Thromboembolism after Astra Zeneca COVID-19 vaccine: Not always PF4- antibody mediated.

Cases of thromboembolic events in 2021 flared up the discussion about the safety of Astra Zeneca's AZD1222 vaccine. We hereby report three cases of pulmonary embolism (PE), one case of extended portal vein thrombosis, and one case of combined portal vein thrombosis and PE within 2 weeks after vaccination with the Astra Zeneca AZD1222 vaccine in a 60-year-old, a 50-year old, a 33-year-old, a 30-year old, and a 40-year-old male in that year. All patients were healthy before. In three patients, we observed thrombocytopenia and to some extent unusually low antibody levels for the Spike Protein (S-protein), while the other two had normal thrombocyte counts. Only one patient had anti-platelet factor 4 (PF4)-antibodies detectable as it has been described in the "heparin-induced thrombocytopenia (HIT)-like" disease of "vaccine-induced prothrombotic immune thrombocytopenia" (VIPIT) and we therefore assume that heterogeneous mechanisms led to PE. Therefore, we advise to collect and report more cases, in order to determine the age-related risks of vaccination balanced against the benefits of immunity to SARS-COV-2 for the AZD1222 vaccine in order to gain knowledge for the next pandemic.

Drug-coated balloon: an effective alternative to stent strategy in small-vessel coronary artery disease-a meta-analysis.

Background: Small-vessel coronary artery disease (CAD) is frequently observed in coronary angiography and linked to a higher risk of lesion failure and restenosis. Currently, treatment of small vessels is not standardized while having drug-eluting stents (DES) or drug-coated balloons (DCBs) as possible strategies. We aimed to conduct a meta-analytic approach to assess the effectiveness of treatment strategies and outcomes for small-vessel CAD. Methods: Comprehensive literature search was conducted using PubMed, Embase, MEDLINE, and Cochrane Library databases to identify studies reporting treatment strategies of small-vessel CAD with a reference diameter of ≤3.0 mm. Target lesion revascularization (TLR), target lesion thrombosis, all-cause death, myocardial infarction (MI), and major adverse cardiac events (MACE) were defined as clinical outcomes. Outcomes from single-arm and randomized studies based on measures by means of their corresponding 95% confidence intervals (CI) were compared using a meta-analytic approach. Statistical significance was assumed if CIs did not overlap. Results: Thirty-seven eligible studies with a total of 31,835 patients with small-vessel CAD were included in the present analysis. Among those, 28,147 patients were treated with DES (24 studies) and 3,299 patients with DCB (18 studies). Common baseline characteristics were equally distributed in the different studies. TLR rate was 4% in both treatment strategies [0.04; 95% CI 0.03-0.05 (DES) vs. 0.03-0.07 (DCB)]. MI occurred in 3% of patients receiving DES and in 2% treated with DCB [0.03 (0.02-0.04) vs. 0.02 (0.01-0.03)]. All-cause mortality was 3% in the DES group [0.03 (0.02-0.05)] compared with 1% in the DCB group [0.01 (0.00-0.03)]. Approximately 9% of patients with DES developed MACE vs. 4% of patients with DCB [0.09 (0.07-0.10) vs. 0.04 (0.02-0.08)]. Meta-regression analysis did not show a significant impact of reference vessel diameter on outcomes. Conclusion: This large meta-analytic approach demonstrates similar clinical and angiographic results between treatment strategies with DES and DCB in small-vessel CAD. Therefore, DES may be waived in small coronary arteries when PCI is performed with DCB.

Predictors of worse outcome after postponing non-emergency cardiac interventions during the COVID-19 pandemic.

OBJECTIVE: Deferral of non-emergency cardiac procedures is associated with increased early emergency cardiovascular hospitalisation. This study aimed to identify predictors of worse clinical outcome after deferral of non-emergency cardiovascular interventions. METHODS: This observational case-control study included consecutive patients whose non-emergency cardiac intervention has been postponed during COVID-19-related lockdown between 19 March and 30 April 2020 (n=193). Cox regression was performed to identify predictors of the combined 1-year end point emergency cardiovascular hospitalisation and death. All patients undergoing non-emergency interventions in the corresponding time period 2019 served as control group (n=216). RESULTS: The combined end point of death and emergency cardiovascular hospitalisation occurred in 70 (36.3%) of 193 patients with a postponed cardiovascular intervention. The planned intervention was deferred by a median of 23 (19-36) days. Arterial hypertension (HR 2.27; 95% CI 1.00 to 5.12; p=0.049), chronic kidney disease (HR 1.89; 95% CI 1.03 to 3.49; p=0.041) as well as severe valvular heart disease (HR 3.08; 95% CI 1.68 to 5.64; p<0.001) were independent predictors of death or emergency hospitalisation. Kaplan-Maier estimators of the combined end point were 31% in patients with arterial hypertension, 56% in patients with severe valvular heart disease and 77% with both risk factors (HR 12.4, 95% CI 3.8 to 40.7; p<0.001) and only 9% in patients without these risk factors (log rank p<0.001). N-terminal pro-B-type natriuretic peptide (NT-proBNP) cut-point of ≥1109 pg/mL best predicts the occurrence of primary end point event in deferred patients (area under the curve 0.71; p<0.001; sensitivity 63.8%, specificity 69.4%). CONCLUSION: Our results suggest that patients with either arterial hypertension, chronic kidney or severe valvular heart disease are at very high risk for emergency hospitalisation and increased mortality in case of postponed cardiac interventions even in supposed stable clinical status. Risk seems to be even higher in patients suffering from a combination of these conditions. If the ongoing or future pandemics force hospitals again to postpone cardiac interventions, the biomarker NT-proBNP is an applicable parameter for outpatient monitoring to identify those at risk for adverse cardiovascular events.

Deferral of Non-Emergency Cardiovascular Interventions Triggers Increased Cardiac Emergency Admissions-Analysis of the COVID-19 Related Lockdown.

BACKGROUND: Data on the relation between non-emergency and emergency cardiac admission rates during the COVID-19 lockdown and post-lockdown period are sparse. METHODS: Consecutive cardiac patients admitted to our tertiary heart center between 1 January and 30 June 2020 were included. The observation period of 6 months was analyzed in total and divided into three defined time periods: the pre-lockdown (1 January-19 March), lockdown (20 March-19 April), and post-lockdown (20 April-30 June) period. These were compared to the reference periods 2019 and 2022 using daily admission rates and incidence rate ratios (IRR). RESULTS: Over the observation period from 1 January to 30 June, cardiac admissions (including non-emergency and emergency) were comparable between 2019, 2020, and 2022 (n = 2889, n = 2952, n = 2956; p = 0.845). However, when compared to the reference period 2019, non-emergency admissions decreased in 2020 (1364 vs. 1663; p = 0.02), while emergency admissions significantly increased (1588 vs. 1226; p < 0.001). Further analysis of the lockdown period revealed that non-emergency admissions dropped by 82% (IRR 0.18; 95%-CI 0.14-0.24; p < 0.001) and 42% fewer invasive cardiac interventions were performed (p < 0.001), whereas the post-lockdown period showed a 52% increase of emergency admissions (IRR 1.47; 95%-CI 1.31-1.65; p < 0.001) compared to 2019. CONCLUSIONS: We demonstrate a drastic surge of emergency cardiac admissions post-COVID-19 related lockdown suggesting that patients who did not keep their non-emergency appointment had to be admitted as an emergency later on.

Symptom burden correlates to impairment of diffusion capacity and exercise intolerance in long COVID patients.

After acute infection with the SARS-CoV-2 virus, a considerable number of patients remains symptomatic with pathological changes in various organ systems. This study aimed to relate the physical and mental burden of symptoms of long COVID patients to the findings of a somatic evaluation. In patients with persistent long COVID symptoms three months after acute infection we assessed physical and mental health status using the SF-36 questionnaire. The cohort was dichotomised by the results (upper two quartiles vs. lower to quartiles) and compared with regard to transthoracic echocardiography, body plethysmography (including diffusion capacity), capillary blood gas analysis and 6-min walk test (6-MWT). From February 22 to September 13, 2021, 463 patients were prospectively examined, of which 367 completed the SF-36 questionnaire. A positive correlation between initial disease severity (need for hospitalization, intensive care medicine) and resulting symptom burden at follow-up could be demonstrated. Patients with impaired subjective physical and mental status were significantly more likely to be women. There was a significant correlation between symptom severity and reduced exercise tolerance in the 6-MWT (495.6 ± 83.7 m vs 549.7 ± 71.6 m, p < 0.001) and diffusion capacity for carbon monoxide (85.6 ± 14.3% of target vs 94.5 ± 14.4, p < 0.001). In long COVID patients, initial disease severity is correlated with symptom burden after at least 3 months of follow-up. Highly symptomatic long COVID patients show impaired diffusion capacity and 6-MWT despite average or mildly affected mechanical lung parameters. It must be further differentiated whether this corresponds to a transient functional impairment or whether it is a matter of defined organ damage.

Sphingosine-1-Phosphate Attenuates Lipopolysaccharide-Induced Pericyte Loss via Activation of Rho-A and MRTF-A.

The high mortality seen in sepsis is caused by a systemic hypotension in part owing to a drastic increase in vascular permeability accompanied by a loss of pericytes. As has been shown previously, pericyte retention in the perivascular niche during sepsis can enhance the integrity of the vasculature and promote survival via recruitment of adhesion proteins such as VE-cadherin and N-cadherin. Sphingosine-1-phosphate (S1P) represents a lipid mediator regulating the deposition of the crucial adhesion molecule VE-cadherin at sites of interendothelial adherens junctions and of N-cadherin at endothelial-pericyte adherens junctions. Furthermore, in septic patients, S1P plasma levels are decreased and correlate with mortality in an indirectly proportional way. In the present study, we investigated the potential of S1P to ameliorate a lipopolysaccharide-induced septic hypercirculation in mice. Here we establish S1P as an antagonist of pericyte loss, vascular hyperpermeability, and systemic hypotension, resulting in an increased survival in mice. During sepsis S1P preserved VE-cadherin and N-cadherin deposition, mediated by a reduction of Src and cadherin phosphorylation. At least in part, this effect is mediated by a reduction of globular actin and a subsequent increase in nuclear translocation of MRTF-A (myocardin-related transcription factor A). These findings indicate that S1P may counteract pericyte loss and microvessel disassembly during sepsis and additionally emphasize the importance of pericyte-endothelial interactions to stabilize the vasculature.

Thymosin ß4 attenuates microcirculatory and hemodynamic destabilization in sepsis.

OBJECTIVE: The actin polymerization regulator Thymosin ß4 (Tß4) has been shown to be involved in angiogenesis, wound healing, cell survival and anti-inflammatory responses. We have previously shown that Tß4 is capable of recruiting pericytes, thus stabilizing the endothelial barrier function. Here, we analyzed whether treatment with Tß4 is able to reduce the pericytes loss in lipopolysaccharides (LPS)-induced sepsis and to improve the hemodynamic function and survival in C57BL/6 mice. METHODS: Fourteen days before LPS injection, the mice were injected with an adeno-associated virus carrying the Tß4 (rAAV.Tß4) or LacZ gene (rAAV.LacZ). A sepsis-severity score was assessed, and non-invasive hemodynamic and permeability measurements were performed. Heart and muscle samples were analyzed for PECAM-1(+) capillaries and NG2(+)pericytes. RESULTS: At 36 h, there was a decrease of sepsis severity score in rAAV.Tß4-treated animals as compared to rAAV.LacZ-treated control. rAAV.Tß4-treated animals displayed lower perivascular leakage and higher blood pressure compared to control. Of note, the rAAV.Tß4 group showed a higher pericyte count in heart and peripheral muscle samples. Finally, Tß4-treatment reduced mortality compared to control. CONCLUSION: The data indicate a preventive role of Tß4 in septic hypercirculation and highlight Tß4 as a potential therapeutic target in severe sepsis.