Association between macrophage-like cell density and ischemia metrics in diabetic eyes.

We previously showed that macrophage-like cells (MLCs) are increased in eyes with advanced diabetic retinopathy (DR). Here, we hypothesized that MLC density was correlated with ischemia using optical coherence tomography angiography (OCTA) and ultra-widefield fluorescein angiography (UWF-FA). Treatment-naïve diabetic eyes were prospectively imaged with repeated OCTA (average 5.3 scans per eye) and UWF-FA imaging. OCTA images were registered and averaged to generate a superficial capillary plexus (SCP), deep capillary plexus (DCP), and MLC slab. We calculated geometric perfusion deficit (GPD), vessel length density, and vessel density for the SCP and DCP. MLC density was quantified by two masked graders and averaged. Ischemia on UWF-FA was measured to generate a non-perfusion area (NPA) and index (NPI). Since MLC density was non-parametrically distributed, MLC density was correlated with ischemia metrics using Spearman correlations. Forty-five treatment-naïve eyes of 45 patients (59 ± 12 years of age; 56% female) were imaged. We included 6 eyes with no DR, 7 eyes with mild non-proliferative DR (NPDR), 22 moderate NPDR, 4 severe NPDR, and 6 PDR eyes. MLC density between graders was highly correlated (r = 0.9592, p < 0.0001). MLC density was correlated with DCP GPD (r = 0.296, p = 0.049), but no other OCTA ischemia metrics. MLC density was also correlated with UWF-FA NPA (r = 0.330, p = 0.035) and NPI (r = 0.332, p = 0.034). MLC density was correlated with total ischemia on UWF-FA and local DCP GPD. Since both UWF-FA and DCP non-perfusion are associated with higher risk for DR progression, MLC density could be another potential biomarker for DR progression.

Cerebral microcirculation mapped by echo particle tracking velocimetry quantifies the intracranial pressure and detects ischemia.

Affecting 1.1‰ of infants, hydrocephalus involves abnormal accumulation of cerebrospinal fluid, resulting in elevated intracranial pressure (ICP). It is the leading cause for brain surgery in newborns, often causing long-term neurologic disabilities or even death. Since conventional invasive ICP monitoring is risky, early neurosurgical interventions could benefit from noninvasive techniques. Here we use clinical contrast-enhanced ultrasound (CEUS) imaging and intravascular microbubble tracking algorithms to map the cerebral blood flow in hydrocephalic pediatric porcine models. Regional microvascular perfusions are quantified by the cerebral microcirculation (CMC) parameter, which accounts for the concentration of micro-vessels and flow velocity in them. Combining CMC with hemodynamic parameters yields functional relationships between cortical micro-perfusion and ICP, with correlation coefficients exceeding 0.85. For cerebral ischemia cases, the nondimensionalized cortical micro-perfusion decreases by an order of magnitude when ICP exceeds 50% of the MAP. These findings suggest that CEUS-based CMC measurement is a plausible noninvasive method for assessing the ICP and detecting ischemia.

Ischemic-Trained Monocytes Improve Arteriogenesis in a Mouse Model of Hindlimb Ischemia.

OBJECTIVE: Monocytes, which play an important role in arteriogenesis, can build immunologic memory by a functional reprogramming that modifies their response to a second challenge. This process, called trained immunity, is evoked by insults that shift monocyte metabolism, increasing HIF (hypoxia-inducible factor)-1α levels. Since ischemia enhances HIF-1α, we evaluate whether ischemia can lead to a functional reprogramming of monocytes, which would contribute to arteriogenesis after hindlimb ischemia. METHODS AND RESULTS: Mice exposed to ischemia by 24 hours (24h) of femoral artery occlusion (24h trained) or sham were subjected to hindlimb ischemia one week later; the 24h trained mice showed significant improvement in blood flow recovery and arteriogenesis after hindlimb ischemia. Adoptive transfer using bone marrow-derived monocytes (BM-Mono) from 24h trained or sham donor mice, demonstrated that recipients subjected to hindlimb ischemia who received 24h ischemic-trained monocytes had remarkable blood flow recovery and arteriogenesis. Further, ischemic-trained BM-Mono had increased HIF-1α and GLUT-1 (glucose transporter-1) gene expression during femoral artery occlusion. Circulating cytokines and GLUT-1 were also upregulated during femoral artery occlusion.Transcriptomic analysis and confirmatory qPCR performed in 24h trained and sham BM-Mono revealed that among the 15 top differentially expressed genes, 4 were involved in lipid metabolism in the ischemic-trained monocytes. Lipidomic analysis confirmed that ischemia training altered the cholesterol metabolism of these monocytes. Further, several histone-modifying epigenetic enzymes measured by qPCR were altered in mouse BM-Mono exposed to 24h hypoxia. CONCLUSIONS: Ischemia training in BM-Mono leads to a unique gene profile and improves blood flow and arteriogenesis after hindlimb ischemia.

Post-ischemic skin peak oxygen saturation is associated with cardiovascular risk factors: a Swedish cohort study.

The objective of this study was to explore the associations between skin microcirculatory function and established cardiovascular risk factors in a large Swedish cohort. As part of the Swedish CArdioPulmonary bioImage Study (SCAPIS), microcirculatory data were acquired at Linköping University hospital, Linköping, Sweden during 2016-2017. The subjects, aged 50-64 years, were randomly selected from the national population register. Microcirculatory reactivity was assessed using a 5-min arterial occlusion-release protocol. Comprehensive skin microcirculatory data were continuously acquired by using a fiberoptic probe placed on the lower right arm. After exclusion of missing data (208), 1557 subjects were remaining. Among the parameters, skin microcirculatory peak oxygen saturation after occlusion release, had the strongest relationship to the cardiovascular risk factors. The linear associations between peak oxygen saturation and cardiovascular risk factors were analyzed adjusted for age and sex. We found a negative association with peak oxygen saturation (standardized regression coefficient) for blood pressure (systolic -0.05 (95% CI: -0.10;-0.003) and diastolic -0.05 (-0.10; -0.003)), BMI -0.18 (-0.23; -0.13), waist circumference (males -0.20 (-0.32; -0.16), females -0.18 (-0.25; -0.11)), prevalent diabetes -0.31 (-0.49; -0.12), hypertension -0.30 (-0.42; -0.18), dyslipidemia -0.24 (-0.40; -0.09), fasting glucose level -0.06 (-0.12; -0.01), HbA1c -0.07 (-0.12; -0.02), triglyceride level -0.09 (-0.14; -0.04), hsCRP -0.12 (-0.17; -0.07), and current smoker versus never smoked -0.50 (-0.67; -0.34). A positive association with peak oxygen saturation was found for cholesterol level 0.05 (0.005; 0.11) and HDL 0.11 (0.06; 0.17). This is the first study showing that post-ischemic skin microvascular peak oxygen saturation is associated with virtually all established cardiovascular risk factors in a population-based middle-aged cohort.

Protection of ischemic white matter and oligodendrocytes in mice by 3K3A-activated protein C.

Subcortical white matter (WM) stroke accounts for 25% of all strokes and is the second leading cause of dementia. Despite such clinical importance, we still do not have an effective treatment for ischemic WM stroke, and the mechanisms of WM postischemic neuroprotection remain elusive. 3K3A-activated protein C (APC) is a signaling-selective analogue of endogenous blood protease APC that is currently in development as a neuroprotectant for ischemic stroke patients. Here, we show that 3K3A-APC protects WM tracts and oligodendrocytes from ischemic injury in the corpus callosum in middle-aged mice by activating protease-activated receptor 1 (PAR1) and PAR3. We show that PAR1 and PAR3 were also required for 3K3A-APC's suppression of post-WM stroke microglia and astrocyte responses and overall improvement in neuropathologic and functional outcomes. Our data provide new insights into the neuroprotective APC pathway in the WM and illustrate 3K3A-APC's potential for treating WM stroke in humans, possibly including multiple WM strokes that result in vascular dementia.

Loss of Id3 (Inhibitor of Differentiation 3) Increases the Number of IgM-Producing B-1b Cells in Ischemic Skeletal Muscle Impairing Blood Flow Recovery During Hindlimb Ischemia.

OBJECTIVE: Neovascularization can maintain and even improve tissue perfusion in the setting of limb ischemia during peripheral artery disease. The molecular and cellular mechanisms mediating this process are incompletely understood. We investigate the potential role(s) for Id3 (inhibitor of differentiation 3) in regulating blood flow in a murine model of hindlimb ischemia (HLI). Approach and Results: HLI was modeled through femoral artery ligation and resection and blood flow recovery was quantified by laser Doppler perfusion imaging. Mice with global Id3 deletion had significantly impaired perfusion recovery at 14 and 21 days of HLI. Endothelial- or myeloid cell-specific deletion of Id3 revealed no effect on perfusion recovery while B-cell-specific knockout of Id3 (Id3BKO) revealed a significant attenuation of perfusion recovery. Flow cytometry revealed no differences in ischemia-induced T cells or myeloid cell numbers at 7 days of HLI, yet there was a significant increase in B-1b cells in Id3BKO. Consistent with these findings, ELISA (enzyme-linked immunoassay) demonstrated increases in skeletal muscle and plasma IgM. In vitro experiments demonstrated reduced proliferation and increased cell death when endothelial cells were treated with conditioned media from IgM-producing B-1b cells and tibialis anterior muscles in Id3BKO mice showed reduced density of total CD31+ and αSMA+CD31+ vessels. CONCLUSIONS: This study is the first to demonstrate a role for B-cell-specific Id3 in maintaining blood flow recovery during HLI. Results suggest a role for Id3 in promoting blood flow during HLI and limiting IgM-expressing B-1b cell expansion. These findings present new mechanisms to investigate in peripheral artery disease pathogenesis.

Sex differences in microvascular function across lower leg muscles in humans.

Studies have reported sex-based differences in conduit artery function, however little is known about possible sex-based differences in microvascular function, and possible influence of muscle group. Blood-oxygen-level-dependent (BOLD) MR images acquired during ischemia-reperfusion assess the reactive hyperemic response in the microvasculature of skeletal muscle. We tested the hypothesis that women have greater microvascular reactivity, reflected by faster time-to-peak (TTP) and time-to-half-peak (TTHP) of the BOLD response, across all lower leg muscles. In healthy, young men (n = 18) and women (n = 12), BOLD images of both lower legs were acquired continuously during 30 s of rest, 5 min of cuff occlusion and 2 min of reperfusion, in a 3 T MR scanner. Segmentation of tibialis anterior (TA), soleus (SO), gastrocnemius medial (GM), and the peroneal group (PG) were performed using image registration, and TTP and TTHP of the BOLD response were determined for each muscle. Overall, women had faster TTP (p = 0.001) and TTHP (p = 0.01) than men. Specifically, women had shorter TTP and TTHP in TA (27.5-28.4%), PG (33.9-41.6%), SO (14.7-19.7%) and GM (15.4-18.8%). Overall, TTP and TTHP were shorter in TA compared with PG (25.1-31.1%; p ≤ 0.007), SO (14.3-16%; p ≤ 0.03) and GM (15.6-26%; p ≤ 0.01). Intra class correlations analyses showed large variation in absolute agreement (range: 0.10-0.81) of BOLD parameters between legs (within distinct muscles). Faster TTP and TTHP across all lower leg muscles, in women, provide novel evidence of sex-based differences in microvascular function of young adults matched for age, body mass index, and physical activity level.

Role of microRNA­218­5p in sevoflurane­induced protective effects in hepatic ischemia/reperfusion injury mice by regulating GAB2/PI3K/AKT pathway.

Hepatic ischemia/reperfusion (I/R) injury (HIRI) often occurs following tissue resection, hemorrhagic shock or transplantation surgery. Previous investigations showed that sevoflurane (Sevo), an inhalation anesthetic, had protective properties against different organ damage in animal models including HIRI. This study is aimed to investigate the underlying mechanisms involved in the protective effects of Sevo on HIRI. The present study results showed that treatment with Sevo improved histologic damage, inflammatory response, oxidative stress and apoptosis after hepatic I/R, indicating the protective role of Sevo against liver I/R injury. Importantly, in order to determine the molecular mechanism of Sevo in HIRI, the focus of the study was on microRNA (miR) regulation. By retrieving the microarray data in the Gene Expression Omnibus dataset (GSE72315), miR­218­5p was found to be significantly downregulated by Sevo. Moreover, miR­218­5p overexpression using agomiR­218­5p reversed the protective roles of Sevo against HIRI. Furthermore, GAB2, a positive regulator of PI3K/AKT signaling pathway, was found as a target gene of miR­218­5p. It was also found that the Sevo­mediated protective effects may be dependent on the activation of GAB2/PI3K/AKT. Collectively, these data revealed that Sevo alleviated HIRI in mice by restraining apoptosis, relieving oxidative stress and inflammatory response through the miR­218­5p/GAB2/PI3K/AKT pathway, which helps in understanding the novel mechanism of the hepatic­protection of Sevo.

Comparison of nerve conduction velocity distribution methods by cold exposure and ischemia.

PURPOSE: Non-invasive estimation of the conduction velocity distribution (CVD) of a peripheral nerve has the potential to both improve clinical diagnoses of pathology and to observe the progress of the disease or the efficacy of treatments. Comparisons were made of the performance of three non-invasive CVD estimation methods proposed by independent research groups on peripheral nerve bundles under different conditions. METHODS: The first method (Cummins) uses a nerve compound action potential (CAP) with temporal dispersion and a mathematical single fiber action potential (SFAP). The second method (Barker) uses two CAPs and a non-mathematical SFAP waveform. The third method (Hirose) uses two CAPs recorded from distal and proximal sites. The Cummins and Barker methods have iterative solutions in the time domain while the Hirose method is a deconvolution estimator in the frequency domain. In order to compare these methods, we used cold exposure to affect primarily motor fibers and ischemia to affect primarily sensory fibers on rat caudal nerve bundles. RESULTS: The Cummins method is sensitive to changes in motor and sensory fiber percentages in CVD if it is used with the volume conductor model. The Barker and Hirose methods are sensitive to motor fiber percentages in CVD but they cannot detect changes in sensory fiber percentages accurately. CONCLUSIONS: Estimation of the CVD using a priori SFAP created with a volume conductor model can non-invasively supply accurate and precise information about fiber groups in a peripheral nerve bundle.

Assessment of Tissue Viability Following Amputation Surgery Using Near-Infrared Fluorescence Imaging With Indocyanine Green.

BACKGROUND: Patients with chronic limb threatening ischemia have a risk of undergoing a major amputation within 1 year of nearly 30% with a substantial risk of re-amputation since wound healing is often impaired. Quantitative assessment of regional tissue viability following amputation surgery can identify patients at risk for impaired wound healing. In quantification of regional tissue perfusion, near-infrared (NIR) fluorescence imaging using Indocyanine Green (ICG) seems promising. METHODS: This pilot study included adult patients undergoing lower extremity amputation surgery due to peripheral artery disease or diabetes mellitus. ICG NIR fluorescence imaging was performed within 5 days following amputation surgery using the Quest Spectrum PlatformⓇ. Following intravenous administration of ICG, the NIR fluorescence intensity of the amputation wound was recorded for 10 minutes. The NIR fluorescence intensity videos were analyzed and if a fluorescence deficit was observed, this region was marked as "low fluorescence." All other regions were marked as "normal fluorescence." RESULTS: Successful ICG NIR fluorescence imaging was performed in 10 patients undergoing a total of 15 amputations. No "low fluorescence" regions were observed in 11 out of 15 amputation wounds. In 10 out of these 11 amputations, no wound healing problems occurred during follow-up. Regions with "low fluorescence" were observed in 4 amputation wounds. Impaired wound healing corresponding to these regions was observed in all wounds and a re-amputation was necessary in 3 out of 4. When observing time-related parameters, regions with low fluorescence had a significantly longer time to maximum intensity (113 seconds vs. 32 seconds, P = 0.003) and a significantly lesser decline in outflow after five minutes (80.3% vs. 57.0%, P = 0.003). CONCLUSIONS: ICG NIR fluorescence imaging was able to predict postoperative skin necrosis in all four cases. Quantitative assessment of regional perfusion remains challenging due toinfluencing factors on the NIR fluorescence intensity signal, including camera angle, camera distance and ICG dosage. This was also observed in this study, contributing to a large variety in fluorescence intensity parameters among patients. To provide surgeons with reliable NIR fluorescence cut-off values for prediction of wound healing, prospective studies on the intra-operative use of this technique are required. The potential prediction of wound healing using ICG NIR fluorescence imaging will have a huge impact on patient mortality, morbidity as well as the burden of amputation surgery on health care.

Hybrid Deep Venous ARterialisation (DVAR) for No-Option Chronic Limb Threatening Ischemia.

BACKGROUND: Hybrid Deep Venous ARterialisation (DVAR) is offered as a last-ditch attempt for limb salvage in patients with chronic limb threatening ischemia (CLTI). It provides non-selective arterialisation independent of the angiosome, which harnesses the complex venous capillary network bed developed in the leg and foot. METHODS: We present two elderly men who underwent DVAR to salvage limb with CLTI. DVAR was performed by creating an arteriovenous connection by anastomosis of the great saphenous vein (GSV) at the level of the distal popliteal and proximal tibio-peroneal trunk. Fasciotomy was performed over the length of the GSV. Subsequently, proximal in-situ catheter valvotomies of the GSV valves were undergone with the adjuvant on-table balloon maturation. The distal tarsal veins underwent balloon valvotomy under direct vision with subsequent proximal and distal tarsal veins valvuloplasties. Completion angiogram demonstrated restoration of the flow in the foot and both the patients were relieved of rest pain. CONCLUSION: We successfully performed DVAR in 2 elderly patients. Our experience shows that DVAR is a simple and safe option that is easily reproducible without the need for complex endovascular hardware, only if a suitable GSV to the foot is available with no history of deep vein thrombosis.

Evaluation of Long-Term Outcomes of Femoropopliteal Bypass Surgery in Patients With Chronic Limb-Threatening Ischemia in an Endovascular Era.

BACKGROUND: To investigate the long-term outcomes of femoropopliteal bypass surgery in patients with chronic limb-threatening ischemia (CLTI) and TransAtlantic Inter-Society Consensus II (TASC II), type D (TASC D) femoropopliteal disease. METHODS: A retrospective analysis was performed for all consecutive patients undergoing above-knee (AK) femoropopliteal bypass surgery at an academic vascular centre between January 2007 and March 2019. Patients with claudication (IC) and patients with CLTI were included. Patency rates and freedom from major adverse limb events (MALE) after 5 years were analysed. RESULTS: In total, 432 femoropopliteal grafts were performed. Indications for surgery were claudication and CLTI in 232 (53.7%) and 200 (46.3%) patients, respectively. Graft material was autologous vein in 186 patients (43.1%), polytetrafluoroethylene (PTFE) in 128 patients (29.6%), and heparin-bonded expanded polytetrafluoroethylene (HePTFE) in 118 patients (27.3%). At the 5-year follow-up, the primary patency rate was 58.1% and 58.3% in patients with CLTI and claudication, respectively. Secondary patency rates were 74.1% and 68.6%, respectively. Freedom from MALE was 64.5% and 61.9%, respectively. Analyses of graft material in the CLTI group showed that, at 5 years, autologous vein grafts had better long-term patency rates than PTFE and HePTFE grafts. At 5 years, the primary and secondary patency rate for autologous vein grafts were 63.2% (P= 0.324) and 83.2% (P = 0.020), respectively. Freedom from MALE was 72.0% with the use of autologous vein grafts, 47.9% using PTFE and, 52.9% using HePTFE, respectively (P= 0.021). CONCLUSIONS: Our study shows that femoropopliteal bypass surgery in patients with TASC D lesions is safe and effective in the long term. Autologous vein grafts remain the first choice for patients with CLTI, also for bypasses in AK position. However, prosthetic grafts in AK the position are an acceptable alternative for revascularisation when the saphenous vein is not available.

Viabahn-Assisted Extra-Arterial Bypass Combined With Surgical Arterial Endarterectomy as a Salvage Technique to Treat Critical Limb Ischemia.

BACKGROUND: Revascularization of patients with critical limb ischemia (CLI) is always challenging because of long occlusive arterial lesions with severe calcification and poor general condition. Here we describe a novel hybrid technique to treat a CLI patient. METHODS: The patient was a 60-year-old male with left foot ulcer. Preoperative scan showed long calcific and occlusive lesions running from the left proximal common femoral artery to P1 of the popliteal artery (PA). Surgical endarterectomy was performed on the proximal femoral artery. Then, retrograde PA access was achieved to protect the vital collateral artery at the proximal PA. When the retrograde V18 guidewire failed to advance because of severe occlusion in the middle one-third of the SFA, we punctured the artery with the V18 guidewire, and manually introduced it into the lumen of the proximal SFA. Three Viabahn stent grafts were successively implanted, parts of which were situated outside the SFA. RESULTS: Computed tomography 1 week after surgery showed patent blood flow to the left toes. Good recovery was observed during a 1-year follow up, the toe wound healed after amputation, and no rest pain recurred. Ultrasound showed 60% stenosis in the PA stent, while the other stents were patent. The anklebrachial index of the left limb was 0.48. CONCLUSIONS: This case illustrates successful use of Viabahn-assisted extra-arterial bypass combined with surgical arterial endarterectomy to salvage the limb after CLI. This novel technique might be an alternative in carefully selected patients.

Early ABI Testing May Decrease Risk of Amputation for Patients With Lower Extremity Ulcers.

BACKGROUND: Patients with lower extremity wounds from diabetes mellitus or peripheral artery disease (PAD) have a risk of amputation as high as 25%. In patients with arterial disease, revascularization decreases the risk of amputation. We aimed to determine if the early assessment of arterial perfusion correlates with the risk of amputation. METHODS: We retrospectively reviewed patients referred to the vascular clinic over 18 months with Rutherford Grade 5 and 6 chronic limb-threatening ischemia to determine if patients had a pulse exam done at the time the wound was identified and when ankle brachial index (ABI) testing to evaluate perfusion was performed. Kaplan Meier analysis was used to determine if the timing of ABI testing affected the time to revascularization, wound healing, and risk of amputation. RESULTS: Ninety-three patients with lower extremity wounds were identified. Of these, 59 patients (63%) did not have a pulse exam performed by their primary care provider when the wound was identified. Patients were classified by when they underwent ankle brachial index testing to assess arterial perfusion. Twenty-four had early ABI (<30 days) testing, with the remaining 69 patients having late ABI testing. Patients in the early ABI group were more likely to have a pulse exam done by their PCP than those in the late group, 12 (50%) vs. 22 (32%), P = 0.03. Early ABI patients had a quicker time to vascular referral (13 days vs. 91 days, P < 0.001). Early ABI patients also had quicker times to wound healing than those in the late group (117 days vs. 287 days, P < 0.001). Finally, patients that underwent early ABI were less likely to require amputation (Fig. 1), although this did not reach statistical significance (P = 0.07). CONCLUSIONS: Early ABI testing expedites specialty referral and time to revascularization. It can decrease the time to wound healing. Larger cohort studies are needed to determine the overall effect of early ABI testing to decrease amputation rates.

Long-term results of ulnar and radial reconstruction with interpositional grafting using the deep inferior epigastric artery for chronic hand ischemia.

Chronic hand ischemia causes cold intolerance, intractable pain, and digital ulceration. If ischemic symptoms persist despite pharmacologic treatments, surgical interventions should be considered. This retrospective study evaluated the long-term results after ulnar and radial reconstruction using an interpositional deep inferior epigastric artery (DIEA) graft combined with periarterial sympathectomy. Patients who underwent this surgery from March 2003 to February 2019 were included. To evaluate variables influencing recurrence after the procedure, patients were divided into the recurred and non-recurred groups and their data were compared. Overall, 62 cases involving 47 patients were analyzed (16 and 46 cases in the recurred and non-recurred groups, respectively). The median DIEA graft length was 8.5 cm. The rates of rheumatic disease and female patients were significantly higher in the recurred than in the non-recurred group, without significant between-group differences in postoperative complication rates. In the multivariate analysis, underlying rheumatic disease and graft length had significant effects on recurrence. In Kaplan-Meier analysis, the 5- and 10-year symptom-free rates were 81.3% and 68.0%, respectively, with lower rates for cases with rheumatic disease. Thus, arterial reconstruction using an interpositional DIEA graft provides long-term sustainable vascular supply in patients with chronic hand ischemia, especially in those without rheumatic disease.

Effects of long-term anti-ischemic drug treatment on Na,K-ATPase isoforms in cardiomyopathic hamsters.

We investigated the effects of long-term anti-ischemic therapy with trimetazidine on Na,K-ATPase (NKA) activity and protein expression in cardiomyopathy. NKA isoforms in membrane fractions from cardiomyopathic hamsters of the BIO 14.6 strain were studied and compared with those from healthy Syrian golden hamsters (F1B). Trimetazidine was orally administered to a subset of cardiomyopathic hamsters in the early stage of active disease (30 days) until the congestive stage (350 days). In the congestive stage of cardiac failure, the cardiomyopathic hamsters displayed altered NKA activity (-55 % vs. F1B; p<0.01), which was related to a specific decrease in abundance of the membrane NKA ?1 isoform (-27 % vs. F1B). Trimetazidine partially prevented the cardiomyopathy-induced changes in NKA activity (+38 %) and ?1 membrane expression (+ 66 %) without inducing changes in the expression of the ?2 isoform or 1 isoform of NKA. Cardiac hypertrophy and remodeling were reduced after trimetazidine treatment. Additionally, the abundance of NKA ?1 in membranes was negatively correlated with the ventricular weight/body weight ratio (an index of cardiac hypertrophy) (r2 = 0.99; p<0.0015). These findings suggest that some of the cardioprotective effect of trimetazidine during long-term cardiomyopathy may be achieved via regulation of cardiac remodeling and selective modulation cardiac NKA isoforms.

Pre hospital delay and its associated factors in acute myocardial infarction in a developing country.

BACKGROUND: Early revascularization and treatment is key to improving clinical outcomes and reducing mortality in acute myocardial infarction (AMI). In low- and middle-income countries such as Bangladesh, timely management of AMI is challenging, with pre-hospital delays playing a significant role. This study was designed to investigate pre-hospital delay and its associated factors among patients presenting with AMI in the capital city of Dhaka. METHODS: This retrospective cohort study was conducted on 333 patients presenting with AMI over a 3-month period at two of the largest primary reperfusion-capable tertiary cardiac care centres in Dhaka. Of the total patients, 239(71.8%) were admitted in the National Institute of Cardiovascular Diseases, Dhaka and 94(28.2%) at Ibrahim Cardiac Hospital & Research Institute, Dhaka Data were collected from patients by semi-structured interview and hospital medical records. Pre-hospital delay (median and inter-quartile range) was calculated. Statistical significance was determined by Chi-square test. Multivariate logistic regression analysis was done to determine the independent predictors of pre-hospital delay. RESULTS: The mean age of the respondents was 53.8±11.2 years. Two-thirds (67.6%) of the respondents were males. Median total pre-hospital delay was 11.5 (IQR-18.3) hours with median decision time from symptom onset to seeking medical care being 3.0 (IQR: 11.0) hours. Nearly half (48.9%) of patients presented to the hospital more than 12 hours after symptom onset. On multivariate logistic regression analysis, AMI patients with absence of typical chest pain [OR 5.21; (95% CI: 2.5-9.9)], diabetes [OR: 1.7 (95% CI: 1.0-2.9)], residing/staying > 30 km away from nearest hospital at the time of onset [OR: 4.3(95% CI = 2.3-7.2)] and belonged to lower and middle class [OR: 1.9(95% CI = 1.0-3.5)] were significantly associated with pre-hospital delays. CONCLUSION: Acute myocardial infarction (AMI) patients with atypical chest pain, diabetes, staying far away from nearest hospital and belonged to lower and middle socioeconomic strata were significantly associated with pre-hospital delays. The findings could have immense implications for improvements about timely reaching of AMI patients to the hospital within the context of their sociodemographic status and geographic barriers of the city.

Risk-Benefit of 1-Year DAPT After DES Implantation in Patients Stratified by Bleeding and Ischemic Risk.

BACKGROUND: Although a 1-year duration of dual antiplatelet therapy (DAPT) is used in many patients after drug-eluting stent (DES) implantation, the evidence supporting this duration is uncertain. OBJECTIVES: The authors investigated the risk-benefit profile of 1-year vs ≤6-month DAPT after DES using 2 novel scores to risk stratify bleeding and ischemic events. METHODS: Ischemic and bleeding risk scores were generated from ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents), a multicenter, international, "all-comers" registry that enrolled 8,665 patients treated with DES. The risk-benefit profile of 1-year vs ≤6-month DAPT was then investigated across risk strata from an individual patient data pooled dataset of 7 randomized trials that enrolled 15,083 patients treated with DES. RESULTS: In the derivation cohort, the ischemic score and the bleeding score had c-indexes of 0.76 and 0.66, respectively, and both were well calibrated. In the pooled dataset, no significant difference was apparent in any ischemic endpoint between 1-year and ≤6-month DAPT, regardless of the risk strata. In the overall dataset, there was no significant difference in the risk of clinically relevant bleeding between 1-year and ≤6-month DAPT; however, among 2,508 patients at increased risk of bleeding, 1-year compared with ≤6-month DAPT was associated with greater bleeding (HR: 2.80; 95% CI: 1.12-7.13) without a reduced risk of ischemic events in any risk strata, including those with acute coronary syndromes. These results were consistent in a network meta-analysis. CONCLUSIONS: In the present large-scale study, compared with ≤6-month DAPT, a 1-year duration of DAPT was not associated with reduced adverse ischemic events in any risk strata (including acute coronary syndromes) but was associated with greater bleeding in patients at increased risk of bleeding.

Local intramuscular administration of ANG1 and VEGF genes using plasmid vectors mobilizes CD34+ cells to peripheral tissues and promotes angiogenesis in an animal model.

INTRODUCTION: Patients with peripheral artery disease have poor prognosis despite advances in vascular surgery. Therefore, attempts have been made at using gene and cell therapy to stimulate angiogenesis in the lower limbs in patients with critical lower limb ischemia (CLI). METHODS: The study included 30 rats divided into 3 groups. An intramuscular injection of a therapeutic gene or cells in the right hind limb was administered in each group: angiopoietin-1 (ANG1) plasmid in group 1, ANG1/vascular endothelial growth factor (ANG1/VEGF) bicistronic construct in group 2, and naked plasmid in group 3 (control). After 3 months of follow-up, tissue samples were harvested, and vessels that stained positively for CD34 cells were quantified. RESULTS: The highest CD34+ cell count was noted in the ANG1/VEGF group (98.26 cells), followed by the ANG1 group (80.31) and control group (47.93). The CD34+ cell count was significantly higher in the ANG1/VEGF and ANG1 groups than in the control group. There was no significant difference in the CD34+ cell count between the ANG1/VEGF and ANG1 groups. CONCLUSION: Our study confirmed that therapy with ANG1 plasmid alone or ANG1/VEGF bicistronic construct is safe and effective in a rat model. The therapy resulted in the recruitment of more CD34+ vascular endothelial cells than in the control group receiving naked plasmid.