BMI-Stratified Exploration of the 'Obesity Paradox': Heart Failure Perspectives from a Large German Insurance Database.

Background: The global rise of obesity and its association with cardiovascular risk factors (CVRF) have highlighted its connection to chronic heart failure (CHF). Paradoxically, obese CHF patients often experience better outcomes, a phenomenon known as the 'obesity paradox'. This study evaluated the 'obesity paradox' within a large cohort in Germany and explored how varying degrees of obesity affect HF outcome. Methods: Anonymized health claims data from the largest German insurer (AOK) for the years 2014-2015 were utilized to analyze 88,247 patients hospitalized for myocardial infarction. This analysis encompassed baseline characteristics, comorbidities, interventions, complications, and long-term outcomes, including overall survival, freedom from CHF, and CHF-related rehospitalization. Patients were categorized based on body mass index. Results: Obese patients encompassed 21.3% of our cohort (median age 68.69 years); they exhibited a higher prevalence of CVRF (p < 0.001) and comorbidities than non-obese patients (median age 70.69 years). Short-term outcomes revealed lower complication rates and mortality (p < 0.001) in obese compared to non-obese patients. Kaplan-Meier estimations for long-term analysis illustrated increased incidences of CHF and rehospitalization rates among the obese, yet with lower overall mortality. Multivariable Cox regression analysis indicated that obese individuals faced a higher risk of developing CHF and being rehospitalized due to CHF but demonstrated better overall survival for those classified as having low-level obesity (p < 0.001). Conclusions: This study underscores favorable short-term outcomes among obese individuals. The 'obesity paradox' was confirmed, with more frequent CHF cases and rehospitalizations in the long term, alongside better overall survival for certain degrees of obesity.

Unused potential of lipid-lowering therapy in very high-risk patients with atherosclerotic cardiovascular disease. A retrospective data analysis.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is the most common cause of death in Europe. Although the 2019 European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidaemias claim a target low-density lipoprotein cholesterol (LDL-C) value of <55 mg/dL for very high-risk patients by use of lipid-lowering therapy (LLT) and lifestyle adaptations, the target level achievement is not satisfactory. We examined LLT use in ASCVD patients exceeding LDL-C target levels at admission and its adaptations at discharge. METHODS AND RESULTS: Between January 2017 and February 2020, 1091 patients with LDL-C >100 mg/dL and ASCVD defined as diagnosis of angina pectoris (AP, n = 179), acute myocardial infarction (AMI, n = 317), chronic ischemic heart disease (CHD, n = 195), or peripheral artery disease (PAD, n = 400) were extracted from hospital records. LLT use on admission and discharge as well as recommendations on lifestyle and nutrition were analysed. On admission, 51% of the patients were not taking LLT. At discharge, 91% were prescribed statins and 87% were advised on lifestyle adaptation and/or pharmacological treatment. High-intensity statin use at discharge was present in 63% of the AP-group, 92% of the AMI-group, 62% of the CHD-group and 71% of the PAD-group. Ezetimibe was present in 16% and proprotein convertase subtilisin/kexin 9 inhibitors (PCSK9i) in 1%. However, of those on high-intensity statin, 25% remained on insufficient statin dosage. CONCLUSION: Switch to high-intensity statins and use of ezetimibe and PCSK9i was low in chronic ASCVD patients. Even though statin intake was high in high-risk patients, target levels were still not reached.

Complications and Outcomes in 39,864 Patients Receiving Standard Care Plus Mechanical Circulatory Support or Standard Care Alone for Infarct-Associated Cardiogenic Shock.

BACKGROUND: Temporary mechanical circulatory support devices (tMCS) are increasingly being used in patients with infarct-associated cardiogenic shock (AMICS). Evidence on patient selection, complications and long-term outcomes is lacking. We aim to investigate differences in clinical characteristics, complications and outcomes between patients receiving no tMCS or either intra-aortic balloon pump (IABP), veno-arterial extracorporeal membrane oxygenation (V-A ECMO) or Impella® for AMICS, with a particular focus on long-term outcomes. METHODS: Using health claim data from AOK-Die Gesundheitskasse (local health care funds), we retrospectively analysed complications and outcomes of all insured patients with AMICS between 1 January 2010 and 31 December 2017. RESULTS: A total of 39,864 patients were included (IABP 5451; Impella 776; V-A ECMO 833; no tMCS 32,804). In-hospital complications, including renal failure requiring dialysis (50.3% V-A ECMO vs. 30.5% Impella vs. 29.2 IABP vs. 12.1% no tMCS), major bleeding (38.1% vs. 20.9% vs. 18.0% vs. 9.3%) and sepsis (22.5% vs. 15.9% vs. 13.9% vs. 9.3%) were more common in V-A ECMO patients. In a multivariate analysis, the use of both V-A ECMO (HR 1.57, p < 0.001) and Impella (HR 1.25, p < 0.001) were independently associated with long-term mortality, whereas use of IABP was not (HR 0.89, p < 0.001). Kaplan-Meier estimates showed better survival for patients on IABP compared with Impella, V-A ECMO and no-tMCS. Short- and long-term mortality was high across all groups. CONCLUSIONS: Our data show noticeably more in-hospital complications in patients on tMCS and higher mortality with V-A ECMO and Impella. The use of both devices is an independent risk factor for mortality, whereas the use of IABP is associated with a survival benefit.

PACE: randomized, controlled, multicentre, multinational, phase III study of PLX-PAD for critical limb ischaemia in patients unsuitable for revascularization: randomized clinical trial.

BACKGROUND: Revascularization is the primary treatment modality for chronic limb-threatening ischaemia (CLTI), but is not feasible in all patients. PLX-PAD is an off-the-shelf, placental-derived, mesenchymal stromal cell-like cell therapy. This study aimed to evaluate whether PLX-PAD would increase amputation-free survival in people with CLTI who were not candidates for revascularization. METHODS: People with CLTI and minor tissue loss (Rutherford 5) who were unsuitable for revascularization were entered into a randomized, parallel-group, placebo-controlled, multinational, blinded, trial, in which PLX-PAD was compared with placebo (2 : 1 randomization), with 30 intramuscular injections (0.5 ml each) into the index leg on days 0 and 60. Planned follow-up was 12-36 months, and included vital status, amputations, lesion size, pain and quality-of-life assessments, haemodynamic parameters, and adverse events. RESULTS: Of 213 patients enrolled, 143 were randomized to PLX-PAD and 70 to placebo. Demographics and baseline characteristics were balanced. Most patients were Caucasian (96.2%), male (76.1%), and ambulatory (85.9%). Most patients (76.6%) reported at least one adverse event, which were mostly expected events in CLTI, such as skin ulcer or gangrene. The probability of major amputation or death was similar for placebo and PLX-PAD (33 and 28.6% respectively; HR 0.93, 95% c.i. 0.53 to 1.63; P = 0.788). Revascularization and complete wound healing rates were similar in the two groups. A post hoc analysis of a subpopulation of 121 patients with a baseline haemoglobin A1c level below 6.5% showed improved 12-month amputation-free survival (HR 0.46, 0.21 to 0.99; P = 0.048). CONCLUSION: Although there was no evidence that PLX-PAD reduced amputation-free survival in the entire study population, benefit was observed in patients without diabetes mellitus or whose diabetes was well controlled; this requires confirmation in further studies. Trial registration: NCT03006770 (http://www.clinicaltrials.gov); 2015-005532-18 (EudraCT Clinical Trials register - Search for 2015-005532-18).

In-patient characteristics of peripheral artery disease in Germany.

Background: Peripheral artery disease (PAD) frequently leads to hospital admission. Sex related differences in in-patient care are a current matter of debate. Patients and methods: Data were provided from the German national in-patient sample provided by the Federal Bureau of Statistics (DESTATIS). Trends on risk profiles, therapeutic procedures, and outcomes were evaluated from 2014 until 2019 stratified by sex and PAD severity. Results: Two-thirds of an annual >191,000 PAD in-patient cases applied to male sex. Chronic limb-threatening ischemia (CLTI) was recorded in 49.6% of male and 55.2% of female cases (2019). CLTI was as a major risk factor of in-hospital amputation (OR 229) and death (OR 10.5), whereas endovascular revascularisation (EVR) with drug-coated devices were associated with decreased risk of in-hospital amputation (OR 0.52; all p<0.001). EVR applied in 47% of CLTI cases compared to 71% in intermittent claudication (IC) irrespective of sex. In-hospital mortality was 4.3% in male vs. 4.8% in female CLTI cases, minor amputations 18.4% vs. 10.9%, and major amputation 7.5% vs. 6.0%, respectively (data 2019; all p<0.001). After adjustment, female sex was associated with lower risk of amputation (OR 0.63) and death (OR 0.96) during in-patient stay. Conclusions: Male PAD patients were twice as likely to be admitted for in-patient treatment despite equal PAD prevalence in the general population. Among in-patient cases, supply with invasive therapy did not relevantly differ by sex, however is strongly reduced in CLTI. CLTI is a major risk factor of adverse short-term outcomes, whereas female sex was associated with lower risk of in-patient amputation and/or death.

Protocol for the induction of innate immune memory in human smooth muscle cells and endothelial cells in vitro.

Non-immune cells, like innate immune cells, can develop a memory-like phenotype in response to priming with microbial compounds or certain metabolites, which enables an enhanced response to a secondary unspecific stimulus. This paper describes a step-by-step protocol for the induction and analysis of trained immunity in human endothelial and smooth muscle cells. We then describe steps for cell culture with cryopreserved vascular cells, subcultivation, and induction of trained immunity. We then provide detailed procedures for downstream analysis using ELISA and qPCR. For complete details on the use and execution of this protocol, please refer to Sohrabi et al. (2020)1 and Shcnack et al.2.

Contemporary secondary prevention in survivors of ST-elevation myocardial infarction with and without chronic kidney disease: a retrospective analysis.

Background: Survivors of myocardial infarction have an elevated risk of long-term mortality. We sought to evaluate guideline-directed medical treatment and its impact on long-term mortality in survivors of ST-elevation myocardial infarction (STEMI) according to their chronic kidney disease (CKD) stage. Methods: Using German health insurance claims data, 157 663 hospitalized survivors of STEMI were identified. Regarding different CKD stages, we retrospectively analysed the filled prescriptions of platelet inhibitors (PAI)/oral anticoagulation, statins, beta-blocker and angiotensin-converting enzyme inhibitors/angiotensin II type 1 receptor antagonists (ACE-I/AT1-A) and their association with long-term mortality. Results: Prescription rates for all four guideline-directed drugs were highest in patients without or with mild CKD and lowest in patients on dialysis. They dropped from 73.4% to 39.2% in patients without CKD and from 47.1% to 29% in patients on dialysis within the 5-year follow-up period. Mortality rates were dramatically increased in patients with CKD compared with patients without CKD (5-year mortality: no CKD, 16.7%; CKD stage 3, 47.1%; CKD stage 5d, 69.7%). Filled prescriptions of at least one drug class [one drug: hazard ratio (HR) 0.70, 95% confidence interval (95% CI) 0.66-0.74; four drugs: HR 0.28, 95% CI 0.27-0.30; P < .001 for both] as well as the distinct drug classes (statins: HR 0.55, 95% CI 0.54-0.56; ACE-I/AT1-A: HR 0.68, 95% CI 0.67-0.70; beta-blocker: HR 0.87, 95% CI 0.85-0.90; PAI/oral anticoagulation: HR 0.97, 95% CI 0.95-1.00; all P < .05) improved long-term mortality. Conclusions: An improved long-term guideline-recommended drug therapy after STEMI regardless of renal impairment might lead to beneficial effects on long-term mortality.

Survival of Patients with Acute Coronary Syndrome and Hematologic Malignancies-A Real-World Analysis.

BACKGROUND: The impact of the encounter between coronary heart disease (CHD) and cancer, and in particular hematologic malignancies (HM), remains poorly understood. OBJECTIVE: The aim of this analysis was to clarify how HM affects the prognosis of acute coronary syndrome (ACS). We analyzed German health insurance data from 11 regional Ortskrankenkassen (AOK) of patients hospitalized for ACS between January 2010 and December 2018, matched by age, sex and all comorbidities for short- and long-term survival and major adverse cardiac events (MACE). RESULTS: Of 439,716 patients with ACS, 2104 (0.5%) also had an HM. Myelodysplastic/myeloproliferative disorders (27.7%), lymphocytic leukemias (24.8%), and multiple myeloma (22.4%) predominated. These patients were about 6 years older (78 vs. 72 years *). They had an ST-segment elevation myocardial infarction (STEMI, 18.2 vs. 34.9% *) less often and more often had a non-STEMI (NSTEMI, 81.8 vs. 65.1% *). With the exception of dyslipidemia, these patients had more concomitant and previous cardiovascular disease and a worse NYHA stage. They were less likely to undergo coronary angiography (65.3 vs. 71.6% *) and percutaneous coronary intervention (PCI, 44.3 vs. 52.0% *), although the number of bleeding events was not relevantly increased (p = 0.22). After adjustment for the patients' risk profile, the HM was associated with reduced long-term survival. However, this was not true for short-term survival. Here, there was no difference in the STEMI patients, * p < 0.001. CONCLUSION: Survival in ACS and HM is significantly lower, possibly due to the avoidance of PCI because of a perceived increased risk of bleeding.

Contemporary Treatment and Outcome of Patients with Ischaemic Lower Limb Amputation: A Focus on Sex Differences.

OBJECTIVE: Chronic limb threatening ischaemia (CLTI) has a devastating prognosis with high rates of lower limb amputation (LLA) and deaths. This is an illustration of contemporary management and the long term fate of patients after ischaemic LLA, particularly with respect to sex, using real world data. METHODS: This was a multisectoral cross sectional and longitudinal analysis of health claims data from the largest German health insurance database (AOK). Data of 39 796 propensity score matched patients hospitalised for ischaemic LLA between 2010 and 2018 were analysed for cardiovascular comorbidities, treatment, and for subsequent cardiovascular and limb events, with a distinct focus on sex. Matching was performed, to ensure that the rate of major amputations and the age distribution were equal in both groups (in both sexes). An observation period of two years before index and a follow up (FU) period until 2019 were included. RESULTS: Before index amputation, 68% of patients had received any kind of peripheral revascularisation. The use of statins (37.0% vs. 42.6%) and antithrombotic substances (54.9% vs. 61.8%) was lower in women than in men (p < .001). During two year FU, cardiovascular and limb events occurred among women and men as follows: limb re-amputation (26.7% vs. 31.2%), myocardial infarction (10.9% vs. 14.5%), stroke (20.8% vs. 20.7%), and death from any cause (51.0% vs. 53.3%, p < .001 except for stroke). After adjustment for cardiovascular comorbidities and vascular procedures, female sex was associated with a higher probability of death (HR 1.04, 95% CI 1.04 - 1.04). CONCLUSION: Patients undergoing ischaemic LLA still have a poor prognosis marked by high rates of recurrent cardiovascular and limb events resulting in a > 50% mortality rate within two years. The continuous lack of guideline recommended therapies, particularly in women, may be associated with the persisting poor outcome, necessitating urgent further investigation.

Depression and Anxiety in Heart Transplant Recipients: Prevalence and Impact on Post-Transplant Outcomes.

BACKGROUND: Depression and anxiety (DA) are common mental disorders in patients with chronic diseases, but the research regarding their prevalence in heart transplantation (HTx) is still limited. METHODS: We performed an analysis of the prevalence and prognostic relevance of DA in patients who underwent HTx between 2010 and 2018 in Germany. Data were obtained from Allgemeine Ortskrankenkasse (AOK), which is the largest public health insurance provider. RESULTS: Overall, 694 patients were identified. More than a third of them were diagnosed with DA before undergoing HTx (n = 260, 37.5%). Patients with DA more often had an ischaemic cardiomyopathy (p < 0.001) and a history of previous myocardial infarction (p = 0.001) or stroke (p = 0.002). The prevalence of hypertension (p < 0.001), diabetes (p = 0.004), dyslipidaemia (p < 0.001) and chronic kidney disease (p = 0.003) was higher amongst transplant recipients with DA. Patients with DA were more likely to suffer an ischaemic stroke (p < 0.001) or haemorrhagic stroke (p = 0.032), or develop septicaemia (p = 0.050) during hospitalisation for HTx. Our analysis found no significant differences between the groups with respect to in-hospital mortality. The female sex and mechanical circulatory support were associated with an inferior prognosis. Pretransplant non-ischaemic cardiomyopathy was related to a favourable outcome. CONCLUSIONS: DA affect up to a third of the population undergoing HTx, with a greater prevalence in patients with comorbidities. DA are associated with a higher incidence of stroke and septicaemia after HTx.

Effects of Angiotensin Receptor-Neprilysin Inhibitors (ARNIs) on the Glucose and Fat Metabolism Biomarkers Leptin and Fructosamine.

(1) Background: Heart failure with reduced ejection fraction (HFrEF) remains a major health burden. Angiotensin-Receptor-Neprilysin-Inhibitors (ARNIs) are an established HFrEF therapy which increases natriuretic peptide levels by inhibiting neprilysin. Leptin is a lipid metabolism parameter, which is also involved in glucose metabolism and is suggested to correlate with HF burden. While the hormone also seems to interact with neprilysin, potential associations with ARNI therapy have not been investigated yet. (2) Methods: To study this issue, we measured levels of leptin and fructosamine in consecutive 72 HFrEF patients before initiation of ARNI therapy and 3-6 months after initiation of therapy in two European centers. Biomarker levels were correlated with clinical parameters including ejection fraction, LVEF, and NYHA class. (3) Results: During a follow-up of up to 6 months, clinical parameters improved significantly (LVEF: 30.2 ± 7.8% to 37.6 ± 10.0%, (p < 0.001) and a significant improvement of the mean NYHA class with initial 32 patients in NYHA III or IV and 8 patients in NYHA class III/IV during the follow up (p < 0.001). The initial NT-proBNP levels of 2251.5 ± 2566.8 pg/mL significantly improved to 1416.7 ± 2145 pg/mL, p = 0.008) during follow up. ARNI therapy was also associated with an increase in leptin levels (17.5 ± 23.4 µg/L to 22.9 ± 29.3, p < 0.001) and furthermore, affected glucose metabolism indicated by elevation of fructosamine values (333.9 ± 156.8 µmol/L to 454.8 ± 197.8 µmol/L, p = 0.013). (4) Conclusion: while in the early phase of therapy, ARNI promotes clinical improvement of HFrEF, and it also seems to affect fat and glucose parameters, indicating significant metabolic implications of this therapy regime.

Sex disparities in guideline-recommended therapies and outcomes after ST-elevation myocardial infarction in a contemporary nationwide cohort of patients over an eight-year period.

BACKGROUND AND AIMS: Acute myocardial infarction (AMI) is the leading cause of death worldwide. Outcome has improved during the last decades due to secondary prevention and widespread coronary interventions, but recent studies still show sex differences and insufficient drug adherence. We aimed to determine differences in the treatment strategies and outcomes between women and men with ST-elevation myocardial infarction (STEMI) in Germany. METHODS: From the Federal Association of the Local Health Insurance Funds (Allgemeine Ortskrankenkasse), 175,187 patients were identified who were hospitalized due to STEMI in Germany between January 1, 2010 and December 31, 2017. RESULTS: Compared to men, women were older (median 76 vs. 64 years) and had more often diabetes, hypertension, chronic heart failure, and chronic kidney disease (all p <0.001). Women suffered from higher rates of in-hospital complications such as bleeding (9.3 vs. 6.6%), longer hospitalizations (12.2 vs. 11.7 days) and were less likely to undergo percutaneous coronary intervention (75.5 vs. 85.2%). After adjustment for patient's risk profile, female sex was associated with decreased overall survival (HR 1.02, 95% confidence interval (CI) 1.00-1.04; p=0.036). Notably, more men received all four guideline-recommended drugs after STEMI (women 65.7% vs. men 69.8% after 90 days; p <0.001). With increasing number of prescribed drugs, patients benefit even more. This concerned both sexes, but was more pronounced in men (with 4 prescribed drugs: women HR 0.52, 95%CI 0.50-0.55; men HR 0.48, 95% CI 0.47-0.50, pint = 0.014). CONCLUSIONS: In a contemporary nationwide analysis, women with STEMI were older, had more comorbidities, underwent revascularization less often and had an increased risk for major complications as well as overall survival. Guideline-recommended drug therapy was applied less frequently in women although associated with an improved overall-survival.

Bioimpedance based determination of cardiac index does not show enough trueness for point of care use in patients with systolic heart failure.

Cardiac output (CO) is a key parameter in diagnostics and therapy of heart failure (HF). The thermodilution method (TD) as gold standard for CO determination is an invasive procedure with corresponding risks. As an alternative, thoracic bioimpedance (TBI) has gained popularity for CO estimation as it is non-invasive. However, systolic heart failure (HF) itself might worsen its validity. The present study validated TBI against TD. In patients with and without systolic HF (LVEF ≤ 50% or > 50% and NT-pro-BNP < 125 pg/ml, respectively) right heart catheterization including TD was performed. TBI (Task Force Monitor©, CNSystems, Graz, Austria) was conducted semi-simultaneously. 14 patients with and 17 patients without systolic HF were prospectively enrolled in this study. In all participants, TBI was obtainable. Bland-Altman analysis indicated a mean bias of 0.3 L/min (limits of agreement ± 2.0 L/min, percentage error or PE 43.3%) for CO and a bias of -7.3 ml (limits of agreement ± 34 ml) for cardiac stroke volume (SV). PE was markedly higher in patients with compared to patients without systolic HF (54% vs. 35% for CO). Underlying systolic HF substantially decreases the validity of TBI for estimation of CO and SV. In patients with systolic HF, TBI clearly lacks diagnostic accuracy and cannot be recommended for point-of-care decision making. Depending on the definition of an acceptable PE, TBI may be considered sufficient when systolic HF is absent.Trial registration number: DRKS00018964 (German Clinical Trial Register, retrospectively registered).

Association of age with 1-year outcome in patients with acute ischaemic stroke treated with thrombectomy: real-world analysis in 18 506 patients.

BACKGROUND: To evaluate the association of age with long-term outcome after thrombectomy. METHODS: In a retrospective cohort study based on routine healthcare data from Germany between 2010 and 2018, we included 18 506 patients with acute ischaemic stroke treated with mechanical thrombectomy. Association between age and mortality, disability, and level of care at 1 year was assessed. RESULTS: The median age was 76 years, 36.3% were aged ≥80 years and 55.8% were women. Patients aged ≥80 compared with those <80 years had a higher mortality (55.4% vs 28.5%; adjusted HR 1.13; 95% CI 1.05 to 1.31), more often had moderate/severe disability (35.5% vs 33.2%, adjusted HR 1.14; 95% CI 1.06 to 1.23) and less frequently had no/slight disability (17.4% vs 41.0%) at 1 year. Older age was associated with a higher likelihood of living in a nursing home (13.4% vs 9.2%, adjusted HR 1.09; 95% CI 0.97 to 1.22) and a lower likelihood of living at home (33.8% vs 62.8%) at 1 year. These associations were also robust when analysed in patients with no disability prior to stroke. Factors most strongly associated with worse 1-year outcomes in elderly patients were chronic limb-threatening ischaemia (67.9% vs 56.4%; HR 1.59, 95% CI 1.38 to 1.82), dementia at baseline (65.2% vs 47.3%; HR 1.29, 95% CI 1.17 to 1.44) and ventilation >48 hours (79.3% vs 52.2%; HR 2.91, 95% CI 2.66 to 3.18). CONCLUSIONS: In this large 'real-world' cohort, outcomes after mechanical thrombectomy were strongly associated with age. Of patients aged ≥80 years more than half were dead and less than one-fifth were functionally independent at 1 year. Certain comorbidities and ventilation >48 hours were associated with even worse outcomes.

Contemporary in-hospital and long-term prognosis of patients with acute ST-elevation myocardial infarction depending on renal function: a retrospective analysis.

BACKGROUND: Cardiovascular disease is often associated with chronic kidney disease (CKD), resulting in an increased risk for poor outcome. We sought to determine short-term mortality and overall survival in ST-elevation myocardial infarction (STEMI) patients with different stages of CKD. METHODS: In our retrospective cohort study with health insurance claims data of the Allgemeine Ortskrankenkasse (AOK), anonymized data of all STEMI patients hospitalized between 2010 and 2017 were analyzed regarding presence and severity of concomitant CKD. RESULTS: A total of 175,187 patients had an index-hospitalisation for STEMI (without CKD: 78.6% patients, CKD stage 1: 0.8%, CKD stage 2: 4.8%, CKD stage 3: 11.7%, CKD stage 4: 2.8%, CKD stage 5: 0.7%, CKD stage 5d: 0.6%). Patients with CKD were older and had more co-morbidities than patients without CKD. With increasing CKD severity, patients received less revascularization therapies (91.2%, 85.9%, 87.0%, 81.8%, 71.7%, 76.9% and 78.6% respectively, p < 0.001). After 1 year, guideline-recommended medications were prescribed less frequently in advanced CKD (83.4%, 79.3%, 81.5%, 74.7%, 65.0%, 59.4% and 53.7%, respectively, p < 0.001). CKD stages 4, 5 and 5d as well as chronic limb threatening ischemia (CLTI) were associated with decreased overall survival [CKD stage 4: hazard ratio (HR) 1.72; 95% CI 1.66-1.78; CKD stage 5: HR 2.55; 95% CI 2.37-2.73; CKD stage 5d: 5.64; 95% CI 5.42-5.86; CLTI: 2.06; 95% CI 1.98-2.13; all p < 0.001]. CONCLUSIONS: CKD is a frequent co-morbidity in patients with STEMI and is associated with a worse prognosis especially in advanced stages. Guideline-recommended therapies in patients with STEMI and CKD are still underused.

Pharmacological Targeting of the RAGE-NFκB Signalling Axis Impedes Monocyte Activation under Diabetic Conditions through the Repression of SHP-2 Tyrosine Phosphatase Function.

Monocytes play a vital role in the development of cardiovascular diseases. Type 2 diabetes mellitus (T2DM) is a major CVD risk factor, and T2DM-induced aberrant activation and enhanced migration of monocytes is a vital pathomechanism that leads to atherogenesis. We recently reported the upregulation of SHP-2 phosphatase expression in mediating the VEGF resistance of T2DM patient-derived monocytes or methylglyoxal- (MG, a glucose metabolite and advanced glycation end product (AGE) precursor) treated monocytes. However, the exact mechanisms leading to SHP-2 upregulation in hyperglycemic monocytes are unknown. Since inflammation and accumulation of AGEs is a hallmark of T2DM, we hypothesise that inflammation and AGE-RAGE (Receptor-for-AGEs) signalling drive SHP-2 expression in monocytes and blockade of these pathways will repress SHP-2 function. Indeed, monocytes from T2DM patients revealed an elevated SHP-2 expression. Under normoglycemic conditions, the serum from T2DM patients strongly induced SHP-2 expression, indicating that the T2DM serum contains critical factors that directly regulate SHP-2 expression. Activation of pro-inflammatory TNFα signalling cascade drove SHP-2 expression in monocytes. In line with this, linear regression analysis revealed a significant positive correlation between TNFα expression and SHP-2 transcript levels in T2DM monocytes. Monocytes exposed to MG or AGE mimetic AGE-BSA, revealed an elevated SHP-2 expression and co-treatment with an NFκB inhibitor or genetic inhibition of p65 reversed it. The pharmacological inhibition of RAGE was sufficient to block MG- or AGE-BSA-induced SHP-2 expression and activity. Confirming the importance of RAGE-NFκB signalling in regulating SHP-2 expression, the elevated binding of NFκB to the SHP-2 promoter-induced by MG or AGE-BSA-was reversed by RAGE and NFκB inhibition. Besides, we detected elevated RAGE levels in human and murine T2DM monocytes and monocytes exposed to MG or AGE-BSA. Importantly, MG and AGE-BSA treatment of non-T2DM monocytes phenocopied the aberrant pro-migratory phenotype of T2DM monocytes, which was reversed entirely by either SHP-2- or RAGE inhibition. In conclusion, these findings suggest a new therapeutic approach to prevent accelerated atherosclerosis in T2DM patients since inhibiting the RAGE-NFκB-SHP-2 axis impeded the T2DM-driven, SHP-2-dependent monocyte activation.

A Randomized Controlled Trial Comparing Apixaban With the Vitamin K Antagonist Phenprocoumon in Patients on Chronic Hemodialysis: The AXADIA-AFNET 8 Study.

BACKGROUND: Non-vitamin K oral anticoagulants have become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation (AF). The effectiveness and safety of non-vitamin K oral anticoagulants in patients on hemodialysis is not well known. METHODS: From June 2017 through May 2022, AXADIA-AFNET 8 (Compare Apixaban and Vitamin K Antagonists in Patients With Atrial Fibrillation and End-Stage Kidney Disease), an investigator-initiated PROBE (prospective randomized open blinded end point) outcome assessment trial, randomized patients with AF on chronic hemodialysis to either apixaban (2.5 mg BID) or the vitamin K antagonist (VKA) phenprocoumon (international normalized ratio, 2.0 to 3.0). The composite primary safety outcome was defined by a first event of major bleeding, clinically relevant nonmajor bleeding, or all-cause death. The primary efficacy outcome was a composite of ischemic stroke, all-cause death, myocardial infarction, and deep vein thrombosis or pulmonary embolism. Our hypothesis was that apixaban is noninferior to VKA. RESULTS: Thirty-nine sites randomized 97 patients (30% women; mean age 75 years; mean CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female sex] score, 4.5; baseline characteristics balanced between groups): 48 to apixaban and 49 to VKA. The median follow-up time was 429 days (range, 37 to 1370) versus 506 days (range, 101 to 1379), respectively. Adherence to apixaban was >80% in 44 of 48 patients; the median time in therapeutic range on VKA was 50.7%. Composite primary safety outcome events occurred in 22 patients (45.8%) on apixaban and in 25 patients (51.0%) on VKA (hazard ratio, 0.93 [95% CI, 0.53-1.65]; Pnoninferiority=0.157). Composite primary efficacy outcome events occurred in 10 patients (20.8%) on apixaban and in 15 patients (30.6%) on VKA (P=0.51; log rank). There were no significant differences regarding individual outcomes (all-cause mortality, 18.8% versus 24.5%; major bleeding, 10.4% versus 12.2%; and myocardial infarction, 4.2% versus 6.1%, respectively). CONCLUSIONS: In this randomized trial comparing apixaban and VKA in patients with AF on hemodialysis with long follow-up, no differences were observed in safety or efficacy outcomes. Even on oral anticoagulation, patients with AF on hemodialysis remain at high risk of cardiovascular events. Larger randomized trials are needed to determine the optimal anticoagulation regimen for patients with AF on hemodialysis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02933697.

To hit a home run as a heterotopic heart recipient-living with two hearts for over three decades: a case report.

Heterotopic heart transplantation (HHT) is an alternative to the orthotopic technique in selected patients with terminal heart failure. We report the case of the longest survival after HHT, with an uneventful follow-up for over three decades after transplantation. At the age of 25 years, endomyocardial fibrosis following myocarditis rendered the patient's native heart unable to maintain the body's needs. An allograft provided a second chance at life. The HHT technique was favoured due to severe pulmonary hypertension. The patient had an uneventful follow-up since then. The scarcity of donors and the revolutionary advances in the mechanical circulatory device field restricted the utilization of the HHT technique, but it has the potential to provide an excellent prognosis with a good quality of life.