The Impact of COVID-19 on Mortality and Clinical Characteristics in Hospitalized Patients With Peripheral Artery Disease in the Year 2020 in Germany.

BACKGROUND: The COVID-19 pandemic developed its full destructive capacity in 2020. This retrospective study aimed to examine the effects of COVID-19 on the mortality and the clinical characteristics in PAD patients with COVID-19 compared to PAD patients without COVID-19. METHODS AND RESULTS: Data derived from a German nationwide register of the year 2020 which encompassed all hospitalized patients with PAD (n = 173.075); N = 2553 also suffered from a COVID-19 infection and had significantly higher mortality rates of 11.2%. PAD + COVID-19 patients presented more clinical complications like major amputations (11.59%), myocardial infarction (2.08%), cardiogenic shock (2.98%), chronic kidney failure with GFR<= 15 mL/min (5.33%) and prolonged ventilation time >48 h (3.37%). Rates of pulmonary thromboembolism (0.24%), myocardial infarction (2.08%), and stroke (1.02%) were low in patients with PAD + COVID-19. Adjusted regression analyses for risk differences revealed possible causes of higher mortality rates, such as prolonged ventilation time, pneumonia, major amputations, multiple organ system failure, and length of hospital stay in patients with severe PAD (Rutherford 5-6) + COVID-19. CONCLUSION: Pneumonia and major amputations were associated with high mortality rates in PAD + COVID-19 in 2020. However, we could not detect a relevant influence of pulmonary thromboembolism, myocardial infarction or stroke on higher death rates of PAD + COVID-19.

Muscle ultrasound shear wave elastography for detection of early onset lower limb ischemia in patients with veno-arterial extracorporeal membrane oxygenation.

BACKGROUND AND OBJECTIVES: Limb ischemia or compartment syndrome, requiring surgery, are some of the frequent cannula-related complications in patients supported with veno-arterial extracorporeal membrane oxygenation (VA-ECMO). The purpose of this exploratory study is to depict and evaluate the dynamic changes in the lower limb muscles with ultrasound shear wave elastography as marker for early lower limb ischemia. METHODS: Eleven patients with VA-ECMO after cardiac arrest were included in this study. Seven patients received distal perfusion cannula (DPC) after implantation of the VA-ECMO, whereas 4 had no DPC after VA-ECMO. Compartment syndrome was clinically excluded in all patients. Both lower limbs, e.g., with and without arterial cannula, were monitored with near-infrared spectroscopy (NIRS) for the oxygen saturation of the local tissue. We performed ultrasound shear wave elastrography (SWE) to assess dynamic changes of the medial gastrocnemius muscle at maximum passive muscle stretch (exercise) of both legs. Color-coded duplexsonography was conducted to examine the blood flow velocity of the popliteal artery of the lower limb. RESULTS: We found no difference between DPC and no DPC (p = 0.115) during use of VA-ECMO. However, we detected marked lower limb muscle perfusion deficits of cannulated (58.9 ± 13.5 kPa) vs. cannula-free limb (95.7 ± 27.9 kPa: p < 0.001), applying SWE. No relationship was detected between NIRS measurements and SWE values (kPa) of both lower limbs. The mean peak systolic velocity of the popliteal artery at the cannulated side (30.0 ± 11.7 cm/s) was reduced compared to the non-cannulated side (39.3 ± 18.6 cm/s; p = 0.054). CONCLUSIONS: Regardless of DPC after implantation of VA-ECMO, the gastrocnemius muscles seem to lose function due to cannula-related microcirculatory deficits. Muscle function analysis via SWE combined with NIRS might offer a sensitive indicator for early onset leg ischemia during VA-ECMO-related arterial cannulation.

Weakness of lower limb muscle in symptomatic peripheral artery disease with media sclerosis detected by ultrasound shear wave elastography.

Background: Symptomatic peripheral arterial disease (PAD) is difficult to non-invasively diagnose in the presence of calcified, media sclerotic arteries that are incompressible by blood pressure cuffs. Standard ankle-brachial index (ABI) measurements in these PAD patients are very often not helpful. Shear wave elastography (SWE) is a modern ultrasound technique to detect peripheral muscle stiffness changes i.e. muscle weakness during exercise. In a pilot study, we examined whether SWE could be a reproducible tool for diagnosing ischemic loss of muscle stiffness in patients with PAD and concomitant arterial media sclerosis. Patients and methods: N=13 consecutive patients with peripheral artery disease and media sclerosis were enrolled in the pilot study. All 13 patients were symptomatic in different stages of their PAD due to hemodynamically relevant arterial stenosis or occlusions of limb arteries as confirmed by oscillography, color-coded duplex sonography or angiography. Results: ABI measurements were invalid in all 13 patients. Mean SWE measurements of medial gastrocnemius muscles showed a significant transient muscle stiffness loss (weakness) at maximum exercise (active dorsal flexion of the foot, 103.4±25.9 kPa on the asymptomatic vs. 62.5±21.9 kPa on the symptomatic limb (p<0.001). Conclusions: SWE can reproducibly detect peripheral muscle weakness during exercise in the symptomatic leg of media sclerotic PAD patients. SWE of lower limb muscles may help to identify symptomatic PAD in patients presenting with invalid ABI measurements and unclear vascular status.

Circulating Autoantibodies Recognizing Immunodominant Epitopes From Human Apolipoprotein B Associate With Cardiometabolic Risk Factors, but Not With Atherosclerotic Disease.

Rationale: Atherosclerosis is a chronic inflammatory disease of large arteries that involves an autoimmune response with autoreactive T cells and auto-antibodies recognizing Apolipoprotein B (ApoB), the core protein of low-density lipoprotein (LDL). Here, we aimed to establish a clinical association between circulating human ApoB auto-antibodies with atherosclerosis and its clinical risk factors using a novel assay to detect auto-antibodies against a pool of highly immunogenic ApoB-peptides. Methods and Results: To detect polyclonal IgM- and IgG-antibodies recognizing ApoB, we developed a chemiluminescent sandwich ELISA with 30 ApoB peptides selected by an in silico assay for a high binding affinity to MHC-II, which cover more than 80% of known MHC-II variants in a Caucasian population. This pre-selection of immunogenic self-peptides accounted for the high variability of human MHC-II, which is fundamental to allow T cell dependent generation of IgG antibodies. We quantified levels of ApoB-autoantibodies in a clinical cohort of 307 patients that underwent coronary angiography. Plasma anti-ApoB IgG and IgM concentrations showed no differences across healthy individuals (n = 67), patients with coronary artery disease (n = 179), and patients with an acute coronary syndrome (n = 61). However, plasma levels of anti-ApoB IgG, which are considered pro-inflammatory, were significantly increased in patients with obesity (p = 0.044) and arterial hypertension (p < 0.0001). In addition, patients diagnosed with the metabolic syndrome showed significantly elevated Anti-ApoB IgG (p = 0.002). Even when normalized for total plasma IgG, anti-ApoB IgG remained highly upregulated in hypertensive patients (p < 0.0001). We observed no association with triglycerides, total cholesterol, VLDL, or LDL plasma levels. However, total and normalized anti-ApoB IgG levels negatively correlated with HDL. In contrast, total and normalized anti-ApoB IgM, that have been suggested as anti-inflammatory, were significantly lower in diabetic patients (p = 0.012) and in patients with the metabolic syndrome (p = 0.005). Conclusion: Using a novel ELISA method to detect auto-antibodies against ApoB in humans, we show that anti-ApoB IgG associate with cardiovascular risk factors but not with the clinical appearance of atherosclerosis, suggesting that humoral immune responses against ApoB are shaped by cardiovascular risk factors but not disease status itself. This novel tool will be helpful to develop immune-based risk stratification for clinical atherosclerosis in the future.

Genetic Deficiency of TRAF5 Promotes Adipose Tissue Inflammation and Aggravates Diet-Induced Obesity in Mice.

Objective: The accumulation of inflammatory leukocytes is a prerequisite of adipose tissue inflammation during cardiometabolic disease. We previously reported that a genetic deficiency of the intracellular signaling adaptor TRAF5 (TNF [tumor necrosis factor] receptor-associated factor 5) accelerates atherosclerosis in mice by increasing inflammatory cell recruitment. Here, we tested the hypothesis that an impairment of TRAF5 signaling modulates adipose tissue inflammation and its metabolic complications in a model of diet-induced obesity in mice. Approach and Results: To induce diet-induced obesity and adipose tissue inflammation, wild-type or Traf5-/- mice consumed a high-fat diet for 18 weeks. Traf5-/- mice showed an increased weight gain, impaired insulin tolerance, and increased fasting blood glucose. Weight of livers and peripheral fat pads was increased in Traf5-/- mice, whereas lean tissue weight and growth were not affected. Flow cytometry of the stromal vascular fraction of visceral adipose tissue from Traf5-/- mice revealed an increase in cytotoxic T cells, CD11c+ macrophages, and increased gene expression of proinflammatory cytokines and chemokines. At the level of cell types, expression of TNF[alpha], MIP (macrophage inflammatory protein)-1[alpha], MCP (monocyte chemoattractant protein)-1, and RANTES (regulated on activation, normal T-cell expressed and secreted) was significantly upregulated in Traf5-deficient adipocytes but not in Traf5-deficient leukocytes from visceral adipose tissue. Finally, Traf5 expression was lower in adipocytes from obese patients and mice and recovered in adipose tissue of obese patients one year after bariatric surgery. Conclusions: We show that a genetic deficiency of TRAF5 in mice aggravates diet-induced obesity and its metabolic derangements by a proinflammatory response in adipocytes. Our data indicate that TRAF5 may promote anti-inflammatory and obesity-preventing signaling events in adipose tissue.

Use and Outcomes of Acute Treatment Strategies in Patients with Severe Aortic Valve Stenosis.

Background: This study aimed to evaluate the acute treatment of patients with severe aortic valve stenosis in Germany. Methods and Results: Three treatment strategies in 11,027 patients acutely admitted due to aortic valve stenosis were compared from 2014 until 2018 using German nationwide records: The annual number of transcatheter aortic valve replacement (TAVR) procedures (1,294 to 1,827) and balloon valvuloplasty (BV only) procedures (170 to 233) in patients acutely admitted increased, but surgical aortic valve replacement (SAVR) procedures decreased (426 to 316). In comparison to BV only patients (mean age 81.3; EuroSCORE 23.2) SAVR patients were younger and at lower logistic EuroSCORE (mean age 66.9; EuroSCORE 9.4). Patients treated with TAVR were at comparable age and operative risk (mean age 81.3; EuroSCORE 24.4) as those patients treated with BV only. Primary outcome was in-hospital mortality. Reimbursement was considered secondary outcome. After risk adjustment using multivariable logistic and linear regression analyses, SAVR (OR 0.26 [96%CI 0.16;0.45], p < 0.001) and TAVR (OR 0.38 [0.29;0.49], p < 0.001) were associated with lower risk for mortality compared to BV only. Compared to BV only, hospitalization costs of patients undergoing SAVR were reduced by €5,578 ([95%CI €8,023; €3,133], p < 0.001). TAVR procedures were associated with higher hospitalization costs than BV only (risk-adjusted difference €4,143 [€2,330; €5,926], p < 0.001). Conclusions: BV only was associated with a substantially increased risk of in-hospital mortality in acute patients. We conclude that a definitive aortic valve replacement should be preferred as primary treatment in patients with severe aortic valve stenosis causing an acute admission.

Symptom patterns and clinical outcomes in women versus men with systolic heart failure and depression.

BACKGROUND: Depression is more common in females than in males and is 3-5 times more prevalent in patients with heart failure (HF) than in the general population. The 9-item Patient Health Questionnaire (PHQ-9) is a validated depression screening instrument; higher sum-scores predict adverse clinical outcomes. Sex- and gender differences in PHQ-9 symptom profile, diagnostic and prognostic properties, and impact on health-related quality of life (HRQOL) have not been comprehensively studied in HF patients. METHODS AND RESULTS: This post hoc analysis from the Interdisciplinary Network Heart Failure program enrolled 852/1022 participants (67 ± 13 years, 28% female) who completed the PHQ-9 at hospital discharge after cardiac decompensation. All had a left ventricular ejection fraction ≤ 40%. Women had a higher mean PHQ-9 sum-score than men (8.4 ± 5.6 vs. 7.4 ± 5.5; p = 0.027), and higher proportions rated the following items ≥ 2 (i.e., present on ≥ 50% of days): 'feeling down, hopeless' (25.8 vs. 18.0%; p = 0.011); 'fatigue' (51.9 vs. 37.2%; p < 0.001); and 'trouble concentrating' (21.6 vs. 15.4%; p = 0.032). A PHQ-9 sum-score ≥ 10 predicted increased mortality in women [hazard ratio 1.91 (95% confidence interval 1.06-3.43); p = 0.030] and men [2.10 (1.43-3.09); p < 0.001] and was associated with worse HRQOL (p < 0.001 for all comparisons). Sum-scores ≥ 10 predicted higher re-hospitalization rates in men only [1.35 (1.08-1.69); p = 0.008]. CONCLUSIONS: Differences in several PHQ-9 items indicated sex- or gender-specific depression symptomatology in HF. For both sexes, HRQOL and survival were worse when PHQ-9 sum-score was ≥ 10, but higher sum-scores predicted higher re-hospitalization rates in men only. Considering these specific aspects might help optimize care strategies in HF.

[Depression and heart failure - a dangerous combination]. / Depression und Herzinsuffizienz - eine gefährliche Kombination.

Depression is common in heart failure and associated with impaired quality of life. It impacts adversely on clinical outcomes. Both diseases are widespread in the general population with increasing prevalence and treatment costs. They are therefore also of socio-economic relevance. Various interrelated biological and behavioral factors (e.g. lower treatment adherence in depressed patients with heart failure) seem to play a pathophysiological role, and there is growing evidence that both diseases may also share genetic susceptibilities. Simple screening tools ease depression diagnosis in clinical practice, although the clinical profile of both disorders overlaps. To date, there is no evidence that antidepressant pharmacotherapy improves depressive symptoms, mortality and morbidity in patients with heart failure and comorbid depression, but physical training, cognitive behavioral therapy and comprehensive disease management improved symptoms and/or prognosis in individual randomized studies.

Comparative potential of the 2-item versus the 9-item patient health questionnaire to predict death or rehospitalization in heart failure.

BACKGROUND: Depression is common in heart failure and associated with adverse clinical outcomes. We investigated the potential of the 2-item patient health questionnaire (PHQ-2) versus that of the 9-item version (PHQ-9) to predict death or rehospitalization. METHODS AND RESULTS: Participants of the Interdisciplinary Network for Heart Failure program were eligible, if they completed the PHQ-9 during baseline assessment. All participants were hospitalized for cardiac decompensation and had a left ventricular ejection fraction ≤40% before discharge. PHQ-2 scores were extracted from the answers to the first 2 PHQ-9 questions. To analyze associations of PHQ-2 and PHQ-9 with both, death and rehospitalization, univariable Cox regression models were used. To compare screening efficacy of both tools, c-statistics were computed. The sample consisted of 852 patients, (67.6±12.1 years; 27.7% women; 42.3% New York Heart Association class III/IV). Follow-up was 18 months (100% complete). During follow-up, 152 patients died and 482 were rehospitalized. Both, PHQ-2 and PHQ-9, predicted death in univariable analysis (hazard ratio, 1.18; 95% confidence interval, 1.09-1.29; P<0.001 and hazard ratio, 1.07; 95% confidence interval, 1.04-1.09; P<0.001, respectively), as well as rehospitalization (hazard ratio, 1.07; confidence interval, 1.01-1.21; P=0.02 and hazard ratio, 1.03; confidence interval, 1.01-1.04; P=0.001, respectively). These results were confirmed by c-statistics. CONCLUSIONS: In univariable models and confirmed by c-statistics the potential of both PHQ-2 and PHQ-9 to predict death and hospitalization was similar. In clinical practice, PHQ-2 screening seems thus sufficiently reliable and more feasible than the time-consuming PHQ-9 to identify patients at an increased risk of adverse outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.controlled-trials.com. Unique identifier: ISRCTN 23325295.