Effect of Cold Atmospheric Plasma Therapy vs Standard Therapy Placebo on Wound Healing in Patients With Diabetic Foot Ulcers: A Randomized Clinical Trial.

Importance: Diabetic foot ulcers are a common complication of diabetes and require specialized treatment. Cold atmospheric plasma (CAP) has been associated with benefits in wound infection and healing in previous smaller series of case reports. Yet the effect of CAP compared with standard care therapy in wound healing in diabetic foot ulcers remains to be studied. Objective: To determine whether the application of CAP accelerates wound healing in diabetic foot ulcers compared with standard care therapy. Design, Setting, and Participants: A prospective, randomized, placebo-controlled, patient-blinded clinical trial was conducted at 2 clinics with recruitment from August 17, 2016, to April 20, 2019. Patients were scheduled to remain in follow-up until April 30, 2024. Patients with diabetes and diabetic foot ulcers described using the combined Wagner-Armstrong classification of 1B or 2B (superficial or infected diabetic foot ulcers extending to tendon) were eligible. A patient could participate with 1 or more wounds in both groups in both intervention and control groups. Wounds were randomized separately, allowing a participant to be treated several times within the study following a 2 × 2 × 2 randomization strata considering sex, smoking status, and age (≤68 years and >68 years). Interventions: Standard care treatment with 8 applications of either CAP generated from argon gas in an atmospheric pressure plasma jet or 8 applications of placebo treatment in a patient-blinded manner. Main Outcomes and Measures: Primary end points were reduction in wound size, clinical infection, and microbial load compared with treatment start. Secondary end points were time to relevant wound reduction (>10%), reduction of infection, parameters of patient's well-being, and treatment-associated adverse events. Results: Of 65 diabetic foot ulcer wounds from 45 patients assessed for study, 33 wounds from 29 patients were randomized to CAP and 32 wounds from 28 to placebo, with 62 wounds from 43 patients (31 wounds per group) included for final evaluation (mean [SD] age, 68.5 [9.1] years for full sample). Four patients with 5 wounds of 31 (16.1%) wounds in the CAP group and 3 patients with 4 wounds of 31 (13%) wounds in the placebo group were active smokers. CAP therapy yielded a significant increase in wound healing, both in total mean (SD) area reduction (CAP vs placebo relative units, -26.31 [11.72]; P = .03) and mean (SD) time to relevant wound area reduction (CAP vs placebo relative units, 10% from baseline, 1.60 [0.58]; P = .009). Reduction of infection and microbial load was not significantly different between CAP and placebo. No therapy-related adverse events occurred during therapy; patient's perceptions during therapy were comparable. Conclusions and Relevance: In this randomized clinical trial, CAP therapy resulted in beneficial effects in chronic wound treatment in terms of wound surface reduction and time to wound closure independent from background infection. Trial Registration: ClinicalTrials.gov Identifier: NCT04205942.

Results From the International Drug Coated Balloon Registry for the Treatment of Bifurcations. Can a Bifurcation Be Treated Without Stents?

OBJECTIVES: This observational study assessed the 9-month clinical outcomes in patients with coronary bifurcation lesions suitable for drug-coated balloon (DCB) angioplasty. It was the intention to use DCB's without additional stenting (DCB-only strategy) in selected patients for this chosen strategy. Bail-out main branch (MB) and/or side branch (SB) stenting, however, were permissible when flow limiting dissections or excessive recoil occurred. BACKGROUND: A multitude of interventional strategies have been studied to treat bifurcation lesions. With the availability of DCB angioplasty, investigators have been using this interventional tool with the optional implantation of bare metal stents (BMS). METHODS: This study is an international, prospective, multicenter registry enrolling patients with coronary bifurcation lesions including a side branch ≥2 mm in diameter. Patients with stable angina and documented ischemia or selected forms of unstable angina due to a culprit bifurcation lesion of any Medina classification type were recruited. The primary endpoint was clinically driven target-lesion revascularization (TLR) at 9 months. Secondary endpoints included 9-month major adverse cardiac events (death, myocardial infarction, or TLR), technical success, in-hospital outcomes and vessel thrombosis rates. RESULTS: A total 127 patients 66.1 ± 10.1 years of age were enrolled. Demographic characteristics were 80.3% (102/127) male gender, 31.5% (40/127) diabetes, 91.3% (116/127) hypertension, 7.1% (9/127) ST-elevation myocardial infarction (STEMI), and 9.4% (12/127) non ST-elevation myocardial infarction (NSTEMI). The 130 lesions were treated with 184 DCB's and 64 BMS. In 53.8% (70/130) of all lesions the DCB-only strategy could be used while 34.6% (45/130) of lesions had at least 1 stent (BMS) in the main branch, 8.5% (11/130) had at least 1 stent in the side branch and 3.1% (4/130) needed at least 1 stent in the main and side branch. 94.5% patients (121/127) were available for follow-up after 9.8 ± 2.0 months. The TLR rate was 4.6% in the absence of any thrombotic events in the treated vessels whereas the 9-month MACE rate was 6.2%. CONCLUSION: This observational study suggests that the DCB-only strategy is safe and effective to treat selected bifurcations while benefiting from a shortened dual antiplatelet therapy (DAPT).

Five-year results of the Multicenter Randomized Controlled Open-Label Study of the CYPHER Sirolimus-Eluting Stent in the Treatment of Diabetic Patients with De Novo Native Coronary Artery Lesions (SCORPIUS) study: a German multicenter investigation on the effectiveness of sirolimus-eluting stents in diabetic patients.

BACKGROUND: Because a delayed arterial healing response after drug-eluting stent implantation has raised concerns about safety in diabetic patients, long-term effects of treatment with sirolimus-eluting stent (SES), as compared with bare-metal stent (BMS), have to be established. The aim of the 5-year follow-up of the randomized, controlled, open-label multicenter SCORPIUS study was to assess long-term safety and efficacy of the CYPHER (Cordis, Johnson & Johnson, Bridgewater, NJ) SES in percutaneous coronary intervention of diabetic patients. METHODS: A total of 190 patients with type 2 diabetes mellitus were randomized to receive either a SES (n = 95) or a BMS (n = 95). Dual-antiplatelet therapy (aspirin plus clopidogrel) was prescribed for at least 6 months. Clinical follow-up data were scheduled at 1, 8, and 12 months and 5 years. RESULTS: Treatment with SES resulted in a 16% decrease in the rate of major adverse cardiac events (36% vs 52%; hazard ratio 0.6, 95% CI 0.4-0.9; P = .02). This reduction in major adverse cardiac events with SES at 5 years was mostly attributable to a lower number of repeat target lesion revascularization (13% vs 29%; hazard ratio 0.4, 95% CI 0.2-0.7; P = .003). No differences between groups were observed for safety end points (all-cause mortality 21% vs 21%, cardiac death 15% vs 13%, repeat myocardial infarction 8% vs 9%, and stent thrombosis 5% vs 6%) at 5 years. CONCLUSIONS: The 5-year follow-up of the SCORPIUS trial demonstrates the long-term antirestenotic efficacy of SES in diabetic patients with significantly reduced target lesion revascularization and comparable rates of mortality, myocardial infarction, and stent thrombosis compared with BMS.

Six sequence variants on chromosome 9p21.3 are associated with a positive family history of myocardial infarction: a multicenter registry.

BACKGROUND: Recent genome-wide association studies have identified several genetic loci linked to coronary artery disease (CAD) and myocardial infarction (MI). The 9p21.3 locus was verified by numerous replication studies to be the first common locus for CAD and MI. In the present study, we investigated whether six single nucleotide polymorphisms (SNP) rs1333049, rs1333040, rs10757274, rs2383206, rs10757278, and rs2383207 representing the 9p21.3 locus were associated with the incidence of an acute MI in patients with the main focus on the familial aggregation of the disease. METHODS: The overall cohort consisted of 976 unrelated male patients presenting with an acute coronary syndrome (ACS) with ST-elevated (STEMI) as well as non-ST-elevated myocardial infarction (NSTEMI). Genotyping data of the investigated SNPs were generated and statistically analyzed in comparison to previously published findings of matchable control cohorts. RESULTS: Statistical evaluation confirmed a highly significant association of all analyzed SNP's with the occurrence of MI (p<0.0001; OR: 1.621-2.039). When only MI patients with a positive family disposition were comprised in the analysis a much stronger association of the accordant risk alleles with incident disease was found with odds ratios up to 2.769. CONCLUSIONS: The findings in the present study confirmed a strong association of the 9p21.3 locus with MI particularly in patients with a positive family history thereby, emphasizing the pathogenic relevance of this locus as a common genetic cardiovascular risk factor.

Megakaryocyte impairment by eptifibatide-induced antibodies causes prolonged thrombocytopenia.

Glycoprotein (GP) IIbIIIa inhibitors are used in the treatment of acute coronary syndromes. Transient immune-mediated acute thrombocytopenia is a recognized side effect of GPIIbIIIa inhibitors. We provide evidence that GPIIbIIIa inhibitor-induced antibodies can affect megakaryocytes in the presence of eptifibatide. In a patient with acute coronary syndrome, acute thrombocytopenia occurred after a second exposure to eptifibatide 20 days after the initial treatment. Despite the short half-life of eptifibatide (t(1/2) = 2 hours), thrombocytopenia less than 5 x 10(9)/L and gastrointestinal and skin hemorrhage persisted for 4 days. Glycoprotein-specific enzyme-linked immunosorbent assay showed eptifibatide-dependent, GPIIbIIIa-specific antibodies. Bone marrow examination showed predominance of early megakaryocyte stages, and platelet transfusion resulted in an abrupt platelet count increase. Viability of cultured cord blood-derived megakaryocytes was reduced in the presence of eptifibatide and patient IgG fraction. These findings can be explained by impaired megakaryocytopoiesis complicating anti-GPIIbIIIa antibody-mediated immune thrombocytopenia. This mechanism may also apply to some patients with autoimmune thrombocytopenia.

[ESC/EASD joint guidelines on diabetes and cardiovascular diseases]. / ESC/EASD-Leitlinien zu Diabetes und kardiovaskulären Erkrankungen.

The ESC/EASD (European Society of Cardiology/European Association for the Study of Diabetes) joint Guidelines on diabetes, pre-diabetes, and cardiovascular diseases have, for the first time, addressed diabetes mellitus and cardiovascular diseases (CVD) as a pathophysiological entity in Europe. Based on these guidelines, diabetes mellitus is regarded from the outset to be a cardiovascular disease, whose life-threatening complications myocardial infarction and stroke can only be avoided by an interdisciplinary concerted action. The most important information of these guidelines for the interdisciplinary cooperation of primary-care physicians, diabetologists and cardiologists are the postulations that patients with the main diagnosis diabetes mellitus with or without known CVD should, at regular intervals, be referred to a cardiologist, and patients with the main diagnosis CVD with or without diabetes mellitus should, at regular intervals, be referred to a diabetologist. Of fundamental importance is the prevention of diabetes and CVD by a comprehensive lifestyle modification including smoking cessation, regular physical activity and weight control, flanked by an evidence-based drug therapy. Within the framework of a multimodal risk management, an optimal antihypertensive therapy of a concomitant elevated blood pressure; a statin therapy in case of elevated LDL cholesterol or regardless of an elevated LDL in proven CVD; ACE inhibitors, angiotensin II receptor blockers, or beta-blockers in case of heart failure; and an anticoagulant therapy for the prevention of cardioembolic stroke in patients with atrial fibrillation all have class I recommendations. Concerning the preferred coronary revascularization procedure in diabetics, today no rigid general recommendation can be given in favor of or against coronary bypass surgery, or in favor of or against percutaneous coronary intervention. The decision for a specific revascularization procedure should, in any case, be based on a detailed analysis of the individual coronary anatomy.

Serum thyrotropin levels predict all-cause and circulatory mortality in patients with invasively treated coronary artery disease.

The aim of the present study was to analyze the relation of low or high serum thyrotropin (TSH) with mortality in patients with invasively treated coronary artery disease. We followed-up 942 patients who underwent coronary angioplasties or coronary artery bypass graft surgery over a mean follow-up period of 6.4+/-1.6 years. The study population was divided into three groups using the reference limits of serum TSH (0.25-2.12 mIU/l) as cut-offs. There were 118 patients (12.5%) with low and 125 patients (13.3%) with high serum TSH. One hundred and seventy-four subjects (18.5%) deceased during follow-up. Multivariable analyses revealed that both subjects with low and high serum TSH had a lower all-cause and circulatory mortality than subjects with serum TSH within the reference range. We conclude that low and high serum TSH levels are associated with a reduced all-cause and circulatory mortality in patients with coronary artery disease.

The PHARAO study: prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure: a prospective, randomized, controlled prevention trial of the German Hypertension League.

BACKGROUND: The prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure study addresses the issue of whether progression to manifest hypertension in patients with high-normal blood pressure can be prevented with treatment. METHODS: A total of 1008 participants with high-normal office blood pressure were randomized to ramipril treatment group (n = 505) and a control group (n = 503). The patients were followed up for 3 years. Primary endpoint was to prevent or delay the progression to manifest hypertension. Secondary endpoints were reduction in the incidence of cerebrovascular and cardiovascular events, as well as the development of hypertension as defined by ambulatory blood pressure monitoring. FINDINGS: One hundred and fifty-five patients (30.7%) in the ramipril group, and 216 (42.9%) in the control group reached the primary endpoint (relative risk reduction 34.4%, P = 0.0001). Ramipril also proved to be more effective in reducing the incidence of manifest office hypertension in patients with baseline ambulatory blood pressure monitoring high-normal blood pressure. The incidence of cerebrovascular and cardiovascular events showed no statistically significant differences between the two groups. Cough was more frequent in the ramipril group (4.8 vs. 0.4%). INTERPRETATION: There is now good clinical evidence that patients with high-normal blood pressure (prehypertension) are more likely to progress to manifest hypertension than patients with optimal or normal blood pressure. Additional ambulatory blood pressure monitoring seems to be essential to achieve correct diagnosis. Treatment of patients with high-normal office blood pressure with the angiotensin-converting enzyme inhibitor was well tolerated, and significantly reduced the risk of progression to manifest hypertension.

One-year results of the SCORPIUS study: a German multicenter investigation on the effectiveness of sirolimus-eluting stents in diabetic patients.

OBJECTIVES: This study sought to analyze the effectiveness of drug-eluting stents in a high-risk group of diabetic patients. Previously, this had been analyzed only in substudies of larger trials or in clinical investigations enrolling a small number of patients. BACKGROUND: Drug-eluting stents are highly effective in reducing the rate of in-stent restenosis. METHODS: Two hundred patients with diabetes and de novo coronary artery lesions were enrolled in 16 centers: 98 were randomly assigned to sirolimus-eluting stents (SES) and 102 received bare-metal stents (BMS). The primary end point was in-segment late luminal loss. Major adverse cardiac events (MACE) rate was analyzed at 30 days and 8 and 12 months. RESULTS: The extent of in-segment late luminal loss in the SES group was 0.18 mm compared with 0.74 mm in the BMS group. In-segment restenosis was identified on follow-up angiography in 8.8% of the patients in SES and in 42.1% in BMS (p < 0.0001). Target lesion revascularization was performed in 5.3% of the patients in SES and in 21.1% of the patients in BMS (p = 0.002). The SES was effective in the treatment group with oral diabetic medication as well as in the insulin-dependent treatment group (3.6% SES vs. 38.8% BMS). There was no subacute stent thrombosis in the SES group up to 1 year. The MACE rate was not significantly different at 30 days. At 12 months, MACE rate was 14.7% in SES versus 35.8% in BMS. CONCLUSIONS: The SES is safe and highly effective in patients with diabetes mellitus and coronary artery disease and associated with a significant decrease in the extent of late luminal loss.

Outcome after coronary artery bypass graft surgery, coronary angioplasty and stenting.

AIMS: We undertook this prospective observational study to investigate the long-term prognosis after balloon angioplasty (PTCA), coronary stenting (CS) and coronary artery bypass grafting (CABG). METHODS AND RESULTS: A total number of 1038 patients with PTCA (n=499), CS (n=294) or CABG (n=245) were followed-up over a mean time of 6.4+/-1.8 years. Forty-two patients (4.0%) were lost to follow-up, leaving a study population of 996 subjects who were available for analyses. The primary and secondary endpoints were mortality and major adverse cardiac events (MACE), respectively. Overall death rate was 19.3%. Age, pulse pressure, smoking, diabetes, serum LDL cholesterol levels and left ventricular ejection fraction rather than the intervention type independently predicted mortality. The incidence rate of MACE was 53.7%. Compared to PTCA patients, CS patients had lower (hazard ratio 0.693; 95% confidence interval 0.514-0.793) and CABG patients the lowest risk of MACE (hazard ratio 0.343; 95% confidence interval 0.261-0.450). Further risk factors for MACE were serum LDL cholesterol levels, three-vessel coronary artery disease and left ventricular ejection fraction of <30%. CONCLUSION: Long-term mortality does not differ among patients who received percutaneous interventions or CABG. Major adverse cardiac events occur more often in patients with previous percutaneous interventions, whereby CS has advantage over PTCA.

A double-blind, randomized, placebo-controlled multicenter clinical trial to evaluate the effects of the angiotensin II receptor blocker candesartan cilexetil on intimal hyperplasia after coronary stent implantation.

BACKGROUND: Preclinical data suggest beneficial effects of angiotensin II receptor blockers (ARBs) on neointima formation after vascular injury. Preliminary clinical data, however, revealed conflicting results. The AACHEN trial was a double-blind, randomized, placebo-controlled clinical multicenter trial to evaluate the effects of candesartan cilexetil on intimal hyperplasia after coronary stent implantation. METHODS: A total of 120 patients (61 +/- 9 years, 83% male) were randomized to receive either 32 mg candesartan cilexetil (active) or placebo starting 7 to 14 days before elective coronary stent implantation. A follow-up angiography including intravascular ultrasound assessment of the target lesion was performed 24 +/- 2 weeks after stent implantation. The primary end point was defined as the difference in neointimal area between groups as assessed by intravascular ultrasound. Secondary end points included differences in angiographic parameters (ie, restenosis rate) and incidence of major cardiac events. RESULTS: The mean stent length measured 15.0 +/- 4.9 mm in the active and 14.6 +/- 5.7 mm in the placebo group (P = .81). There was no significant difference in neointimal area between groups (2.1 +/- 1.0 vs 2.1 +/- 1.5 mm2, P = 1.00), nor were there differences in angiographic end point parameters. Major cardiac event rates were not significantly different between treatment groups (8% vs 11%, P = .75). CONCLUSIONS: High-dose candesartan cilexetil therapy in patients with symptomatic coronary artery disease undergoing coronary stent implantation does not reduce clinical event rates, restenosis rates, or neointimal proliferation after elective stent implantation.

Interaction between factor V Leiden and serum LDL cholesterol increases the risk of atherosclerosis.

OBJECTIVES: We investigated the association between the factor V Leiden gene variant and carotid atherosclerosis in a cross-sectional study and explored possible associations between this gene variant and coronary artery disease (CAD) in a case-control study. METHODS: The presence (n=1696) or absence (n=703) of carotid atherosclerosis were sonographically assessed among participants of the population-based Study of Health in Pomerania (SHIP). The case-control study included 1021 patients with severe CAD and 2791 healthy SHIP participants. The factor V Leiden gene variant was determined by PCR and MnlI digestion. RESULTS: Multivariable analyses revealed no independent association between the factor V Leiden gene variant per se and carotid atherosclerosis or CAD. In the cross-sectional study, there was an interaction between the factor V Leiden gene variant and serum LDL cholesterol in non-diabetics with respect to the risk of carotid atherosclerosis. In the case-control study a similar interaction was found for CAD. In both studies the atherosclerotic risk increased with rising serum LDL cholesterol concentrations in carriers of the factor V Leiden gene variant. CONCLUSION: The co-existence between the factor V Leiden gene variant and high serum LDL cholesterol is independently associated with the risk of atherosclerosis.

[High blood pressure and coronary heart disease. Are there new therapeutic options?]. / Hochdruck und koronare Herzkrankheit. Gibt es neue Therapieoptionen?

Besides type 2 diabetes and cigarette smoking arterial hypertension represents the most powerful risk factor for the development of coronary artery disease. Independent from the existence of coronary artery disease i. e. coronary macroangiopathy arterial hypertension leads to hypertension-specific organ manifestations such as left ventricular hypertrophy and coronary microangiopathy. In the presence of coronary artery disease left ventricular hypertrophy and coronary microangiopathy aggravate the ischemic predisposition of the myocardium. Thus vascular protection measures should represent an important component of antihypertensive treatment. Due to the present state of the art based upon randomized clinical studies ACE-inhibitors are first-line antihypertensive substances due to their vascular and myocardial protective effects and their few side effects. Angiotensin II receptor blockers are not more effective than ACE-inhibitors in treatment arterial hypertension so far. Calcium channel blockers who do not stimulate the sympathetic system such as slow release verapamil and amlodipin, beta receptor blockers and diuretics are combination partners, if blood pressure cannot be normalized by treatment with ACE-inhibitors only. Since statins reduce cardiovascular morbidity and mortality in hypertensive patients even with not elevated LDL cholesterol levels, statins represent an important component of antihypertensive treatment. An antihypertenive treatment aiming at reducing blood pressure only is no more sufficient due to the present state of the art.

Candidate genetic markers and the risk of restenosis after coronary angioplasty.

The aim of the present study was to test for possible associations between candidate gene polymorphisms and the risk of restenosis and recurrent restenosis after percutaneous transluminal coronary angioplasty (PTCA) without stenting. We followed up 511 PTCA patients, and restenosis and recurrent restenosis were defined according to angiographical criteria. Genotyping of the beta-fibrinogen -455 G/A, glycoprotein (GP) IIIa PlA1/PlA2, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, factor V Leiden 1691 G/A, tumour necrosis factor alpha (TNFalpha) -238 G/A, TNFalpha -308 G/A, interleukin (IL)-1alpha -889 C/T, IL-1beta -511 C/T, methylenetetrahydrofolate reductase (MTHFR) 677 C/T and endothelial nitric oxide synthase (eNOS) 4 b/a gene polymorphisms was performed by PCR and restriction-fragment-length-polymorphism-based techniques. One hundred and sixty patients (31.3%) developed restenosis and in 130 of these patients, of whom 123 were available for analysis, a second PTCA without stenting was performed. Of these patients, 35 (28.5%) developed recurrent restenosis. None of the investigated genotypes were associated with the risk of restenosis or recurrent restenosis after PTCA. The degree of stenosis before and immediately after PTCA and the severity of the lesion were independent predictors for restenosis after PTCA. In conclusion, there was no association between the beta-fibrinogen -455 G/A, GP IIIa PlA1/A2, PAI-1 4G/5G, factor V Leiden 1691 G/A, TNFalpha -238 G/A, TNFalpha -308 G/A, IL-1alpha -889 C/T, the IL-1beta -511 C/T, MTHFR 677 C/T and eNOS 4 b/a gene polymorphisms and the risk of restenosis after PTCA as well as recurrent restenosis after repeated PTCA.

Angiotensinogen M235T gene polymorphism and recurrent restenosis after repeated percutaneous transluminal coronary angiography.

The present study was designed to prospectively test the hypothesis that gene polymorphisms of the renin-angiotensin system are associated with recurrent restenosis after repeated percutaneous transluminal coronary angioplasty. Five hundred and eleven patients after first successful angioplasty were characterized with respect to the angiotensinogen M235T, angiotensin-converting enzyme insertion/deletion and angiotensin II type 1 receptor A1166C gene polymorphisms. In 164 of these patients repeated angioplasty on a restenotic lesion was performed. After repeated angioplasty, 46 patients had recurrent restenosis as defined by a greater than 50% progression of residual stenosis. In the recurrent restenosis group there was a statistically significant higher percentage of patients receiving cholesterol-lowering drugs compared with the group of patients without recurrent restenosis. The two groups of patients did not differ with respect to procedural and angiographic parameters. There were significantly more carriers of the angiotensinogen 235T allele in the recurrent restenosis group than in the control group without recurrent restenosis. No differences between the two groups were found with respect to the other gene polymorphisms investigated. According to the results of a multifactorial analysis of variance, only the 235T allele of the angiotensinogen gene and not cholesterol drug therapy independently affected the increase of stenosis at follow-up angiography. In conclusion, the angiotensinogen 235T allele may be an independent predictor for recurrent restenosis after repeated angioplasty.