Peripheral Vascular Occlusive Disease Research Articles

Clinical Efficacy Of Infra Popliteal Angioplasty For Below The Knee Peripheral Vascular Occlusive Disease.

Peripheral arterial disease (PAD) affects a substantial proportion of the global population, particularly older individuals, affecting around 200 million people worldwide highlighting its significant impact on human health. Critical limb ischemia (CLI) is the most severe clinical presentation of PAD characterized by ischemic rest pain tissue ulceration or gangrene. The objective of the study is to assess the efficacy of infra popliteal angioplasty (in terms of wound healing and limb salvage) in patients with below-the-knee total chronic occlusion (TCO). In this cross-sectional study, all consecutive patients in one year with TCO and fulfilling the inclusion criteria were included. A total of 64 limbs underwent angioplasty. The mean age was 55.38 ± 13.12 (Range 22-88) years and there were 73% (n=47) males. Diabetes mellitus was the most prevalent risk factor in 59.4% (n=38) of patients. 48.4 % (n=31) of patients had below-knee TCO in all three arteries. Technical Success was achieved in 95.3% (n=61/64). All 3 patients who had technical failure ended up with below-the-knee amputation. Furthermore, 2 more patients who had technical success also ended up with below-the-knee amputation. The difference between these two rates was significant (100% vs 3.3%; p-value =0.004). In terms of wound healing, statistically significant improvement was noted within the first 6 months (p-value = 0.05). The limb salvage rate was 90.6% (n=59/64). The primary patency rate was 81.3% (n=52) and 76.6% (n=49) at 6 and 12 months respectively. Angioplasty results in statistically significant wound healing leading to a higher limb salvage rate, in patients with TCO of infrapopliteal arteries.

Blood pressure targets for the treatment of people with hypertension and cardiovascular disease.

This is the third update of the review first published in 2017. Hypertension is a prominent preventable cause of premature morbidity and mortality. People with hypertension and established cardiovascular disease are at particularly high risk, so reducing blood pressure to below standard targets may be beneficial. This strategy could reduce cardiovascular mortality and morbidity but could also increase adverse events. The optimal blood pressure target in people with hypertension and established cardiovascular disease remains unknown. To determine if lower blood pressure targets (systolic/diastolic 135/85 mmHg or less) are associated with reduction in mortality and morbidity compared with standard blood pressure targets (140 mmHg to 160mmHg/90 mmHg to 100 mmHg or less) in the treatment of people with hypertension and a history of cardiovascular disease (myocardial infarction, angina, stroke, peripheral vascular occlusive disease). For this updated review, we used standard, extensive Cochrane search methods. The latest search date was January 2022. We applied no language restrictions. We included randomized controlled trials (RCTs) with more than 50 participants per group that provided at least six months' follow-up. Trial reports had to present data for at least one primary outcome (total mortality, serious adverse events, total cardiovascular events, cardiovascular mortality). Eligible interventions involved lower targets for systolic/diastolic blood pressure (135/85 mmHg or less) compared with standard targets for blood pressure (140 mmHg to 160 mmHg/90 mmHg to 100 mmHg or less). Participants were adults with documented hypertension and adults receiving treatment for hypertension with a cardiovascular history for myocardial infarction, stroke, chronic peripheral vascular occlusive disease, or angina pectoris. We used standard Cochrane methods. We used GRADE to assess the certainty of the evidence. We included seven RCTs that involved 9595 participants. Mean follow-up was 3.7 years (range 1.0 to 4.7 years). Six of seven RCTs provided individual participant data. None of the included studies was blinded to participants or clinicians because of the need to titrate antihypertensive drugs to reach a specific blood pressure goal. However, an independent committee blinded to group allocation assessed clinical events in all trials. Hence, we assessed all trials at high risk of performance bias and low risk of detection bias. We also considered other issues, such as early termination of studies and subgroups of participants not predefined, to downgrade the certainty of the evidence. We found there is probably little to no difference in total mortality (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.91 to 1.23; 7 studies, 9595 participants; moderate-certainty evidence) or cardiovascular mortality (RR 1.03, 95% CI 0.82 to 1.29; 6 studies, 9484 participants; moderate-certainty evidence). Similarly, we found there may be little to no differences in serious adverse events (RR 1.01, 95% CI 0.94 to 1.08; 7 studies, 9595 participants; low-certainty evidence) or total cardiovascular events (including myocardial infarction, stroke, sudden death, hospitalization, or death from congestive heart failure (CHF)) (RR 0.89, 95% CI 0.80 to 1.00; 7 studies, 9595 participants; low-certainty evidence). The evidence was very uncertain about withdrawals due to adverse effects. However, studies suggest more participants may withdraw due to adverse effects in the lower target group (RR 8.16, 95% CI 2.06 to 32.28; 3 studies, 801 participants; very low-certainty evidence). Systolic and diastolic blood pressure readings were lower in the lower target group (systolic: mean difference (MD) -8.77 mmHg, 95% CI -12.82 to -4.73; 7 studies, 8657 participants; diastolic: MD -4.50 mmHg, 95% CI -6.35 to -2.65; 6 studies, 8546 participants). More drugs were needed in the lower target group (MD 0.56, 95% CI 0.16 to 0.96; 5 studies, 7910 participants), but blood pressure targets at one year were achieved more frequently in the standard target group (RR 1.20, 95% CI 1.17 to 1.23; 7 studies, 8699 participants). We found there is probably little to no difference in total mortality and cardiovascular mortality between people with hypertension and cardiovascular disease treated to a lower compared to a standard blood pressure target. There may also be little to no difference in serious adverse events or total cardiovascular events. This suggests that no net health benefit is derived from a lower systolic blood pressure target. We found very limited evidence on withdrawals due to adverse effects, which led to high uncertainty. At present, evidence is insufficient to justify lower blood pressure targets (135/85 mmHg or less) in people with hypertension and established cardiovascular disease. Several trials are still ongoing, which may provide an important input to this topic in the near future.

Uno scompenso per due, col terzo incomodo

The importance of differentiating between primary cardiovascular prevention and secondary prevention in diabetes will be discussed in light of the results obtained by the cardiovascular outcome trials (CVOTs). In patients with diabetes, the distinction between primary and secondary cardiovascular prevention could be artificial. The main criteria for enrollment in cardiovascular outcome trials that define the so-called patient in secondary prevention are, typically: i) the history of heart attack or unstable angina; ii) the history of ischemic or hemorrhagic stroke, iii) subclinical conditions, i.e., multivessel coronary ar¬tery disease, occlusive peripheral vascular disease with stenosis greater than 50%, or with a Winsor index less than 0.9. However, in patients with diabetes, a significant coronary atherosclerotic disease can be asymptomatic: this has important clinical implications, i.e., i. patients with diabetes are frequently undertreated, ii: it is unclear whether all asymptomatic patients should be screened for coronary artery disease for implementing optimal medical therapy. The conclusion is that placing the outpatient in the so-called primary or secondary prevention without a clinical event is impossible.

Ultrasound-Guided Catheterization Using a Driller-Tipped Guidewire With Combined Magnetic Navigation and Drilling Motion

The endovascular intervention has been widely used to treat occlusive peripheral vascular disease (PVD). However, the current procedure has concerns such as low successful rate, undesired trauma, and radiation exposure. This article proposes a robotic solution to mitigate these limitations. A miniature magnetic driller-tipped guidewire (MDG) is designed, which performs 1) controllable bending under directional magnetic fields to navigate in complex vasculature and 2) mechanical drilling under rotating magnetic fields to pass through clogged regions. An integrated actuation system is adopted for magnetic control and ultrasound (US) imaging in a large workspace. A control framework composed of the preoperative and intraoperative stages is developed, which internally coordinates all system modules, addresses noisy US imaging, and provides convenient operation. Demonstrations under an optical camera verify the flexible steering ability and effective unclogging motion of the MDG. Furthermore, US image-monitored <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">in vitro</i> experiments validate the overall hardware platform and control strategy. The designed MDG realizes dual objectives, including controllability at bifurcations and penetrability at clots. The introduced US imaging modality largely reduces radiation hazards in conventional catheterization. This article studies the intervention of the MDG under electromagnetic field navigation and US imaging guidance. The proposed workflow has the potential to improve operational safety and clinical outcomes of the occlusive PVD treatment.

Investigation of the correlation between diabetic retinopathy and prevalent and incident migraine in a national cohort study

Migraine is a disease characterized by cerebral vasodilation. While diabetes has previously been associated with a lower risk of migraine, it is not known if diabetic retinopathy (DR), a retinal peripheral vascular occlusive disease, is a potential biomarker of protection against migraine. Therefore, we aimed to examine diabetic retinopathy as a marker of prevalent and 5-year incident migraine. In a national cohort, we compared patients with diabetes attending DR screening from The Danish National Registry of Diabetic Retinopathy (cases, n = 205,970) to an age- and gender-matched group of patients without diabetes (controls, n = 1,003,170). In the cross-sectional study, a multivariable model demonstrated a lower prevalence of migraine among cases compared with controls (OR 0.83, 95% CI 0.81–0.85), with a lower risk in cases with DR than in those without (OR 0.69, 95% CI 0.65–0.72). In the prospective study, a lower risk of incident migraine was found in a multivariable model in cases (HR 0.76, 95% CI 0.70–0.82), but this did not depend upon the presence of DR. To conclude, in a national study of more than 1.2 million people, patients screened for DR had a lower risk of present migraine, but DR was not a protective marker of incident migraine.

Extravascular Access Artery Closure After Percutaneous Peripheral Intervention

Percutaneous closure of the access artery has become commonplace after endovascular intervention. In patients with peripheral vascular occlusive disease, however, control of the puncture site is more problematic as the access artery is frequently plaque-laden and stenotic. Ischemic complications in the access extremity are more common in these cases, particularly when using devices that depend on the deployment of prosthetic material within the compromised arterial lumen. The purpose of this retrospective clinical study was to assess the efficacy of totally extravascular/bioresorbable closure of the femoral artery puncture sites after percutaneous peripheral intervention (PPI).

Abstract 123: Genetic Deficiency Of The Ectoenzyme CD73 Increases Neutrophil Extracellular Trap Formation In Patients With ACDC

Background/Purpose: CD73 is a ecto-5′-nucleotidase located on the plasma membrane that generates adenosine from AMP in the extracellular space, and functions as a checkpoint against immune and vascular activation. CD73 inhibitors that eliminate this immune checkpoint blockade are being studied in phase 2/3 cancer clinical trials. We recently identified that lack of CD73 promotes vascular thromboinflammation and neutrophil extracellular trap (NET) formation in mice. The role of CD73 in human NETosis, however, remains to be studied. Arterial calcification due to deficiency of CD73 (ACDC) is a rare, autosomal recessive condition (~20 patients globally) that results in occlusive peripheral vascular disease. We hypothesized that the congenital absence of CD73 and its function as an immune checkpoint would heighten innate immune activation in patients with ACDC. Methods: To test this hypothesis, six patients with molecularly confirmed ACDC were recruited to the NIH for mechanistic studies. Using purified neutrophils from ACDC patients and healthy controls, spontaneous and LPS-induced NET formation was quantified by both Sytox extracellular DNA (eDNA) labeling and NET-associated MPO activity. Results: Absence of surface CD73 was confirmed by flow cytometry. Relative to healthy controls, four of six (4/6) patients with ACDC demonstrated increased ex vivo spontaneous NET formation, but not LPS-triggered NETosis. The four ACDC patients with increased spontaneous NETosis had a mean 1.7-fold increase in Sytox-stained eDNA and 2-fold increase in MPO activity compared with contemporary healthy controls. Conclusion: These data reveal marked, spontaneous NETosis in patients deficient in the ectoenzyme CD73. Comparison with LPS-stimulated neutrophils demonstrates near maximal NETosis at baseline in patients with ACDC, consistent with a model where CD73 tonically suppresses neutrophil activation to maintain vascular and immune homeostasis. Ongoing studies are exploring the mechanism of spontaneous NETosis, thrombin formation, and fibrinolysis in patients with ACDC. Taken together, these data will have relevance to patients with ACDC, and inform the thromboinflammatory risk of cancer patients receiving CD73 inhibitors.

Recent Updates and Advances in Winiwarter-Buerger Disease (Thromboangiitis Obliterans): Biomolecular Mechanisms, Diagnostics and Clinical Consequences.

Thromboangiitis obliterans (TAO) or Buerger’s disease is a segmental inflammatory, thrombotic occlusive peripheral vascular disease with unknown aetiology that usually involves the medium and small-sized vessels of young male smokers. Due to its unknown aetiology and similarities with atherosclerosis and vasculitis, TAO diagnosis is still challenging. We aimed to review the status of biomolecular and laboratory para-clinical markers in TAO compared to atherosclerosis and vasculitis. We reported that, although some biomarkers might be common in TAO, atherosclerosis, and vasculitis, each disease occurs through a different pathway and, to our knowledge, there is no specific and definitive marker for differentiating TAO from atherosclerosis or vasculitis. Our review highlighted that pro-inflammatory and cell-mediated immunity cytokines, IL-33, HMGB1, neopterin, MMPs, ICAM1, complement components, fibrinogen, oxidative stress, NO levels, eNOS polymorphism, adrenalin and noradrenalin, lead, cadmium, and homocysteine are common markers. Nitric oxide, MPV, TLRs, MDA, ox-LDL, sST2, antioxidant system, autoantibodies, and type of infection are differential markers, whereas platelet and leukocyte count, haemoglobin, lipid profile, CRP, ESR, FBS, creatinine, d-dimer, hypercoagulation activity, as well as protein C and S are controversial markers. Finally, our study proposed diagnostic panels for laboratory differential diagnosis to be considered at first and in more advanced stages.

Successful modeling of long term outcomes in end-stage renal disease patients undergoing percutaneous coronary intervention with drug-eluting stents.

The objective of this study is to identify and model risk factors for major adverse cardiac events (MACE) and all-cause mortality among patients with ESRD treated with PCI using DES. Patients with end-stage renal disease (ESRD) have poor long-term outcomes after percutaneous coronary intervention (PCI) compared with non-ESRD patients. However, there is a paucity of literature regarding risk factors associated with outcomes of ESRD patients after PCI with drug-eluding stents (DES). This retrospective cohort study includes all patients with ESRD who underwent first-time PCI with DES at a single, high-volume hospital between 1/1/2005 and 12/31/2015, with follow-up through 9/1/2019. Primary outcomes were MACE (cardiac death, myocardial infarction, or unplanned revascularization) and all-cause mortality. Five-year MACE was 83.0% and five-year morality was 77.9% in patients with ESRD (n = 285). Among ESRD patients, factors independently associated with MACE were C-reactive peptide level, SYNTAX score, peripheral vascular occlusive disease, hemoglobin, and treatment of a restenotic lesion (c-index = 0.66). Factors independently associated with mortality in ESRD patients were age, SYNTAX score, non-use of statins at baseline, insulin-dependent diabetes, chronic obstructive pulmonary disease (COPD), peripheral vascular occlusive disease, and platelet count (c-index = 0.65). Despite relatively poor 1-and 5-year outcomes among ESRD patients after PCI, risk of MACE and mortality among this cohort can be successfully modelled, which meaningfully informs clinicians regarding management of ESRD patients with coronary artery disease (CAD). Further investigations are necessary to determine whether or not outcomes might be improved through risk profile modification.

Comparison of Percutaneous Peripheral Intervention Performed in a Dedicated Hybrid Operating Theatre vs. Cardiac Catheterization Laboratory

Objective: Percutaneous Peripheral Intervention (PPI) has emerged as the treatment-of-choice for patients with symptomatic peripheral vascular occlusive disease. The procedure may be performed in a variety of clinical settings including a standard operating theatre, interventional radiology suite, hybrid operating theatre (hybrid room), or cardiac catheterization laboratory (cath lab). The purpose of this retrospective clinical study was to test the hypothesis that PPI could be performed safely by vascular surgery specialists in a cath lab at a reduced cost as compared to a hybrid theatre. Methods: Consecutive PPI procedures performed by three dedicated vascular surgeons were retrospectively analyzed. The choice of venue was primarily related to facility availability although patients with high medical risk were preferentially treated in the hybrid suite. Demographic characteristics, peri-procedural outcomes and cost were tabulated and compared. Results: A total of 146 PPI procedures performed either in the hybrid room (n=97) or the cath lab (n=49) was reviewed. Patient indications and comorbidities including coronary artery disease, hypertension, dialysis-dependence, critical limb ischemia, in-patient status, diagnostic vs. therapeutic procedure, operative time and anatomic level of intervention were similar for the two groups. Patients undergoing PPI in the hybrid room had a higher incidence of prior peripheral revascularization (46% vs. 29%; p=0.049), were more likely to require general anesthesia (18% vs. 0%, p<0.05), were more likely to require open femoral access (9.3% vs. 0%; p=0.03), were accessed with larger sheaths (61% vs. 35%; p<0.01) and were imaged with less contrast dye (73 ± 38 mL vs. 117 ± 57 mL; p<0.01). Major complications including retroperitoneal hematoma (0% vs. 2%; p=0.34), acute limb ischemia (1% vs. 0%; p=1) and/or acute kidney injury (1% vs. 0%; p=1) were rare in both groups. Patients treated in the cath lab were more likely to experience transient hypotension (10% vs. 22%; p=0.08) and/or transient postprocedure creatinine elevation (2.0 ± 2.1 vs. 3.0 ± 3.0; p=0.05). Surprisingly, both hospital charges and hospital costs were significantly less for patients treated in the hybrid room as compared to the cath lab (total charges $18714 ± 9633 vs. $26902 ± 19753; p<0.01, total direct and indirect costs $7174 ± 3847 vs. $9659 ± 7064; p=0.01). Medical supplies indirect cost and room services total direct and indirect costs were also higher in the cath lab (medical supplies indirect $336 ± 557 vs. $836 ± 1893; p=0.02; room services $3183 ± 2068 vs. $5169 ± 3314; p<0.01). Conclusions: PPI can be safely performed in either a hybrid surgical suite or cardiac catheterization laboratory although treatment in a hybrid suite utilizes less hospital resources.

Blood pressure targets for the treatment of people with hypertension and cardiovascular disease.

This is the second update of the review first published in 2017. Hypertension is a prominent preventable cause of premature morbidity and mortality. People with hypertension and established cardiovascular disease are at particularly high risk, so reducing blood pressure to below standard targets may be beneficial. This strategy could reduce cardiovascular mortality and morbidity but could also increase adverse events. The optimal blood pressure target in people with hypertension and established cardiovascular disease remains unknown. To determine if lower blood pressure targets (135/85 mmHg or less) are associated with reduction in mortality and morbidity as compared with standard blood pressure targets (140 to 160/90 to 100 mmHg or less) in the treatment of people with hypertension and a history of cardiovascular disease (myocardial infarction, angina, stroke, peripheral vascular occlusive disease). For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to November 2019: Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE (from 1946), Embase (from 1974), and Latin American Caribbean Health Sciences Literature (LILACS) (from 1982), along with the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. We applied no language restrictions. We included RCTs with more than 50 participants per group that provided at least six months' follow-up. Trial reports had to present data for at least one primary outcome (total mortality, serious adverse events, total cardiovascular events, cardiovascular mortality). Eligible interventions involved lower targets for systolic/diastolic blood pressure (135/85 mmHg or less) compared with standard targets for blood pressure (140 to 160/90 to 100 mmHg or less). Participants were adults with documented hypertension and adults receiving treatment for hypertension with a cardiovascular history for myocardial infarction, stroke, chronic peripheral vascular occlusive disease, or angina pectoris. Two review authors independently assessed search results and extracted data using standard methodological procedures expected by Cochrane. We used GRADE to assess the quality of the evidence. We included six RCTs that involved 9484 participants. Mean follow-up was 3.7 years (range 1.0 to 4.7 years). All RCTs provided individual participant data. None of the included studies was blinded to participants or clinicians because of the need to titrate antihypertensives to reach a specific blood pressure goal. However, an independent committee blinded to group allocation assessed clinical events in all trials. Hence, we assessed all trials at high risk of performance bias and low risk of detection bias. Other issues such as early termination of studies and subgroups of participants not predefined were also considered to downgrade the quality evidence. We found there is probably little to no difference in total mortality (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.91 to 1.23; 6 studies, 9484 participants; moderate-quality evidence) or cardiovascular mortality (RR 1.03, 95% CI 0.82 to 1.29; 6 studies, 9484 participants; moderate-quality evidence). Similarly, we found there may be little to no differences in serious adverse events (RR 1.01, 95% CI 0.94 to 1.08; 6 studies, 9484 participants; low-quality evidence) or total cardiovascular events (including myocardial infarction, stroke, sudden death, hospitalization, or death from congestive heart failure) (RR 0.89, 95% CI 0.80 to 1.00; 6 studies, 9484 participants; low-quality evidence). The evidence was very uncertain about withdrawals due to adverse effects. However, studies suggest more participants may withdraw due to adverse effects in the lower target group (RR 8.16, 95% CI 2.06 to 32.28; 2 studies, 690 participants; very low-quality evidence). Systolic and diastolic blood pressure readings were lower in the lower target group (systolic: mean difference (MD) -8.90 mmHg, 95% CI -13.24 to -4.56; 6 studies, 8546 participants; diastolic: MD -4.50 mmHg, 95% CI -6.35 to -2.65; 6 studies, 8546 participants). More drugs were needed in the lower target group (MD 0.56, 95% CI 0.16 to 0.96; 5 studies, 7910 participants), but blood pressure targets were achieved more frequently in the standard target group (RR 1.21, 95% CI 1.17 to 1.24; 6 studies, 8588 participants). We found there is probably little to no difference in total mortality and cardiovascular mortality between people with hypertension and cardiovascular disease treated to a lower compared to a standard blood pressure target. There may also be little to no difference in serious adverse events or total cardiovascular events. This suggests that no net health benefit is derived from a lower systolic blood pressure target. We found very limited evidence on withdrawals due to adverse effects, which led to high uncertainty. At present, evidence is insufficient to justify lower blood pressure targets (135/85 mmHg or less) in people with hypertension and established cardiovascular disease. Several trials are still ongoing, which may provide an important input to this topic in the near future.

Multisystem vascular disease with successful multisystem percutaneous transcatheter revascularization: Total body stenting

Patients with diabetes mellitus along other risk factors are vulnerable to develop micro and macro vascular disease including coronary artery, carotid, upper and lower extremities peripheral vascular disease. Physicians dealing with patients with coronary artery disease should at least suspect a disease(s) within other vascular territory or system and vies a versa for this at risk patients. We report a case of 74 year old male patient with history of heavy smoking, chronic obstructive pulmonary disease (COPD), hypertension, diabetes, dyslipidemia, old stroke, chronic renal impairment and chronic anemia. He was referred from another hospital, with history of recurrent, transient ischemic attacks (TIAs), right upper limb and bilateral lower limb claudication, chest pain and three episodes of Non ST elevation Myocardial infarction within the last 2 months. Cardiac catheterization showed multivessel Coronary Artery Disease (CAD), severe occlusive peripheral arterial vascular disease (PAD), in addition to occluded right subclavian and critical bilateral internal carotid artery subtotal stenosis were found and managed successfully with multisystem Percutaneous Transcatheter intervention with near total body stenting.

Utility of Palpatory Ankle Brachial Pressure Index as a Screening Tool for Asymptomatic Peripheral Vascular Occlusive Disease in Type II Diabetes Mellitus Patients in a Rural Hospital

Utility of Palpatory Ankle Brachial Pressure Index as a Screening Tool for Asymptomatic Peripheral Vascular Occlusive Disease in Type II Diabetes Mellitus Patients in a Rural Hospital

Risk Factors Associated With Reintervention After Thoracic Endovascular Aortic Repair for Descending Aortic Pathologies.

Thoracic endovascular aortic repair (TEVAR) is associated with several short-term benefits, including reduced morbidity and mortality; however, the long-term durability of TEVAR and the need for secondary aortic reintervention remain unclear. We aimed to determine the adverse outcomes, including aortic reintervention, after TEVAR for thoracic aortic aneurysms and dissection. Between October 2009 and July 2016, 130 patients underwent TEVAR at Kyungpook National University Hospital. We excluded 35 patients with traumatic injury and included the remaining 95 patients in our study after TEVAR. The patients included in this study were categorized into 2 groups (reintervention [R] and nonintervention [N] groups) according to the need for reintervention. The mean follow-up period for all 95 patients was 22.4 (20.6) months. The overall actuarial survival rates were 83.7% (4.1%) and 63.6% (8.8%) at 1 and 5 years, respectively. The rates of freedom from aortic reintervention after TEVAR were 94.0% (3.5%), 72.8% (8.2%), and 48.9% (10.5%) at 2, 3, and 5 years, respectively. The independent risk factors for aortic reintervention were endoleaks after TEVAR (odds ratio [OR] 6.13, P = .017), increase in aortic size by over 5% per year (OR 20.40, P = .001), and peripheral vascular occlusive disease (PVOD; OR 13.62, P = .007). Patients with preoperative hemoptysis tended to show a greater need for aortic reintervention ( P = .059). Increase in aortic size by over 5% per year and PVOD were the primary risk factors for endoleaks (OR 3.82, P = .013 and OR 4.37, P = .021, respectively). Survival after TEVAR for thoracic aortic pathologies was satisfactory in most of the patients chosen as candidates for the procedure. However, the occurrence of endoleaks, increase in aortic size by over 5% per year, and PVOD were the primary causes of aortic reintervention.

Invited commentary

Preventing the advancement of or, better yet, reversing peripheral vascular occlusive disease could save many limbs and provide a better quality of life for our patients. The “magic bullet” of an individual agent placed locally to change the milieu sufficiently to improve collateral vascular development or to stimulate angiogenesis has not been successful to date. However, providing cells that can change the local milieu by providing a slurry of beneficial agents is more promising. Mesenchymal stem cells (MSCs) can provide stromal support and paracrine effects of potential benefit. Unfortunately, one group of patients who could benefit most are those with diabetes, and yet their MSCs (dMSCs) have a deficient expansion capacity. This paper tests the hypothesis that dMSCs have a reversible defect in the epidermal growth factor (EGF) receptor pathway that may blunt cell growth and survival. Human platelet lysate (PL), known to be rich in several growth factors including EGF, might reverse this deficiency, as might EGF alone. It tests whether dMSCs can provide angiogenic stimulus of human umbilical vein endothelial cells (ECs) and, therefore, be a viable regenerative treatment. The study demonstrates that MSCs from the bone marrow and adipose tissue of limbs of well-controlled, nonsmoking diabetic patients have similar population doublings and entered senescence after passage 11, confirming deficient expansion capacity. In addition, dMSCs do not express EGF in their secretome while demonstrating robust expression of other angiogens. Supplementing the dMSCs with PL increased phosphorylation of AKT to healthy MSC levels, whereas providing EGF alone increased only phosphorylated extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) to similar levels as that of PL supplementation. MSC invasion increased over time, but there were inconsistent differences of invasion length and chemokine concentration across MSC types and patients. Both cell types were able to stimulate EC proliferation like standard EC growth media and in co-culture demonstrated longer EC sprouts. In contrast to past literature, this study confirms a lack of EGF expression by dMSCs, providing a deficiency that is cell culture modifiable. Adding EGF increased phosphorylated ERK1/2 levels but not pAKT levels, whereas PL increased both, which may be important because both AKT and ERK1/2 signaling pathways promote cell survival, proliferation, and sustained paracrine activity. The lack of EGF may explain the early senescence noted in the study, but exogenous EGF certainly does not fully correct deficient signaling pathways, whereas PL does better but likely not totally in considering prior studies by the same authors. Both types of dMSCs promote EC proliferation and sprouting, which supports the regenerative benefits of these cells if sufficient numbers for local injection are available. This study has limitations regarding sample size, potential lack of generalization (the population was nonsmoking, well-controlled diabetic patients), and potential bias because the control MSCs were from the iliac crest whereas the experimental MSCs were from the tibia. Provided is some detailed explanation as to how these limitations can be interpreted. Overall, this study is another step forward in the basic science wheel of evidence that will eventually lead to a clinical advancement in regenerative medicine aimed at limb salvage. The opinions or views expressed in this commentary are those of the author and do not necessarily reflect the opinions or recommendations of the Journal of Vascular Surgery the Society for Vascular Surgery. Reversible secretome and signaling defects in diabetic mesenchymal stem cells from peripheral arterial disease patientsJournal of Vascular SurgeryVol. 68Issue 6PreviewRegenerative medicine seeks to stall or to reverse the pathologic consequences of chronic diseases. Many people with diabetes have peripheral arterial disease (PAD), which increases their already high risk of major amputation. Cellular therapies are a promising regenerative medicine approach to PAD that can be used to focally inject regenerative cells to endangered tissue beds. Mesenchymal stem cells (MSCs) are known to promote tissue regeneration through stromal support and paracrine stimulation of new blood vessels (angiogenesis). Full-Text PDF Open Archive

Blood pressure targets for the treatment of people with hypertension and cardiovascular disease.

This is the first update of the review published in 2017. Hypertension is a prominent preventable cause of premature morbidity and mortality. People with hypertension and established cardiovascular disease are at particularly high risk, so reducing blood pressure to below standard targets may be beneficial. This strategy could reduce cardiovascular mortality and morbidity but could also increase adverse events. The optimal blood pressure target in people with hypertension and established cardiovascular disease remains unknown. To determine if 'lower' blood pressure targets (≤ 135/85 mmHg) are associated with reduction in mortality and morbidity as compared with 'standard' blood pressure targets (≤ 140 to 160/90 to 100 mmHg) in the treatment of people with hypertension and a history of cardiovascular disease (myocardial infarction, angina, stroke, peripheral vascular occlusive disease). For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to February 2018: Cochrane Hypertension Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), and Latin American Caribbean Health Sciences Literature (LILACS) (from 1982), along with the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. We applied no language restrictions. We included randomized controlled trials (RCTs) that included more than 50 participants per group and provided at least six months' follow-up. Trial reports had to present data for at least one primary outcome (total mortality, serious adverse events, total cardiovascular events, cardiovascular mortality). Eligible interventions involved lower targets for systolic/diastolic blood pressure (≤ 135/85 mmHg) compared with standard targets for blood pressure (≤ 140 to 160/90 to 100 mmHg).Participants were adults with documented hypertension and adults receiving treatment for hypertension with a cardiovascular history for myocardial infarction, stroke, chronic peripheral vascular occlusive disease, or angina pectoris. Two review authors independently assessed search results and extracted data using standard methodological procedures expected by Cochrane. We included six RCTs that involved a total of 9484 participants. Mean follow-up was 3.7 years (range 1.0 to 4.7 years). All RCTs provided individual participant data.We found no change in total mortality (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.91 to 1.23) or cardiovascular mortality (RR 1.03, 95% CI 0.82 to 1.29; moderate-quality evidence). Similarly, we found no differences in serious adverse events (RR 1.01, 95% CI 0.94 to 1.08; low-quality evidence) or total cardiovascular events (including myocardial infarction, stroke, sudden death, hospitalization, or death from congestive heart failure) (RR 0.89, 95% CI 0.80 to 1.00; low-quality evidence). Studies reported more participant withdrawals due to adverse effects in the lower target arm (RR 8.16, 95% CI 2.06 to 32.28; very low-quality evidence). Blood pressures were lower in the lower target group by 8.9/4.5 mmHg. More drugs were needed in the lower target group, but blood pressure targets were achieved more frequently in the standard target group. We found no evidence of a difference in total mortality, serious adverse events, or total cardiovascular events between people with hypertension and cardiovascular disease treated to a lower or to a standard blood pressure target. This suggests that no net health benefit is derived from a lower systolic blood pressure target. We found very limited evidence on adverse events, which led to high uncertainty. At present, evidence is insufficient to justify lower blood pressure targets (≤ 135/85 mmHg) in people with hypertension and established cardiovascular disease. More trials are needed to examine this topic.

Molecular recognition of flunarizine dihydrochloride and \u03b2-cyclodextrin inclusion complex by NMR and computational approaches

BackgroundFlunarizine dihydrochloride (FLN) is used in the prophylactic treatment of migraine, vertigo, occlusive peripheral vascular disease and epilepsy. Cyclodextrins (CDs) are chiral, truncated cone shaped macrocycles known for their inner hydrophobic and outer hydrophilic site. They form complexes with hydrophobic drug molecules and enhance the solubility and bioavailability of such compounds by enhancing drug permeability through mucosal tissues. NMR spectroscopy and computational docking have been recognized as an important tool for the interaction study of CDs-drug inclusion complexes in solution state.ResultsThe structural assignments of FLN and β-CD protons were determined by 1H NMR and 2D 1H-1H COSY NMR spectroscopy. 1H NMR spectroscopic studies of FLN, β-CD and their mixtures confirmed the formation of β-CD-FLN inclusion complex in solution. 1H NMR titration data for β-CD-FLN inclusion complex showed 1:1 stoichiometry, an association constant of Ka = 157 M−1 and change in Gibbs free energy of ∆G = − 12.65 kJ mol−1. The binding constant of the β-CD inclusion complex with two nearly similar structures, FLN and cetirizine dihydrochloride, were compared. Two-dimensional 1H-1H ROESY spectral data and molecular docking studies showed the modes of penetration of the aromatic rings from the wider rim side into the β-CD cavity. The possible geometrical structures of the β-CD-FLN inclusion complex have been proposed in which aromatic rings protrude close to the narrower rim of the β-CD truncated cone.ConclusionNMR spectroscopic studies of FLN, β-CD and FLN:β-CD mixtures confirmed the formation of 1:1 inclusion complex in solution at room temperature. Two-dimensional 1H-1H ROESY together with molecular docking study confirmed that the F-substituted aromatic ring of FLN penetrates into β-CD truncated cone and the tail of aromatic rings were proximal to narrower rim of β-CD. The splitting of aromatic signals of FLN in the presence of β-CD suggests chiral differentiation of the guest FLN by β-CD.

Vascular endothelial growth factor signaling requires glycine to promote angiogenesis

Peripheral vascular occlusive disease (PVOD) is a common manifestation of atherosclerosis, and it has a high rate of morbidity. Therapeutic angiogenesis would re-establish blood perfusion and rescue ischemic tissue. Vascular endothelial growth factor (VEGF) induces angiogenesis and can potentially be used to treat ischemic diseases, yet in clinical trials VEGF has not fulfilled its full potential with side effects. Whether amino acids promote angiogenesis and the molecular mechanisms are largely unknown. Here we showed that (1) Glycine significantly promoted angiogenesis both in vitro and in vivo and effectively protected mitochondrial function. (2) Activation of glycine transporter 1(GlyT1) induced by VEGF led to an increase in intracellular glycine. (3) Glycine directly bounded to voltage dependent anion channel 1 (VDAC1) on the mitochondrial outer membrane and inhibited its opening. These original results highlight glycine as a necessary mediator in VEGF signalling via the GlyT1-glycine-mTOR-VDAC1 axis pathway. Therefore, the findings in this study are of significance providing new mechanistic insights into angiogenesis and providing better understanding of glycine function in angiogenesis, which may provide valuable information for development of novel therapeutic targets for the treatment of angiogenic vascular disorders.

Blood pressure targets for the treatment of people with hypertension and cardiovascular disease.

Hypertension is a prominent preventable cause of premature morbidity and mortality. People with hypertension and established cardiovascular disease are at particularly high risk, so reducing blood pressure below standard targets may be beneficial. This strategy could reduce cardiovascular mortality and morbidity but could also increase adverse events. The optimal blood pressure target in people with hypertension and established cardiovascular disease remains unknown. To determine if 'lower' blood pressure targets (≤ 135/85 mmHg) are associated with reduction in mortality and morbidity as compared with 'standard' blood pressure targets (≤ 140 to 160/ 90 to 100 mmHg) in the treatment of people with hypertension and a history of cardiovascular disease (myocardial infarction, angina, stroke, peripheral vascular occlusive disease). The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to February 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also searched the Latin American and Caribbean Health Science Literature Database (from 1982) and contacted authors of relevant papers regarding further published and unpublished work. There were no language restrictions. We included randomized controlled trials (RCTs) with more than 50 participants per group and at least six months follow-up. Trial reports needed to present data for at least one primary outcome (total mortality, serious adverse events, total cardiovascular events, cardiovascular mortality). Eligible interventions were lower target for systolic/diastolic blood pressure (≤ 135/85 mmHg) compared with standard target for blood pressure (≤ 140 to 160/90 to 100 mmHg).Participants were adults with documented hypertension or who were receiving treatment for hypertension and cardiovascular history for myocardial infarction, stroke, chronic peripheral vascular occlusive disease or angina pectoris. Two review authors independently assessed search results and extracted data using standard methodological procedures expected by The Cochrane Collaboration. We included six RCTs that involved a total of 9795 participants. Mean follow-up was 3.7 years (range 1.0 to 4.7 years). Five RCTs provided individual patient data for 6775 participants.We found no change in total mortality (RR 1.05, 95% CI 0.90 to 1.22) or cardiovascular mortality (RR 0.96, 95% CI 0.77 to 1.21; moderate-quality evidence). Similarly, no differences were found in serious adverse events (RR 1.02, 95% CI 0.95 to 1.11; low-quality evidence). There was a reduction in fatal and non fatal cardiovascular events (including myocardial infarction, stroke, sudden death, hospitalization or death from congestive heart failure) with the lower target (RR 0.87, 95% CI 0.78 to 0.98; ARR 1.6% over 3.7 years; low-quality evidence). There were more participant withdrawals due to adverse effects in the lower target arm (RR 8.16, 95% CI 2.06 to 32.28; very low-quality evidence). Blood pressures were lower in the lower' target group by 9.5/4.9 mmHg. More drugs were needed in the lower target group but blood pressure targets were achieved more frequently in the standard target group. No evidence of a difference in total mortality and serious adverse events was found between treating to a lower or to a standard blood pressure target in people with hypertension and cardiovascular disease. This suggests no net health benefit from a lower systolic blood pressure target despite the small absolute reduction in total cardiovascular serious adverse events. There was very limited evidence on adverse events, which lead to high uncertainty. At present there is insufficient evidence to justify lower blood pressure targets (≤ 135/85 mmHg) in people with hypertension and established cardiovascular disease. More trials are needed to answer this question.

A study on prostaglandin E1 therapy in critical limb ischaemia patients to evaluate the improvement in vascularity

Background: Diffuse peripheral arterial disease or peripheral occlusive vascular disease (POVD) involving the lower limb is a debilitating illness with high incidence of morbidity and mortality. The objective of this study was to assess the improvement of ulcer healing and improvement of the level of amputation in patients with diffuse peripheral arterial disease after administration of prostaglandin E1.Methods: From June 2013 to November 2014, a total of 45 patients having critical limb ischaemia (Fontaine’s grade III and IV) not suitable for angioplasty and stenting or bypass procedures received different courses of Prostaglandin E1 (PGE1). 20 patients (44.44%) received 6 full courses of PGE1, 3 patients (6.66%) received 5 courses, 5 patients (11.11%) received 4 courses, 4 patients (8.8%) received 3 courses, 4 patients (8.8%) received 2 courses and 9 patients (20%) received one course. PGE1 was administered through intravenous infusion (Alprastodil 100mcg) over 10 hours a day for 5 days in one month (1course). They were followed up for 3 years till June 2017.The improvement in level of amputation, ulcer healing and complications were assessed.Results: 14 patients (31.1%) did not require amputation of limbs/ toes, 24 patients (53.3%) have the same amputated status while 7 patients (15.6%) required higher amputation. This study justifies the role of PGE1 therapy in improving the peripheral arterial pulsations and thereby augmenting ulcer healing and improving the level of amputation.Conclusions: After diagnosing a patient with advanced CLI where angioplasty and stenting or bypass procedures are not possible, aggressive treatment for the non-healing ulcer, amputation of gangrenous limbs or toes and starting the PGE1 therapy early not only arrest the progression of POVD but even reverses it to some extent.