Renal denervation for treatment of uncontrolled hypertension in an Asian population: results from the Global SYMPLICITY Registry in South Korea (GSR Korea).

Reports detailing the response of hypertensive patients to renal denervation (RDN) in Asian patients are limited. We evaluated 6- and 12-month outcomes after RDN in an Asian population and compared outcomes to a primarily Caucasian population. The Global SYMPLICITY Registry (GSR) is a prospective, all-comer, worldwide registry that evaluates the safety and effectiveness of RDN and includes the Korean registry substudy (GSR Korea) and a Caucasian subset (GSR Caucasian). Given differences in baseline characteristics among GSR Korea (n=93) as compared with GSR Caucasian (n=169) patients, including lower baseline office systolic blood pressure (SBP), lower body mass index and differences in medications, propensity score adjustment was performed when comparing the change in SBP between subsets. The 6- and 12-month change in SBP in GSR Korea was -19.4±17.2 and -27.2±18.1 mm Hg, respectively (P<0.001 for both vs baseline). GSR Caucasian had a SBP change similar to GSR Korea at 6 months (-20.9±21.4 mm Hg, unadjusted P=0.547, adjusted P=0.998), whereas at 12 months the change was significantly less pronounced (-20.1±23.9 mm Hg, unadjusted P=0.004, adjusted P=0.002). There were no protocol-defined procedure-related adverse events and no chronic adverse events associated with the device in an Asian population. RDN provided a significant reduction in 6- and 12-month office SBP among Asian patients, with a favorable safety profile. The 12-month SBP reduction was larger than that observed in Caucasian patients.

Preoperative NT-proBNP and CRP predict perioperative major cardiovascular events in non-cardiac surgery.

OBJECTIVE: To investigate whether simple and non-invasive measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) and/or C-reactive protein (CRP) can predict perioperative major cardiovascular event (PMCE). DESIGN: Prospective, single-centre, cohort study. SETTING: A 1900-bed tertiary-care university hospital in Seoul, Korea Design and PATIENTS: The predictive power of NT-proBNP, CRP and Revised Cardiac Risk Index (RCRI) for the risk of PMCE (myocardial infarction, pulmonary oedema or cardiovascular death) were evaluated from a prospective cohort of 2054 elective major non-cardiac surgery patients. Optimal cut-off values were derived from receiver operating characteristic curve (ROC) analysis. MAIN OUTCOME MEASUREMENT: PMCE (myocardial infarction, pulmonary oedema or cardiovascular death) within postoperative 30 days. RESULTS: PMCE developed in a total of 290 patients (14.1%). Each increasing quartile of NT-proBNP or CRP level was associated with a greater risk of PMCE after adjustment for traditional clinical risk factors. The relative risk (RR) of highest versus lowest quartile was 5.2 for NT-proBNP (p<0.001) and 3.7 for CRP (p<0.001). Both NT-proBNP (cut-off = 301 ng/l) and CRP (cut-off = 3.4 mg/l) predicted PMCE better than RCRI (cut-off = 2) by ROC analysis (p<0.001). Moreover, the predictive power of RCRI (adjusted RR = 1.5) could be improved significantly by addition of CRP and NT-proBNP to RCRI (adjusted RR 4.6) (p<0.001). CONCLUSIONS: High preoperative NT-proBNP or CRP is a strong and independent predictor of perioperative major cardiovascular event in non-cardiac surgery. The predictive power of current clinical risk evaluation system would be strengthened by these biomarkers.

The feasibility and safety of fluoroscopy-guided percutaneous intramyocardial gene injection in porcine heart.

BACKGROUND: Catheter-based transendocardial gene injection would be useful for the delivery of genes into the heart. We examined the feasibility and safety of percutaneous intramyocardial gene injections with fluoroscopic guidance alone. METHODS: We performed the procedure through an 8F arterial sheath inserted into the left carotid artery. In protocol 1, a mixture of India ink and normal saline was injected through a needle injection catheter in six pigs. We monitored blood pressure and ECG continuously during the procedure. Echocardiography, left ventriculography, and coronary angiography were performed. All pigs were sacrificed 2 days later and hearts were harvested. In protocol 2, a mixture of India ink and plasmid encoding CAT gene was injected in the same manner in eight pigs. Myocardial tissue was obtained 7 days after the procedure to assess gene expression. In protocol 3, four pigs were intentionally needle-perforated in the ventricular wall and were observed for 7 days. RESULTS: In protocol 1, there was no significant hemodynamic changes or serious arrhythmias during the procedure. Echocardiography and angiography revealed no evidence indicating pericardial effusion or wall motion abnormalities. Harvested hearts revealed one intramyocardial hematoma in a total of 36 injection sites. In protocol 2, the gene expression could be identified in 39 sites out of 48 injections after 7 days. In protocol 3, no animal showed signs indicating cardiac tamponade during the observation period. CONCLUSIONS: Our data suggest that fluoroscopy-guided percutaneous intramyocardial gene injection is a feasible and safe procedure, with no indication of associated significant hemodynamic changes, arrhythmias, or mortality.

Intracardiac echocardiographic guidance and monitoring during percutaneous endomyocardial gene injection in porcine heart.

In an effort to develop a guiding and monitoring tool for transmyocardial gene transfer, we have evaluated the feasibility of intracardiac echocardiography (ICE) to guide percutaneous endomyocardial gene transfer (PEGT), and monitor complications, in a pig model. ICE (5.5-10 MHz), complemented by fluoroscopy, was utilized to guide a needle injection into the heart in 19 normal pigs. Using this system, we injected Evans blue dye into eight pigs (group I), a mixture of pCK-CAT plasmid and India ink into seven pigs (group II), and pCK-LacZ plasmid into four pigs (group III). In all pigs, ICE contributed to the injection procedure by guiding the catheter to anatomically distinct sites, and by assisting stabilization of the catheter-endocardial contact. ICE predicted the injection sites correctly in 56 of 64 sites (87.5%) in group I, and in 42 of 42 sites (100%) in group II. Leakage of injectate into the left ventricular cavity could be detected by the microbubbles generated. The sites of injections appeared as foci of bright myocardial echodensity, which persisted until the end of the procedure. The procedures were not associated with significant morbidity or mortality. The expression of the chloramphenicol acetyltransferase (CAT) gene was identified in 40 sites from 42 injections (95.2%) in group II. In group III, histology showed positive beta-galactosidase staining of myocytes limited around the needle track with low transfection efficiency (<1%). These results suggest that real-time ICE monitoring proves safe and useful during PEGT for guiding needle injection, monitoring leakage, ensuring delivery of injectate into the myocardium, and instantly diagnosing cardiac complications, resulting in successful gene transfer.

Clinical features and prognosis of acute aortic intramural hemorrhage compared with those of acute aortic dissection: a single center experience.

The clinical manifestations and natural history of acute aortic intramural hemorrhage are not well characterized. Therefore, we have evaluated the differences in the clinical features and prognosis between acute intramural hemorrhage and acute classic aortic dissection. One hundred two consecutive patients with acute aortic syndrome were diagnosed between November 1994 and May 1999. The clinical features, treatment modalities and survival of these patients were analyzed. Thirty one of the 102 patients (30%) had intramural hemorrhage and 71 (70%) had aortic dissection. Patients with intramural hemorrhage were older than those with aortic dissection (mean ages 67 and 55 years, respectively) (p < 0.001), and intramural hemorrhage showed a lower proportion of type A than did aortic dissection (32% and 58%, respectively) (p = 0.018). The incidence of severe complications was significantly lower in patients with intramural hemorrhage than in those with aortic dissection (19% and 27%, respectively) (p < 0.001). Mean follow-up duration was 23.1+/-16.0 months. The overall death rate for patients with intramural hemorrhage (2 / 31; 6%) tended to be lower than those with aortic dissection (14 / 71; 20%) (p = 0.104). The Stanford classification and treatment modalities were not correlated with death. Late follow-up imaging studies in intramural hemorrhage showed partial to complete resolution of intramural hematoma (9 / 15; 60%). In this study, intramural hemorrhage was fairly common, more frequent among older patients, had a lower proportion of type A, and showed a lower incidence of severe complications and a more favorable prognosis in terms of mortality, than aortic dissection.

Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia.

BACKGROUND: We investigated the therapeutic potential of ex vivo expanded endothelial progenitor cells (EPCs) for myocardial neovascularization. METHODS AND RESULTS: Peripheral blood mononuclear cells obtained from healthy human adults were cultured in EPC medium and harvested 7 days later. Myocardial ischemia was induced by ligating the left anterior descending coronary artery in male Hsd:RH-rnu (athymic nude) rats. A total of 10(6) EPCs labeled with 1,1'-dioctadecyl-1 to 3,3,3',3'-tetramethylindocarbocyanine perchlorate were injected intravenously 3 hours after the induction of myocardial ischemia. Seven days later, fluorescence-conjugated Bandeiraea simplicifolia lectin I was administered intravenously, and the rats were immediately killed. Fluorescence microscopy revealed that transplanted EPCs accumulated in the ischemic area and incorporated into foci of myocardial neovascularization. To determine the impact on left ventricular function, 5 rats (EPC group) were injected intravenously with 10(6) EPCs 3 hours after ischemia; 5 other rats (control group) received culture media. Echocardiography, performed just before and 28 days after ischemia, disclosed ventricular dimensions that were significantly smaller and fractional shortening that was significantly greater in the EPC group than in the control group by day 28. Regional wall motion was better preserved in the EPC group. After euthanization on day 28, necropsy examination disclosed that capillary density was significantly greater in the EPC group than in the control group. Moreover, the extent of left ventricular scarring was significantly less in rats receiving EPCs than in controls. Immunohistochemistry revealed capillaries that were positive for human-specific endothelial cells. CONCLUSIONS: Ex vivo expanded EPCs incorporate into foci of myocardial neovascularization and have a favorable impact on the preservation of left ventricular function.

Efficient expression of the vascular endothelial growth factor gene in vitro and in vivo, using an adeno-associated virus vector.

Vascular endothelial growth factor (VEGF) has proven to be one of the most effective growth factors for therapeutic angiogenesis. The biological efficacy of the adeno-associated virus (AAV) vector has recently been demonstrated in muscle tissues, including the heart. Apart from these promising insights into VEGF and the AAV vector, studies on VEGF gene transfer using the AAV vector have been limited. Here, we evaluate AAV-mediated VEGF gene transfer, both in vitro and in vivo, using the AAV-mVEGF vector that contains cDNA for murine VEGF(120) within an HCMV-driven expression cassette. Transient transfection of AAV-mVEGF plasmid significantly increased mVEGF expression in 293T cells. The secreted VEGF in the conditioned medium had strong biological activity, as confirmed by the Miles' vascular permeability assay. Transduction of 293T and HeLa cells with AAV-mVEGF stock of high titer, that is essentially adenovirus-free, showed significantly increased mVEGF expression above that of AAV-eGFP-transduced cells. When human umbilical vein endothelial cells were transduced, a higher level of mVEGF expression, together with higher cell counts, was observed compared to AAV-eGFP-transduced cells. In vivo transduction of mouse tibialis anterior muscle resulted in an increased level of mVEGF expression, and higher capillary-to-myofibre ratio, 8 weeks post-transduction. In a rat hindlimb ischemia model, regional blood flow, as well as the capillary-to-myofibre ratio, was significantly increased at 4 weeks post-transduction. These findings demonstrate the efficient delivery of the VEGF gene using an AAV vector, which has implications for angiogenic gene therapy in ischemic diseases.

Prevalence and risk factors of silent cerebral infarction in apparently normal adults.

Cerebrovascular disease is a major cause of death and disability in adults. Silent cerebral infarction (SCI) portends more severe cerebral infarctions or may lead to insidious progressive brain damage resulting in vascular dementia. This study was designed to evaluate the prevalence and risk factors of SCI in an apparently normal adult population. Nine hundred ninety-four consecutive symptom-free adults (mean age 49.0+/-7.7; men:women 830:164) who underwent brain magnetic resonance imaging at the Center for Health Promotion at Samsung Medical Center were assessed. All were neurologically normal in history and physical examination. A total of 121 SCI lesions was observed in 58 subjects. The lesion prevalence adjusted for patient age was 5.1%. There was no gender difference in prevalence. Ninety-nine lesions were <1 cm in diameter, 15 were between 1 and 2 cm, 3 were between 2 and 3 cm, and 4 were >3 cm in diameter. The most frequent site of the SCI lesion was basal ganglia, after which the periventricular white matter, cerebral cortex, and thalamus were the most frequent sites. Old age, hypertension, a history of coronary artery disease, evidence of cardiomegaly in chest radiographs, and high fasting glucose/hemoglobin A1c levels were associated with SCI on univariate analysis. Multivariate analysis demonstrated old age and hypertension to be independent risk factors for SCI, and mild alcohol consumption was revealed as an independent protective factor against SCI.

Myocardial injury-induced fibroblast proliferation facilitates retroviral-mediated gene transfer to the rat heart in vivo.

BACKGROUND: Efficient and stable transfer of therapeutic DNA into injured myocardium would be an initial step towards a genetic treatment aimed at myocardial repair after myocardial infarction. Proliferating cardiac fibroblasts in the healing myocardium could be a compelling target for retroviral infection. We evaluated the feasibility of direct in vivo gene transfer into injured myocardium using a high-titer, stable retroviral vector. METHODS: Using the TE-FLY-A-based MFG retroviral vector harboring nlsLacZ reporter, the gene transfer efficiency was assessed first in vitro in rat cardiac fibroblasts, followed by in vivo evaluation in healing rat myocardium after local freeze-thaw injury. A total of 2.5 x 10(7) infectious units of retrovirus were injected into the injured region of a beating rat heart. The transduced cells were identified by X-gal staining and immunohistochemistry. RESULTS: Highly efficient transduction of cardiac fibroblasts was observed in vitro with 98% of the cells transduced with single infection. The cell proliferation index in the cardiac granulation tissue appeared maximal 3 days after cryoinjury. Retroviral injection into the injured beating heart induced gene expression localized to the wound repair region. One week after retrovirus injection, 14% of the cells in the reparative tissue were beta-gal-positive, while 4% were beta-gal-positive after 4 weeks. The transduced cells were mostly myofibroblasts. CONCLUSIONS: Local gene transfer to the healing rat heart is feasible by retrovirus in vivo. This observation may serve as a useful guide for the development of gene therapy aimed at myocardial repair after myocardial infarction.

Left main coronary artery dissection after blunt chest trauma presented as acute anterior myocardial infarction: assessment by intravascular ultrasound: a case report.

Coronary artery injury after blunt chest trauma is very rare, but this can result in a serious acute myocardial infarction. Coronary artery dissection is an uncommon complication of thoracic injuries. We report a case of a 17-year-old male who was presented with an anterior myocardial infarction following blunt chest trauma after a bicycle accident. His coronary angiography revealed aneurysmal dilatation with dissection of the distal left main stem coronary artery. Intravascular ultrasound showed a dissecting flap at the left main stem coronary artery. The patient was treated conservatively and discharged without serious sequelae. When symptoms and electrocardiographic findings are compatible with acute myocardial infarction, careful evaluation is important in patients with thoracic injuries for proper management. If the patient is stable, medical therapy may be appropriate. But early intervention should be considered in the presence of ongoing myocardial ischemia.

Polymorphism of angiotensin converting enzyme gene is associated with circulating levels of plasminogen activator inhibitor-1.

The deletion (D) allele of the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene is strongly associated with an increased level of circulating ACE. The ACE gene polymorphism may influence the production of angiotensin II (Ang II). It has been shown that Ang II modulates fibrinolysis, that is, Ang II increases plasminogen activator inhibitor-1 (PAI-1) mRNA and plasma PAI-1 levels in vitro and in vivo. Considered together, we tested the hypothesis that the deletion allele of the ACE gene might be associated with increased levels of PAI-1. We related the ACE genotype to PAI-1 antigen levels in 603 men and 221 women attending a routine health screening. As a whole, the plasma PAI-1 level was not strongly associated with ACE genotype. Since the PAI-1 level was significantly influenced by well-known risk factors for coronary artery disease (CAD), we further analyzed the data after excluding subjects with major cardiovascular risk factors. In low-risk male subjects, the DD genotype had significantly higher levels of plasma PAI-1 (DD: 20.3 +/- 2.2; DI: 13.9 +/- 1.1; II: 13.6 +/- 1.3 ng/mL, P = .010 by ANOVA). In low-risk female subjects, the DD genotype showed a tendency to a high level of plasma PAI-1 without statistical significance. When analysis was restricted to postmenopausal women (age > or = 55 or FSH > or = 35 ng/mL), the DD genotype showed a significantly higher level of PAI-1 than subjects with the DI and II genotypes (27.7 +/- 6.2 versus 15.6 +/- 1.8 ng/mL, P = .028). The DD polymorphism of the ACE gene is associated with high PAI-1 levels in male and possibly in postmenopausal female subjects who have lower conventional cardiovascular risk factors. These results suggest that the increased ACE activity caused by DD polymorphism may play an important role in elevating the level of plasma PAI-1. Our data support the notion that the genetic variation of ACE contributes to the balance of the fibrinolytic pathway.