Life-Threatening Thrombosis After Large Amounts of Nitrous Oxide Use.

This case report highlights the development of severe, life-threatening thrombotic complications after chronic recreational use of large quantities of nitrous oxide in a 21-year-old patient. In young patients presenting with thromboembolism and nitrous oxide abuse, swift identification of symptoms and management is critical.

Causes of death after first time venous thromboembolism.

BACKGROUND: Causes of death after first time community-acquired venous thromboembolism (VTE) diagnosed in unselected patients at the emergency department (ED) was investigated. MATERIALS AND METHODS: The study consists of all patients > 18 years of age who had a visit for any medical reason to any of 5 different ED in Stockholm County, Sweden from 1st January 2016 to 31st December 2017. We have identified all patients with a first registered incident VTE; deep vein thrombosis (DVT) and/or pulmonary embolism (PE) during the study period. Cox regression models were used to estimate hazards ratios (HR) with 95% confidence intervals (CIs) for all-cause mortality and cause-specific death in patients with DVT or PE using all other patients as the reference group. RESULTS: In total, 359,884 patients had an ED visit during the study period of whom about 2.1% were diagnosed with VTE (DVT = 4,384, PE = 3,212). The patients with VTE were older compared to the control group. During a mean follow up of 2.1 years, 1567 (21%) and 23,741(6.7%) patients died within the VTE and reference group, respectively. The adjusted risk of all-cause mortality was nearly double in patients with DVT (HR 1.7; 95% CI, 1.5-1.8) and more than 3-fold in patients with PE (HR 3.4; 95% CI, 3.1-3.6). While the risk of cancer related death was nearly 3-fold in patient with DVT (HR 2.7; 95% CI, 2.4-3.1), and 5-fold in PE (HR 5.4; 95% CI, 4.9-6.0 respectively). The diagnosis of PE during the ED visit was associated with a significantly higher risk of cardiovascular death (HR 2.2; 95% CI, 1.9-2.6). CONCLUSION: Patients with VTE have an elevated risk of all-cause mortality, including cardiovascular death.

Association of coronary angiographic lesions and mortality in patients over 80 years with NSTEMI.

OBJECTIVE: Coronary angiography (CA) and percutaneous coronary intervention (PCI) is of great importance during non-ST-segment elevation myocardial infarction (NSTEMI) management. Coronary artery lesions and their association to mortality in elderly patients with NSTEMI was investigated. METHODS: Patients >80 years of age who underwent CA at index NSTEMI during 2011-2014 were included. Data were collected from the Swedish Coronary Angiography and Angioplasty Registry and Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registries. Coronary lesions were categorised into; one vessel disease (1VD), multi-vessel disease (MVD) and left main disease (LMD) and 0%-49% stenosis grade were considered as controls.Cox regression was used to estimate HRs for all-cause mortality associated with coronary lesions. Survival benefit was determined after PCI and in relation to if revascularisation was complete or incomplete and any complications in the Cath lab was assessed. RESULTS: Five thousand seven hundred and seventy patients with history of CA and PCI were included, 10% had normal coronary arteries, 26% had 1VD, 50% MVD and 14% LMD. Mortality was higher in patients with 1VD, MVD and LMD: HR 1.8 (1.3-2.5), HR 2.2 (1.6-3.0) and HR 2.8 (2.1-3.9), respectively. PCI were treated in 84% of 1VD, 73% MVD, and 54% in LMD. Survival was higher with PCI HR 0.85 (0.73-0.99). MVD had lower adjusted mortality HR 0.71 (0.58-0.87) compared with patients with MVD who did not undergo PCI. Complications and mortality were higher in patients with LMD both during CA and PCI, HR 2.9 (1.1-7.6) and HR 4.5 (1.6-12.5). CONCLUSION: Coronary lesions (>50% stenosis) are strong predictors of mortality in elderly patients with NSTEMI. MVD is common and PCI treatment is associated with increased survival.

Early Risk of Stroke in Patients Undergoing Acute Versus Elective Cardioversion for Atrial Fibrillation.

Background Electrical cardioversion (ECV) is routinely used to restore sinus rhythm in patients with symptomatic atrial fibrillation. The European guidelines have been updated in recent years. Current information on differences in the risk for stroke after acute versus elective ECV is lacking. Methods And Results All patients with a first-time acute or elective ECV in the Stockholm regional health care data warehouse from 2011 to 2018 were included. Cox regression analyses were performed evaluating ischemic or unspecified stroke within 30 days after ECV with adjustments for the CHA2DS2-VASc score, medical treatment, and year of inclusion. The study included 9139 patients, 3094 after acute and 6045 after elective ECV. The mean age was 65.9±11.3 years, 69.5% were men, and the mean CHA2DS2-VASc score was 2.4±1.7. Before the intervention, 49.6% of patients with an acute ECV and 96.4% of those with an elective ECV had claimed an oral anticoagulant prescription. Ischemic or unspecified stroke occurred in 26 (0.28%) patients within 30 days. The unadjusted risk was higher after acute compared with elective ECV (hazard ratio [HR], 2.29; 95% CI, 1.06-4.96), whereas there was no difference after multivariable adjustments (adjusted HR, 0.99; 95% CI, 0.36-2.72). Both non-vitamin K oral anticoagulants (adjusted HR, 0.28; 95% CI, 0.08-0.98) and warfarin (adjusted HR, 0.17; 95% CI, 0.05-0.53) were associated with a lower risk for stroke compared with no anticoagulation. Conclusions Acute ECV was associated with a higher unadjusted risk for stroke than elective ECV, but the risk was similar after adjustment for anticoagulant treatment. This study indicates the importance of anticoagulation before ECV according to recent European guidelines.

Statin Therapy and Intensity: Prognosis in Patients with Myocardial Injury.

BACKGROUND: No guideline-directed pharmacological therapy has been established for patients with myocardial injury without type 1 myocardial infarction. We investigated the impact of statin treatment in patients with myocardial injury. METHODS: Patients with myocardial injury (nonischemic acute and chronic myocardial injury), type 2 myocardial infarction, and type 1 myocardial infarction with at least 1 emergency department visit for chest pain from 2011 to 2014 were included. Dispensed prescriptions of all types of statins with dosage within 180 days from the index visit were collected. In total, 2054 patients were divided into 3 groups: 1) acute myocardial injury (type 2 myocardial infarction, acute nonischemic myocardial injury), 2) chronic myocardial injury, and 3) type 1 myocardial infarction. We estimated the adjusted hazard ratio with 95% confidence interval for death with low- (reference), moderate-, and high-intensity statin therapy. RESULTS: The mean follow-up was 4.2 ± 1.8 years. Only 13% of patients with acute and chronic myocardial injury and 30% with type 1 myocardial infarction were treated with high-intensity statins. Adjusted mortality rates were higher in patients with acute and chronic myocardial injury than in those with type 1 myocardial infarction across all statin intensity categories. In patients with type 1 myocardial infarction, the adjusted mortality risk was 20% (hazard ratio, 0.80; 95% confidence interval, 0.36-1.77) lower in patients with high-intensity therapy. Point estimates in the adjusted models indicated similar associations between statin intensity and mortality risk in patients with acute and chronic myocardial injury. CONCLUSION: Patients with myocardial injury may benefit from high-intensity statin treatment, but the associations were not statistically significant when adjusting for confounders.

Treatment With Cardiovascular Medications: Prognosis in Patients With Myocardial Injury.

Background There is no clinical guidance on treatment in patients with non-ischemic myocardial injury and type 2 myocardial infarction (T2MI). Methods and Results In a cohort of 22 589 patients in the emergency department at Karolinska University Hospital in Sweden during 2011 to 2014 we identified 3853 patients who were categorized into either type 1 myocardial infarction, T2MI, non-ischemic acute and chronic myocardial injury. Data from all dispensed prescriptions within 180 days of the visit to the emergency department were obtained concerning ß-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, statins, and platelet inhibitors. We estimated adjusted hazard ratios (HR) with 95% CI for all-cause mortality in relationship to the number of medications (categorized into 0-1 [referent], 2-3 and 4 medications) in the groups of myocardial injury. In patients with T2MI, treatment with 2 to 3 and 4 medications was associated with a 50% and 56% lower mortality, respectively (adjusted HR [95% CI], 0.50 [0.25-1.01], and 0.43 [0.19-0.96]), while corresponding associations in patients with acute myocardial injury were 24% and 29%, respectively (adjusted HR [95% CI], 0.76 [0.59-0.99] and 0.71 [0.5-1.02]), and in patients with chronic myocardial injury 27% and 37%, respectively (adjusted HR [95% CI], 0.73 [0.58-0.92] and 0.63 [0.46-0.87]). Conclusions Patients with T2MI and non-ischemic acute or chronic myocardial injury are infrequently prescribed common cardiovascular medications compared with patients with type 1 myocardial infarction. However, treatment with guideline recommended drugs in patients with T2MI and acute or chronic myocardial injury is associated with a lower risk of death after adjustment for confounders.

Diagnostic Accuracy in Acute Venous Thromboembolism: Comparing D-Dimer, Thrombin Generation, Overall Hemostatic Potential, and Fibrin Monomers.

Introduction For acute venous thromboembolism (VTE), a biomarker with higher specificity than D-dimer would be of great clinical use. Thrombin generation and overall hemostatic potential (OHP) reflect the hemostatic balance by globally assessing multiple coagulation factors and inhibitors. These tests discriminate between healthy controls and patients with a prothrombotic tendency but have yet to be established as clinical biomarkers of VTE. Objective This study compares endogenous thrombin potential (ETP) and OHP to D-dimer and fibrin monomers (FM) in outpatients with suspected VTE. Methods A cross-sectional diagnostic study where 954 patients with suspected pulmonary embolism or deep venous thrombosis were recruited consecutively from the medical emergency department at Karolinska University Hospital. D-dimer, FM, OHP, and ETP were analyzed in a subpopulation of 60 patients with VTE and 98 matched controls without VTE. VTE was verified either by ultrasonography or computed tomography and clinical data were collected from medical records. Results Compared with healthy controls, both VTE and non-VTE patients displayed prothrombotic profiles in OHP and ETP. D-dimer, FM, ETP area under the curve (AUC), and ETP T lag were significantly different between patients with VTE and non-VTE. The largest receiver-operating characteristic AUCs for discrimination between VTE and non-VTE, were found in D-dimer with 0.94, FM 0.77, and ETP AUC 0.65. No useful cutoff could be identified for the ETP or the OHP assay. Conclusion Compared with D-dimer, neither ETP nor OHP were clinically viable biomarkers of acute venous thrombosis. The data indicated that a large portion of the emergency patients with suspected VTE were in a prothrombotic state.

Outcome of Percutaneous Coronary Intervention During Non-ST-Segment-Elevation Myocardial Infarction in Elderly Patients With Chronic Kidney Disease.

Background There is a paucity of data on the benefit of revascularization by percutaneous coronary intervention (PCI) during non-ST-segment-elevation myocardial infarction in patients aged >80 years with concurrent chronic kidney disease. Methods and Results Patients aged >80 years with chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m2 with non-ST-segment-elevation myocardial infarction, during 2011 to 2014 in Sweden retrieved from the SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) Registry. Cox regression was used to estimate adjusted hazard ratios with 95% CIs for all-cause mortality in patients with PCI versus no PCI treatment, stratified for eGFR. Logistic regression was used to evaluate adjusted odds for reinfarction and bleeding during hospitalization. Propensity score weighting analysis was also done as sensitivity analysis. In total, 12 821 patients were included, of whom 47%, 45%, and 8% had an eGFR of >60, 30 to 60, and 15 to <30 mL/min per 1.73 m2, respectively. Patients with eGFR 30 to 60 and 15 to <30 mL/min per 1.73 m2, 22%, and 10%, respectively, underwent PCI, compared with 36% among patients with eGFR >60 mL/min per 1.73 m2. During a mean follow-up of 3.2 years, the absolute risk of death was 42%, 56%, and 76% in patients with eGFR >60, 30 to 60, and 15 to <30 mL/min per 1.73 m2, respectively. Patients who underwent PCI had a lower risk of death in all groups of eGFR (0.47 [95% CI, 0.42-0.53], 0.50 [95% CI, 0.45-0.56], and 0.44 [95% CI, 0.33-0.59], respectively). Patients with eGFR 15 to <30 mL/min per 1.73 m2 had a higher risk of bleeding with PCI. Propensity score weighting showed similar outcomes for mortality risk as the unweighted analysis in all the eGFR groups. Conclusions PCI is rarely used in non-ST-segment-elevation myocardial infarction elderly patients with chronic kidney disease, and it appears to offer a survival benefit.

Causes of Death in Patients With Acute and Chronic Myocardial Injury.

BACKGROUND: Information about causes of death in patients with myocardial injury is limited. The purpose of this study was to explore causes of death in patients with myocardial injury. METHODS: In a cohort of 22,589 patients, 3853 patients with myocardial injury were identified and categorized into: type 1 myocardial infarction, type 2 myocardial infarction, and nonischemic acute and chronic myocardial injury. We included all 1466/3853 (38%) patients who died during follow-up (3.9 ± 2 years). We estimated rates and adjusted odds ratio (OR) with 95% confidence interval (CI) for causes of death in the 4 categories of myocardial injury using patients without myocardial injury 819/17,932 (4.6%) who died as reference. RESULTS: The study cohort included 2285 patients. The proportion of cardiovascular deaths was higher in patients with type 1 myocardial infarction (48%), acute (43%), and chronic (45%) myocardial injury and type 2 myocardial infarction (39%) compared with patients without myocardial injury (25%). Adjusted rates for cardiovascular death were similar in patients with myocardial injury. Type 1 myocardial infarction, acute, and chronic myocardial injury was associated with a 77% (OR: 1.77, 95% CI 1.29-2.41), 40% (OR: 1.40, 95% CI: 1.07-1.84), and 36% (OR: 1.36, 95% CI: 1.05-1.76) higher risk of cardiovascular death. CONCLUSIONS: Patients with type 1 myocardial infarction and acute or chronic myocardial injury have similar proportions and high risks for cardiovascular death. We believe that these findings stress the need for investigating patients without known heart diseases who present with nonischemic myocardial injury, or type 2 myocardial infarction.

Association between reduced left ventricular ejection fraction following non-ST-segment elevation myocardial infarction and long-term mortality in patients of advanced age.

OBJECTIVES: We sought to investigate the association between LVEF and clinical outcomes after NSTEMI, and the benefit of guideline-recommended pharmacotherapy in elderly patients. BACKGROUND: New-onset reduction in LVEF is common after NSTEMI in patients of advanced age. There is little information about outcomes in relation to LVEF, and the benefit of guideline-recommended pharmacotherapy in elderly patients. MATERIALS AND METHODS: The SWEDEHEART registry was used to identify all patients in Sweden >80 years with NSTEMI from 2011 to 2014. A normal LVEF was defined as >50%; mildly reduced, 40%-49%; moderately reduced, 30%-39%; and severely reduced, <30%. Cox regression was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between a reduced LVEF compared with a normal LVEF and all-cause mortality. Similarly, the presence versus absence of treatment with guideline-recommended medications at discharge and mortality was evaluated. RESULTS: 6287 patients were included where 59%, 20%, 13%, and 6% had a normal, mildly reduced, moderately reduced, and severely reduced LVEF, respectively. During a median follow-up of 2.4 years, 2211 (35%) patients died. All three categories of impaired LVEF were associated with higher mortality: mildly reduced (1.44, 1.25-1.65), moderately reduced (1.93, 1.67-2.23), and severely reduced (3.24, 2.74-3.85). Patients who were treated with beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, or statins at discharge had lower mortality. CONCLUSIONS: New-onset reduction of the LVEF is common in advanced-age patients with NSTEMI and is associated with higher mortality. Treatment with guideline-recommended medications is associated with a better prognosis.

Percutaneous coronary intervention versus conservative treatment for non ST-segment elevation myocardial infarction in patients above 80 years of age.

BACKGROUND: There is a paucity of data if there is a benefit for patients above 80 years of age with non-ST-segment elevation myocardial infarction (NSTEMI) to undergo percutaneous coronary intervention (PCI). OBJECTIVES: To investigate the association between PCI or conservative treatment and outcomes in NSTEMI patients above 80 years of age. METHODS: From the SWEDEHEART register were included 13,854 patients above 80 years of age with NSTEMI during 2011-2014 in Sweden. Cox regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI) for the association between PCI compared with conservative treatment for the outcome all-cause mortality. RESULTS: In total 4158 (30%) patients underwent PCI, and 9696 (70%) were treated conservatively. The mean age was 86 (±4) years. During a mean 2.2 (±1.4) years there were 6458 (47%) deaths, where of 1078 (26%) in PCI treated, and 5380 (56%) in conservatively treated patients. Treatment with PCI compared with conservative treatment was associated with a 40% lower risk of death (adjusted HR 0.60, 95% CI 0.55-0.66). Similarly, patients in the PCI group had a 60% lower 30-day, and 51% lower 1-year all-cause mortality, respectively (adjusted HR 0.40, 95% CI 0.25-0.63, and HR, 0.49 95% CI 0.42-0.57, respectively). There were no differences in risk of bleedings (1.4% versus 1.3%). CONCLUSIONS: PCI compared with conservative treatment was associated with a lower mortality in patients above 80 years of age with NSTEMI without an increased risk of bleedings. PCI may be considered as the treatment of choice for elderly with NSTEMI.

Rosuvastatin inhibits TIMP-2 and promotes myocardial angiogenesis.

BACKGROUND: Angiogenesis is usually driven by inflammation. Matrix metalloproteinases MMP-3 and MMP-9 and tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 are implicated in vascular remodeling. TIMP-2 exhibits antiangiogenic properties. Statins show benefits that are additional to lipid lowering including pro- and antiangiogenic properties. Atherosclerotic lesions in the coronary arteries have been well studied, but less is known about the fine terminal branches of the myocardial vasculature. METHODS: To examine this, we studied rosuvastatin (RSV) treatment in ApoE knockout (ApoE(-/-)) mice fed a high cholesterol (HC) diet. Hearts from ApoE(-/-) mice on a normal diet, HC diet and HC diet with RSV were harvested to determine MMP-3, MMP-9, TIMP-1, TIMP-2, vascular endothelial growth factor (VEGF)-A and estrogen receptor-α (ER-α) mRNA. RESULTS: RSV inhibited TIMP-1 and TIMP-2 expression and enhanced myocardial VEGF-A and ER-α expression, independently of plasma lipid level changes, but had no effect on MMP-3 and MMP-9 expression. CONCLUSIONS: These modulations of TIMPs, VEGF and ER-α expression induced by RSV may act as local stimulating factors for arteriolar growth in the myocardium.

Estrogen receptors do not influence angiogenesis after myocardial infarction.

BACKGROUND: There is controversy on whether estrogen receptors are present and functioning in the myocardium. Aims. To explore if after myocardial infarction (MI) estrogen receptors α (ERα) and ß (ERß) are upregulated in myocardial tissue and to explore if the presence/ absence of ERα or ERß influences angiogenesis after MI. METHODS: MI was induced by ligation of the left anterior descending artery in knockout (KO) mice, ERαKO and ERßKO, respectively, and non-KO littermate-controls, C57Bl/6 mice. The hearts were harvested after 12 days. A part of the periinfarct tissue was collected for ERα and ERß mRNA expression determination by real-time polymerase chain reaction. Using immunohistochemistry, ERα and ERß protein expression and capillary and arteriolar densities were blindly determined in the periinfarct area. RESULTS: In myocardium disrupted mRNA was upregulated in both ERαKO and ERßKO, (p < 0.005) and did not change after MI. There was no change in mRNA expression of ERα or ERß in wild type mice after MI. Expression of ERß in ERαKO and of ERα in ERßKO did not change. Following MI ERα or ERß could not be demonstrated by immunohistochemistry in either wild type or ERαKO or ERßKO. The capillary and arteriolar densities after MI did not differ between the groups in the periinfarct area. CONCLUSIONS: Although disrupted ER mRNA is upregulated in myocardium of ER knockout mice, no change in these or native receptors occurs following MI. At least in this model ER therefore seems not to have a role in myocardial arteriogenesis and angiogenesis after MI.

Modulation of ephrinB2 leads to increased angiogenesis in ischemic myocardium and endothelial cell proliferation.

Eph/ephrin signaling is pivotal in prenatal angiogenesis while its potential role in postnatal angiogenesis largely remains to be explored. Therefore its putative angiogenic and therapeutic effects were explored in endothelium and in myocardial ischemia. In culture of human aortic endothelial cells the fusion protein ephrinB2-Fc induced cell proliferation (p<0.0005) and in the murine aortic ring model ephrinB2-Fc induced increased sprouting (p<0.05). Myocardial infarction was induced by ligation of the left anterior descending artery in mouse. During the following 2 weeks mRNA of the receptor/ligand pair EphB4/ephrinB2 was expressed dichotomously (p<0.05) and other Eph/ephrin pairs were expressed to a lesser degree. Twenty-four hours after intraperitoneal administration of ephrinB2-Fc it was detected in abundance throughout the myocardium along capillaries, showing signs of increased mitosis. After 4 weeks the capillary density was increased 28% in the periinfarcted area (p<0.05) to a level not different from healthy regions of the heart where no change was observed. These results implicate that EphB4/ephrinB2 is an important signaling pathway in ischemic heart disease and its modulation may induce therapeutic angiogenesis.

Angiogenic effects of sequential release of VEGF-A165 and PDGF-BB with alginate hydrogels after myocardial infarction.

OBJECTIVE: This study investigates whether local sequential delivery of vascular endothelial growth factor-A(165) (VEGF-A(165)) followed by platelet-derived growth factor-BB (PDGF-BB) with alginate hydrogels could induce an angiogenic effect and functional improvement greater than single factors after myocardial infarction. METHODS: Alginate hydrogels were prepared by combining high and low molecular weight alginate. Growth factor release rates were monitored over time in vitro with 125I-labelled VEGF-A(165) and PDGF-BB included in the gels. One week after myocardial infarction was induced in Fisher rats, gels with VEGF-A(165), PDGF-BB, or both were given intra-myocardially along the border of the myocardial infarction. Vessel density was analysed in hearts and cardiac function was determined by Tissue Doppler Echocardiography. In addition, the angiogenic effect of sequenced delivery was studied in vitro in aortic rings from C57B1/6 mice. RESULTS: Alginate gels were capable of delivering VEGF-A(165) and PDGF-BB in a sustainable manner, and PDGF-BB was released more slowly than VEGF-A(165). Sequential growth factor administration led to a higher density of alpha-actin positive vessels than single factors, whereas no further increment was found in capillary density. Sequential protein delivery increased the systolic velocity-time integral and displayed a superior effect than single factors. In the aortic ring model, sequential delivery led to a higher angiogenic effect than single factor administration. CONCLUSIONS: The alginate hydrogel is an effective and promising injectable delivery system in a myocardial infarction model. Sequential growth factor delivery of VEGF-A(165) and PDGF-BB induces mature vessels and improves cardiac function more than each factor singly. This may indicate clinical utility.

Myocardial angiogenesis after plasmid or adenoviral VEGF-A(165) gene transfer in rat myocardial infarction model.

OBJECTIVE: To compare gene transfer of plasmid (P) and adenovirus (Ad) encoding human vascular endothelial growth factor-A165 (hVEGF-A165) angiogenic efficacy and adverse effects as regards apoptosis and ectopic expression of the transgene in a rat myocardial infarction model. METHODS: Myocardial infarction was provoked in Fisher rats. One week later, PhVEGF-A165, PLacZ, AdhVEGF-A165, or AdLacZ was transferred intramyocardially along the border of the myocardial infarction. hVEGF-A expression was detected with ELISA. Myocardial vessel density was analyzed 1 and 4 weeks after gene transfer. Apoptosis was detected by TUNEL staining. Cardiac function was assessed with Tissue Doppler Velocity Imaging. RESULTS: Although AdhVEGF-A165 had substantially higher myocardial hVEGF-A expression than PhVEGF-A165, AdhVEGF-A165 and PhVEGF-A165 induced angiogenic effects to a similar extent with maintained increased arteriolar density after 4 weeks of gene transfer (p < 0.05). The two treatments also improved left ventricular function similarly. Adenoviral gene transfer induced a higher number of TUNEL positive cells than plasmid (p < 0.02). Ectopic expression of the transgene was present with both vectors but substantially higher after adenoviral gene transfer. CONCLUSIONS: AdhVEGF-A165 has no obvious angiogenic advantage over PhVEGF-A165 but more side effects at least in a rat myocardial infarction model. This indicates that PhVEGF-A165 might be more applicable for therapeutic angiogenesis than AdhVEGF-A165.

Human mesenchymal stem cells do not differentiate into cardiomyocytes in a cardiac ischemic xenomodel.

AIM: As the capability of human mesenchymal stem cells (hMSC) to engraft, differentiate and improve myocardial function cannot be studied in humans, exploration was performed in a xenomodel. METHODS: The rats were divided into three groups depending on the type of rats used (Rowett nude (RNU) or Fischer rats +/- immunosuppression). Different groups were treated with intramyocardial injection of hMSC (1-2 million) either directly or three days after ligation of the left anterior descending artery (LAD). Myocardial function was investigated by echocardiography. The hMSC were identified with fluorescence in situ hybridization and myocardial differentiation was assessed by immunohistochemistry. RESULTS: When hMSC were injected directly after LAD ligation they could be identified in half (8/16) of the RNU rats (without immunosuppression) at 4 weeks. When injected 3 days after LAD ligation in immunosuppressed RNU rats they were identified in all (6/6) rats at 6 weeks. The surviving hMSC showed signs of differentiation into fibroblasts. No cardiomyocyte differentiation was observed. There was no difference in myocardial function in treated animals compared to controls. CONCLUSIONS: The hMSC survived in this xenomodel up to 6 weeks. However, hMSC required implantation into immunoincompetent animals as well as immunosuppression to survive, indicating that these cells are otherwise rejected. Furthermore, these cells did not differentiate into cardiomyocytes nor did they improve heart function in this xenomodel.

Angiogenic and cardiac functional effects of dual gene transfer of VEGF-A165 and PDGF-BB after myocardial infarction.

Therapeutic angiogenesis is a potential treatment modality for myocardial ischemia. phVEGF-A(165), phPDGF-BB, or a combination of the two were injected into the myocardial infarct border zone in rats 7 days after ligation of the coronary left anterior descending artery. Cardiac function was measured by echocardiography. Hearts were harvested 1 and 4 weeks after plasmid injection. phVEGF-A(165) increased capillary density more than phPDGF-BB, and phPDGF-BB preferentially stimulated arteriolar growth. The combination increased both capillaries and arterioles but did not enhance angiogenesis any more than single plasmid treatments did. VEGF-A(165) and the combination of phVEGF-A(165) and phPDGF-BB counteracted left ventricular dilatation after 1 week but did not counteract further deterioration.