoceptor blocker (prazosin). Co-overexpression of G(h) and CRT abolished norepinephrine-induced ERKs activation. Taken together, norepinephrine induces hypertrophy in neonatal rat cardiomyocytes through alpha(1)-AR stimulation and G(h) is partly involved in norepinephrine-induced MEK1,2/ERKs activation. Activation of G(h)-mediated MEK1,2/ERKs was completely inhibited by CRT.

Clopidogrel pretreatment before primary percutaneous coronary stenting in patients with acute ST-segment elevation myocardial infarction: comparison of high loading dose (600 mg) versus low loading dose (300 mg)

BackgroundAggressive platelet inhibition is crucial to reduce myocardial injury and early cardiac events after coronary intervention. As compared with the conventional 300-mg dose, pretreatment with a 600-mg loading dose of clopidogrel significantly reduced periprocedural myocardial infarction (MI) in patients undergoing percutaneous coronary intervention (PCI). We investigated that the advantage of the 600-mg dose in inhibiting platelet aggregation more rapidly than the 300-mg dose may actually have special value for acute ST-segment elevation MI patients. MethodsA total of 171 patients with ST-segment elevation MI underwent primary PCI. A 600-mg (n=73) or 300-mg (n=98) loading regimen of clopidogrel was given before the procedure. We did a follow-up of all patients clinically for 30 days after coronary intervention. The primary endpoint was the 30-day occurrence of death, MI, urgent revascularization, or stroke. ResultsThe primary endpoint occurred in 1.4% (1 of 73) of patients in the high dose versus 11.2% (11 of 98) of those in the conventional loading dose group (P=0.013). Death, recurrent MI, urgent revascularization, and stroke were lower in patients treated with the high dose of clopidogrel compared with conventional dose. Safety endpoints were similar in the two groups. ConclusionPretreatment with a 600-mg loading dose of clopidogrel before the procedure is safe and, as compared with the conventional 300-mg dose, significantly reduces recurrent MI and urgent revascularization in patients with primary PCI.

Effects of atrial fibrillation on arterial stiffness in patients with hypertension.

Arterial stiffness is significantly correlated with cardiovascular risk in patients with hypertension. Although arterial stiffness increases with age and other vascular risk factors, the effect of heart rhythm on arterial stiffness is uncertain. The aim of this study was to determine whether the presence of atrial fibrillation is associated with arterial stiffness, as determined by heart to femoral pulse wave velocity, in patients with hypertension. Heart to femoral pulse wave velocity was measured, and comprehensive transthoracic echocardiography was performed in 68 subjects (35 subjects with sinus rhythm, 33 subjects with atrial fibrillation). Potential determinants of heart to femoral pulse wave velocity were identified by univariate and multivariate analyses. Individuals with atrial fibrillation had higher heart to femoral pulse wave velocity than those with sinus rhythm (1028 ± 222 vs 923 ± 110 cm/s, P = .03). Age, the presence of atrial fibrillation, systolic blood pressure, and pulse pressure were found to be significantly correlated with heart to femoral pulse wave velocity. After adjusting for possible con-founders, multivariate analysis identified systolic blood pressure (P = .003) and the presence of atrial fibrillation (P = .007) as independent determinants of heart to femoral pulse wave velocity. The presence of atrial fibrillation was significantly correlated with a higher pulse wave velocity, independently of age or blood pressure in patients with hypertension.

Acute myocardial infarction due to vasospasm induced by prostaglandin.

Prostaglandin E (PGE) is the preferred agent for second-trimester pregnancy termination. Hypotension, bradycardia, ventricular arrhythmias, myocardial infarction, cardiac arrest and death associated with PGE have been reported. A case of acute myocardial infarction due to coronary vasospasm induced by PGE is described in the present report. The diagnosis was confirmed by electrocardiography and coronary angiography.

Efficacy of fixed-dose amlodipine and losartan combination compared with amlodipine monotherapy in stage 2 hypertension: a randomized, double blind, multicenter study

BackgroundThe objective of this trial was to compare the blood-pressure lowering efficacy of amlodipine/losartan combination with amlodipine monotherapy after 6 weeks of treatment in Korean patients with stage 2 hypertension.ResultsIn this multi-center, double-blind, randomized study, adult patients (n = 148) with stage 2 hypertension were randomized to amlodipine 5 mg/losartan 50 mg or amlodipine 5 mg. After 2 weeks, patients with systolic blood pressure (SBP) > 140 mmHg were titrated to amlodipine 10 mg/losartan 50 mg or amlodipine 10 mg. After 4 weeks of titration, hydrochlorothiazide 12.5 mg could be optionally added to both groups. The change from baseline in SBP was assessed after 6 weeks. The responder rate (defined as achieving SBP < 140 mmHg or DBP < 90 mmHg) was also assessed at 2, 6 and 8 weeks as secondary endpoints. Safety and tolerability were assessed through adverse event monitoring and laboratory testing. Baseline demographics and clinical characteristics were generally similar between treatment groups. Least-square mean reduction in SBP at 6 weeks (primary endpoint) was significantly greater in the combination group (36.5 mmHg vs. 31.6 mmHg; p = 0.0117). The responder rate in SBP (secondary endpoints) was significantly higher in the combination group at 2 weeks (52.1% vs. 33.3%; p = 0.0213) but not at 6 weeks (p = 0.0550) or 8 weeks (p = 0.0592). There was no significant difference between groups in the incidence of adverse events.ConclusionThese results demonstrate that combination amlodipine/losartan therapy provides an effective and generally well-tolerated first line therapy for reducing blood pressure in stage 2 hypertensive patients.Trial RegistrationClinicalTrials.gov: NCT01127217

Noninvasive Brachial-Ankle Pulse Wave Velocity in Hypertensive Patients With Left Ventricular Hypertrophy

BACKGROUND The elevation of left ventricular filling pressure (LVFP) could be an important prognostic factor in patients with hypertension. We hypothesized that noninvasive brachial-ankle pulse wave velocity (baPWV) is associated with increased LVFP in hypertensive patients with LV hypertrophy (LVH). METHODS We enrolled patients with well-controlled hypertension for more than 1 year with LV ejection fraction (LVEF) > or = 55%, and LVH. The relationship between Doppler echocardiographic parameters of LVFP and baPWV with B-type natriuretic peptide (BNP) was also evaluated. RESULTS A total of 62 patients were enrolled (31 patients with E/E(a) >15 and 31 patients with E/Ea < or = 15) and the baPWV of the E/Ea >15 group was significantly increased compared to the E/Ea < or = 15 group (1,664.3 +/- 270.5 vs. 1,381.9 +/- 159.1 cm/s, P < 0.01). The baPWV showed better correlation with E/Ea (r = 0.69, P < 0.01) than the BNP (r = 0.47, P < 0.01). A multivariate linear regression model showed that only baPWV was significantly correlated with E/E(a), and that the association was independent of other factors. The area under the receiver-operating characteristic (ROC) curve of baPWV for the detection of elevated LVFP (E/Ea >15) was 0.79 (P < 0.01) and the optimal cutoff point of 1,440 cm/s produced 75% sensitivity and 62% specificity (the positive and negative predictive values were 68 and 71%, respectively). CONCLUSIONS In this study, we have demonstrated that elevated baPWV is associated with noninvasive markers of increased LVFP in hypertensive LVH patients with preserved LV systolic function.