Platelet mass cytometry reveals dysregulation of prothrombotic pathways in essential thrombocythemia.

Thromboembolic events are common in patients with essential thrombocythemia (ET). However, the pathophysiological mechanisms underlying the increased thrombotic risk remain to be determined. Here, we perform the first phenotypical characterization of platelet expression using single-cell mass cytometry in six ET patients and six age- and sex-matched healthy individuals. A large panel of 18 transmembrane regulators of platelet function and activation were analyzed, at baseline and after ex-vivo stimulation with thrombin receptor-activating peptide (TRAP). We detected a significant overexpression of the activation marker CD62P (p-Selectin) (p = .049) and the collagen receptor GPVI (p = .044) in non-stimulated ET platelets. In contrast, ET platelets had a lower expression of the integrin subunits of the fibrinogen receptor GPIIb/IIIa CD41 (p = .036) and CD61 (p = .044) and of the von Willebrand factor receptor CD42b (p = .044). Using the FlowSOM algorithm, we identified 2 subclusters of ET platelets with a prothrombotic expression profile, one of them (cluster 3) significantly overrepresented in ET (22.13% of the total platelets in ET, 2.94% in controls, p = .035). Platelet counts were significantly increased in ET compared to controls (p = .0123). In ET, MPV inversely correlated with platelet count (r=-0.96). These data highlight the prothrombotic phenotype of ET and postulate GPVI as a potential target to prevent thrombosis in these patients.

Essential thrombocythemia (ET) is a rare disease characterized by an increased number of platelets in the blood. As a complication, many of these patients develop a blood clot, which can be life-threatening. So far, the reason behind the higher risk of blood clots is unclear. In this study, we analyzed platelet surface markers that play a critical role in platelet function and platelet activation using a modern technology called mass cytometry. For this purpose, blood samples from 6 patients with ET and 6 healthy control individuals were analyzed. We found significant differences between ET platelets and healthy platelets. ET platelets had higher expression levels of p-Selectin (CD62P), a key marker of platelet activation, and of the collagen receptor GPVI, which is important for clot formation. These results may be driven by a specific platelet subcluster overrepresented in ET. Other surface markers, such as the fibrinogen receptor GPIIb/IIIa CD41, CD61, and the von Willebrand factor receptor CD42b, were lower expressed in ET platelets. When ET platelets were treated with the clotting factor thrombin (thrombin receptor-activating peptide, TRAP), we found a differential response in platelet activation compared to healthy platelets. In conclusion, our results show an increased activation and clotting potential of ET platelets. The platelet surface protein GPVI may be a potential drug target to prevent abnormal blood clotting in ET patients.

[Palliative aspects in clinical acute and emergency medicine as well as intensive care medicine: consensus paper of the DGIIN, DGK, DGP, DGHO, DGfN, DGNI, DGG, DGAI, DGINA and DGPalliativmedizin]. / Palliativmedizinische Aspekte in der klinischen Akut- und Notfallmedizin sowie Intensivmedizin: Konsensuspapier der DGIIN, DGK, DGP, DGHO, DGfN, DGNI, DGG, DGAI, DGINA und DGPalliativmedizin.

The timely integration of palliative medicine is an important component in the treatment of various advanced diseases. While a German S-3-guideline on palliative medicine exists for patients with incurable cancer, a recommendation for non-oncological patients and especially for palliative patients being treated in the emergency department or intensive care unit is missing to date. Based on the present consensus paper, the palliative care aspects of the respective medical disciplines are addressed. The timely integration of palliative care aims to improve quality of life and symptom control in clinical acute and emergency medicine as well as intensive care.

[Palliative aspects in clinical acute and emergency medicine as well as intensive care medicine : Consensus paper of the DGIIN, DGK, DGP, DGHO, DGfN, DGNI, DGG, DGAI, DGINA and DGPalliativmedizin]. / Palliativmedizinische Aspekte in der klinischen Akut- und Notfallmedizin sowie Intensivmedizin : Konsensuspapier der DGIIN, DGK, DGP, DGHO, DGfN, DGNI, DGG, DGAI, DGINA und DGPalliativmedizin.

The timely integration of palliative medicine is an important component in the treatment of various advanced diseases. While a German S­3-guideline on palliative medicine exists for patients with incurable cancer, a recommendation for non-oncological patients and especially for palliative patients presenting in the emergency department or intensive care unit is missing to date. Based on the present consensus paper, the palliative care aspects of the respective medical disciplines are addressed. The timely integration of palliative care aims to improve quality of life and symptom control in clinical acute and emergency medicine as well as intensive care.

Ligand-activated RXFP1 gene therapy ameliorates pressure overload-induced cardiac dysfunction.

Recurrent episodes of decompensated heart failure (HF) represent an emerging cause of hospitalizations in developed countries with an urgent need for effective therapies. Recently, the pregnancy-related hormone relaxin (RLN) was found to mediate cardio-protective effects and act as a positive inotrope in the cardiovascular system. RLN binds to the RLN family peptide receptor 1 (RXFP1), which is predominantly expressed in atrial cardiomyocytes. We therefore hypothesized that ventricular RXFP1 expression might exert potential therapeutic effects in an in vivo model of cardiac dysfunction. Thus, mice were exposed to pressure overload by transverse aortic constriction and treated with AAV9 to ectopically express RXFP1. To activate RXFP1 signaling, RLN was supplemented subcutaneously. Ventricular RXFP1 expression was well tolerated. Additional RLN administration not only abrogated HF progression but restored left ventricular systolic function. In accordance, upregulation of fetal genes and pathological remodeling markers were significantly reduced. In vitro, RLN stimulation of RXFP1-expressing cardiomyocytes induced downstream signaling, resulting in protein kinase A (PKA)-specific phosphorylation of phospholamban (PLB), which was distinguishable from ß-adrenergic activation. PLB phosphorylation corresponded to increased calcium amplitude and contractility. In conclusion, our results demonstrate that ligand-activated cardiac RXFP1 gene therapy represents a therapeutic approach to attenuate HF with the potential to adjust therapy by exogenous RLN supplementation.

[Drop in oxygen saturation and blood pressure as well as increase in central venous pressure during mitral valve clipping in an 81-year-old female patient]. / Abfall von Sauerstoffsättigung und Blutdruck sowie Anstieg des zentralen Venendrucks im Rahmen eines Mitralklappenclippings bei einer 81-Jährigen.

BACKGROUND: Atrial septal defects (ASD) following endovascular mitral valve clipping are potentially hemodynamically relevant complications. Immediate closure with an occluder can represent a safe and effective treatment. An 81-year-old female patient suffering from severe dyspnea due to previously known severe mitral valve regurgitation was scheduled for elective mitral valve clipping. The clip was successfully implanted. Removal of the transseptal cannula resulted in a sudden drop in oxygen saturation and systolic blood pressure as well as an immediate increase in central venous pressure. An iatrogenic left-right shunt was observed at the atrial level with a relevant shunt volume. Immediate closure using an atrial septal occluder successfully restored the oxygen saturation and hemodynamic parameters. CONCLUSION: An increase in central venous pressure, reduction of systolic blood pressure or oxygen saturation after withdrawal of the transseptal cannula during mitral valve clipping should always be further investigated regarding a possible ASD.

Initial experience with percutaneous mitral valve repair in patients with cardiac amyloidosis.

BACKGROUND: Percutaneous mitral valve repair (PMVR) is a therapeutic option for severe mitral regurgitation (MR) in patients with heart failure due to differential aetiologies. However, only little is known about the safety and efficacy of this procedure in patients with amyloid cardiomyopathy. METHODS: Five patients with cardiac amyloidosis and moderate to severe or severe MR undergoing PMVR were analysed retrospectively and compared to seven patients with cardiac amyloidosis and severe MR without intervention. Clinical and functional data, renal function and cardiac biomarkers as well as established risk scores for cardiac amyloidosis were assessed. Primary endpoint was the reduction in MR one year after PMVR. Secondary endpoints were safety, overall mortality after 12 months compared with the control group, as well as changes in clinical and functional parameters. RESULTS: Amyloidosis risk assessment documented amyloid cardiomyopathy at an advanced stage in all patients. Procedural, technical and device success of PMVR were all 100% and residual MR remained mild to moderate at 12 months follow-up (P = .038 vs before PMVR). Differences in survival compared with the control (no PMVR) group pointed to a possible survival benefit in the PMVR group (P = .02). CONCLUSION: PMVR is a feasible and safe procedure in patients with cardiac amyloidosis and might carry a possible survival benefit in this patient group.

Percutaneous mitral valve repair in recurrent severe mitral valve regurgitation after mitral annuloplasty : MitraClip-in-the-ring as a complementary strategy.

BACKGROUND: Patients with reduced left ventricular (LV) function undergoing coronary artery bypass graft surgery or/and aortic valve replacement occasionally show severe mitral valve (MV) regurgitation and thus also undergo surgical mitral annuloplasty. Over time, further deterioration of LV function and additional ischemic events cause recurrence of severe MV regurgitation due to the Carpentier IIIb morphology of the MV that is not adequately addressed by the previously implanted annuloplasty ring. METHODS: Seven patients (Society of Thoracic Surgeons score: 7.5 ± 1.5%) with Carpentier type-IIIb recurrent severe MV regurgitation, having undergone prior cardiothoracic surgery (median: 40 months) including mitral annuloplasty, were treated with the MitraClip device. RESULTS: MitraClip implantation resulted in significantly reduced MV regurgitation and improved New York Heart Association functional state, translating into an increased exercise capability and improved cardiac biomarkers. The morphology of the MV was adequately addressed without causing relevant MV stenosis, while the MV annulus area remained unaltered. The procedure was safe with a 30-day mortality rate of 0%. CONCLUSION: MitraClip-in-the-ring is feasible and in principle safe for treating Carpentier type IIIb severe MV regurgitation after surgical MV repair using mitral annuloplasty. MitraClip-in-the-ring resulted in immediate amelioration of clinical symptoms and increased physical exercise capacity.

ECPELLA 2.0-Minimally invasive biventricular groin-free full mechanical circulatory support with Impella 5.0/5.5 pump and ProtekDuo cannula as a bridge-to-bridge concept: A first-in-man method description.

BACKGROUND: Cardiogenic shock (CS) from biventricular heart failure that requires acute mechanical circulatory support (MCS) is associated with high mortality. Different MCS methods and techniques have emerged as a standard of care in CS. Nevertheless, the routine MCS approach carries multiple limitations such as limb ischemia, missing of left ventricular unloading and immobilization. We describe a method to establish a groin-free full support MCS in patients with CS without the need for thoracotomy. This is the first report of the ECPELLA 2.0 concept, a peripheral groin-free biventricular MCS in patients with acute CS. METHODS AND RESULTS: We discuss two patients in acute CS (INTERMACS I) treated with two peripheral MCS devices (Impella 5.0 or 5.5 surgically via an axillary artery and ProtekDuo cannula percutaneously via a right internal jugular vein) as a bridge before the implantation of a durable left ventricular assist device (LVAD). Biventricular assist device (BIVAD)-support duration was 9 and 15 days and both of the patients were successfully bridged to a durable LVAD. As our BIVAD-concept is groin-free, the patients started full mobilization as early as they were weaned from the respirator 2 days after the BIVAD-implantation. ECPELLA 2.0 provides a high cardiac output, right and left ventricular unloading with end-organ recovery and a possibility of administration of a membrane oxygenator. There were no device-related complications. CONCLUSION: The ECPELLA 2.0 biventricular support concept for patients suffering from an acute CS. Allows for rapid extubation, mobilization, and physical exercise while on full support. Additional application of a membrane oxygenator is easily feasible if required.

Cardiac surgery in the heart transplant recipient: Outcome analysis and long-term results.

BACKGROUND: Survival rates following cardiac transplantation continue to improve. Due to the scarcity of available organs, extended donor criteria have become more prevalent in clinical practice. In this context, the risk of developing cardiac pathology requiring surgical correction is increasing. METHODS: Between January 1991 and October 2010, a total of 479 patients received cardiac transplantations at the University Hospital Heidelberg. Of those, 18 (3.8%) patients required subsequent cardiac surgery until 2018. Short- and long-term analyses were performed. RESULTS: Indications for cardiac surgery included valvular disease (n = 16) with the majority of cases affecting the tricuspid valve (n = 10), while 6 patients received mitral valve surgery, of whom 3 patients underwent concomitant valve surgery. Other indications included CABG (n = 1) and re-transplantation (n = 1) for allograft dysfunction. Mean follow-up time was 6.5 years, while mean interval to surgery was 6.0 years. Early mortality was 11.1% (n = 2), while overall survival at 1, 5, and 10 years were, 88.1%, 81.4%, and 52.2%, respectively. Compared to an overall survival of that transplant cohort at 1, 5, and 10 years of 76.7%, 66.7%, and 52.4% percent, respectively (P = .271). CONCLUSION: According to our data, redo cardiac surgery can be performed with acceptable mortality and morbidity. Atrioventricular valve pathology plays a chief role in these patients.

Percutaneous repair of severe mitral valve regurgitation secondary to chordae rupture in octogenarians using MitraClip.

OBJECTIVES: The aim of this study was to assess feasibility and clinical effectiveness of the MitraClip device in octogenarians suffering from severe mitral valve regurgitation due to chordae rupture. BACKGROUND: The MitraClip procedure is a suitable technique in high-risk surgical patients to achieve safe and effective percutaneous repair of mitral valve regurgitation. Octogenarians show cumulative risk and social aspects hindering mitral valve surgery. No data exists regarding the use of the MitraClip device in high-risk octogenarians suffering from mitral valve chordae rupture. METHODS: Between October 2009 and March 2017 98 high-risk octogenarians (society of thoracic surgeons score [STS]: 9.7% ± 0.8) with mitral valve prolapse and consecutively chordae rupture were treated with the MitraClip after interdisciplinary discussion. RESULTS: Successful mitral valve repair was achieved in 91% of the octogenarians. Repair of the mitral valve caused immediate and significant reduction of dyspnoea (NYHA class: 3.5 ± 0.4 vs 2.0 ± 0.3; P < 0.001), cardiac reverse remodeling (LVESD: 39 ± 0.8 vs 35 ± 0.8; P < 0.01) and amelioration of cardiac biomarkers (NTproBNP (4884 ± 52 ng/L vs 2473 ± 210 ng/L; P < 0.05,). Effects were stable over the 12 months observation period. None of our patients died intraprocedurally. CONCLUSIONS: Percutaneous repair of chordae rupture is feasible and safe in high-risk octogenarians. The MitraClip should be considered to repair severe mitral valve regurgitation due to mitral valve chordae rupture in high-risk octogenarians after interdisciplinary discussion even facing a challenging anatomy.

Heart re-transplantation in Eurotransplant.

Internationally 3% of the donor hearts are distributed to re-transplant patients. In Eurotransplant, only patients with a primary graft dysfunction (PGD) within 1 week after heart transplantation (HTX) are indicated for high urgency listing. The aim of this study is to provide evidence for the discussion on whether these patients should still be allocated with priority. All consecutive HTX performed in the period 1981-2015 were included. Multivariate Cox' model was built including: donor and recipient age and gender, ischaemia time, recipient diagnose, urgency status and era. The study population included 18 490 HTX, of these 463 (2.6%) were repeat transplants. The major indications for re-HTX were cardiac allograft vasculopathy (CAV) (50%), PGD (26%) and acute rejection (21%). In a multivariate model, compared with first HTX hazards ratio and 95% confidence interval for repeat HTX were 2.27 (1.83-2.82) for PGD, 2.24 (1.76-2.85) for acute rejection and 1.22 (1.00-1.48) for CAV (P < 0.0001). Outcome after cardiac re-HTX strongly depends on the indication for re-HTX with acceptable outcomes for CAV. In contrast, just 47.5% of all hearts transplanted in patients who were re-transplanted for PGD still functioned at 1-month post-transplant. Alternative options like VA-ECMO should be first offered before opting for acute re-transplantation.

Percutaneous repair of mitral valve regurgitation in patients with severe heart failure: comparison with optimal medical treatment.

BACKGROUND: Occurrence of severe mitral valve (MV) regurgitation (MR) is an independent negative predictor of mortality in patients with severe systolic heart failure (HF). This study examines clinical effects and cardiac reverse remodelling in patients with severe systolic HF receiving percutaneous mitral valve repair (PMVR) using MitraClip in comparison to patients receiving optimal medical therapy only. METHODS: Between 2010 and 2014, 86 patients (Society of Thoracic Surgeons score: 10.5% ± 1.2%) with severe HF (left ventricular [LV] ejection fraction; LVEF: 25% ± 2%; LV endsystolic diameter [LVESD]: 55 ± 3 mm) and severe MR received PMVR using MitraClip. Cardiac reverse remodelling and clinical parameters were compared to HF patients with severe MR (from our HF outpatient clinic; n = 69; LVEF: 26% ± 1.4%; LVESD: 53 ± 2 mm) receiving optimal medical therapy (OMT) only. All patients received stable OMT and were characterised by echocardiography, 6-minwalk-distance test and cardiac biomarkers within a 24 months observation period. RESULTS: PMVR in patients with end-stage HF and severe MR resulted in reduction of MR and significant additional cardiac reverse remodelling (LVEF: 26 ± 1.4 vs. 33% ± 2%, p < .05; LVESD: 53 ± 2 vs. 47 ± 2 mm, p < .05) over the 24 months observation period as compared to pharmacologically-only managed comparators. CONCLUSIONS: Both OMT and PMVR cause cardiac reverse remodelling and relief of symptoms in patients with HF and severe MR. PMVR results in significant additional cardiac reverse remodelling compared to pharmacologically-only managed patients.

Central Extracorporeal Life Support With Left Ventricular Decompression to Berlin Heart Excor: A Reliable "Bridge to Bridge" Strategy in Crash and Burn Patients.

The aim of this study was to compare patients with severe biventricular heart failure who underwent Berlin Heart Excor implantation with (cardiogenic shock [CS] status) or without the need for preoperative extracorporeal life support (ECLS) as a bridge to long-term device. A total of 40 consecutive patients with severe biventricular heart failure underwent Berlin Heart Excor implantation with (CS status, n = 20, 50%) or without (control, n = 20, 50%) the need for preoperative ECLS as a bridge to long-term device from March 2007 to May 2015 at our institution. Demographics and preoperative baseline characteristics as well as early and long-term outcomes including mortality and complication rates were retrospectively compared between the two groups. There were no statistically significant differences in terms of demographics and most preoperative clinical characteristics. The mean age in the ECLS (CS group) and control group was 43.5 ± 19.4 and 41.3 ± 16.4 (P = 0.705), whereas 20 and 25% of patients were females (P = 1.000). However, patients from the ECLS group had preoperatively higher lactate (P = 0.037), aspartate aminotransferase (P < 0.001), and alanine aminotransferase (P < 0.001) levels, all of them significantly decreased after surgery (P  = 0.004, P = 0.017, and P = 0.001, respectively) and did not show any statistical differences to the corresponding values from the control group (P = 0.597, P = 0.491, and P = 0.339, respectively). Postoperatively, patients from the control and ECLS groups had statistically similar incidences of liver failure (30 vs. 35%, P = 0.736), renal failure (45 vs. 70%, P = 0.110), need for reopening (35 vs. 60%, P = 0.113), major cerebrovascular events (35 vs. 30%, P = 0.736), sepsis (10 vs. 25%, P = 0.407), wound infection (20 vs. 30%, P = 0.716), abdominal ischemia requiring surgery (28.6 vs. 36.8%, P = 0.719), and acute respiratory distress syndrome (25 vs. 35.3%, P = 1.000). The proportion of patients who were bridged to transplantation was statistically similar between the ECLS and the control groups (40 vs. 52.6%, P = 0.429). Furthermore, there were no statistically significant differences in terms of early (Breslow [generalized Wilcoxon] P = 0.907) and long-term (log-rank [Mantel-Cox] P = 0.787) overall cumulative survival accounting for 30-day survival of 75 versus 75%, 6-month survival of 60 versus 55%, 1-year survival of 54 versus 40%, and 7-year survial of 47 versus 40% in the control and ECLS groups, respectively. ECLS in critical CS as a bridge to implantation of the Berlin Heart Excor ventricular assist device is safe and is associated with improvement in end-organ function leading to similar excellent early and long-term survival and incidences of major complications as in patients without the need for preoperative ECLS support.

Heart failure gene therapy: the path to clinical practice.

Gene therapy, aimed at the correction of key pathologies being out of reach for conventional drugs, bears the potential to alter the treatment of cardiovascular diseases radically and thereby of heart failure. Heart failure gene therapy refers to a therapeutic system of targeted drug delivery to the heart that uses formulations of DNA and RNA, whose products determine the therapeutic classification through their biological actions. Among resident cardiac cells, cardiomyocytes have been the therapeutic target of numerous attempts to regenerate systolic and diastolic performance, to reverse remodeling and restore electric stability and metabolism. Although the concept to intervene directly within the genetic and molecular foundation of cardiac cells is simple and elegant, the path to clinical reality has been arduous because of the challenge on delivery technologies and vectors, expression regulation, and complex mechanisms of action of therapeutic gene products. Nonetheless, since the first demonstration of in vivo gene transfer into myocardium, there have been a series of advancements that have driven the evolution of heart failure gene therapy from an experimental tool to the threshold of becoming a viable clinical option. The objective of this review is to discuss the current state of the art in the field and point out inevitable innovations on which the future evolution of heart failure gene therapy into an effective and safe clinical treatment relies.

AAV6.ßARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model.

AIMS: G protein-coupled receptor kinase 2 (GRK2), which is markedly upregulated in failing human myocardium, has been implicated as a contributing factor or consequence of heart failure (HF). Importantly, cardiac-specific GRK2 knockout mice have recently proved the pathological nature of GRK2 in HF. Targeted inhibition of GRK2 is possible using a peptide inhibitor known as the ßARKct, which has rescued several disparate small animal HF models. This study was designed to evaluate long-term ßARKct expression in a clinically relevant large animal HF model, using stable myocardial gene delivery with adeno-associated virus serotype 6 (AAV6). METHODS AND RESULTS: A porcine model of HF subsequent to left ventricular (LV) myocardial infarction (MI) was used to study the effects of retrograde injection into the anterior interventricular vein of either AAV6.ßARKct or AAV6.luciferase as a control 2 weeks after MI. Echocardiography and LV hemodynamics were performed before and 6 weeks after gene transfer. Robust and long-term ßARKct expression was found after AAV6-mediated delivery, leading to significant amelioration of LV haemodynamics and contractile function in HF pigs compared with AAV6.luciferase-treated control animals that showed a continued decline in cardiac function. Interestingly, the neurohormonal axis was virtually normalized in AVV6.ßARKct-treated HF animals, represented by reductions in plasma norepinephrine levels, whereas AAV6.luciferase-treated pigs showed further increases in plasma catecholamine levels. As a result, LV remodelling and foetal gene expression was reversed by AVV6.ßARKct gene therapy. CONCLUSION: These data--showing sustained amelioration of cardiac function in a post-MI pig HF model--demonstrate the therapeutic potential of ßARKct gene therapy for HF.

Depression mediates the association between health literacy and health-related quality of life after myocardial infarction.

Introduction: So far, health literacy (HL) and its related factors in patients with acute myocardial infarction received little attention. Thus, the objective of this study was to investigate the associations between the different dimensions of HL and disease-specific health-related quality of life (HRQOL), and factors that may affect these relations in patients after acute myocardial infarction (AMI). Methods: All survivors of AMI between June 2020 and September 2021, from the Myocardial Infarction Registry Augsburg (n=882) received a postal questionnaire on HL [Health Literacy Questionnaire (HLQ)], HRQOL (MacNew Heart Disease HRQOL questionnaire) and depression (Patient Health Questionnaire). From the 592 respondents, 546 could be included in the analysis. Multivariable linear regression models were performed to investigate the associations between the nine subscales of the HLQ and the total score and three subscales of the MacNew questionnaire. A mediation analysis was performed to estimate direct and indirect effects of HL on HRQOL taking into account the mediating effect of depression. Results: In the sample of 546 patients (72.5% male, mean age 68.5 ± 12.2 years), patients with poor education showed significantly lower HLQ scores. Significant associations between the subscales of the HLQ and the MacNew were found, which remained significant after adjustment for sociodemographic variables with few exceptions. More than 50% of the association between HL and HRQOL was mediated by depression in seven HLQ subscales and a complete mediating effect was found for the HLQ subscales 'Actively managing my health' and 'Appraisal of health information'. Discussion: Depression mediates the associations between HL and disease-specific HRQOL in patients with myocardial infarction.

Do patients with diabetes with new onset acute myocardial infarction present with different symptoms than non-diabetic patients?

Background: The objective of this study was to investigate the differences in presenting symptoms between patients with and without diabetes being diagnosed with an acute myocardial infarction (AMI). Methods: A total of 5,900 patients with a first-time AMI were included into the analysis. All patients aged between 25 and 84 years were recorded by the population-based Myocardial Infarction Registry in Augsburg, Germany, between 2010 and 2017. The presence (yes/no) of 12 AMI typical symptoms during the acute event was assessed within the scope of a face-to-face interview. Multivariable adjusted logistic regression models were calculated to analyze the associations between presenting symptoms and diabetes mellitus in AMI patients. Results: Patients with diabetes had significantly less frequent typical pain symptoms, including typical chest pain. Also, other symptoms like sweating, vomiting/nausea, dizziness/vertigo and fear of death/feeling of annihilation occurred significantly more likely in non-diabetic patients. The only exception was the symptom of shortness of breath, which was found significantly more often in patients with diabetes. In multivariable-adjusted regression models, however, the observed effects were attenuated. In patients younger than 55 years, the associations between diabetes and various symptoms were mainly missing. Conclusions: Type 2 diabetes mellitus is a risk factor not only for the development of AMI, but is also associated with an adverse outcome after AMI. Atypical clinical presentation additionally complicates the diagnostic process. It is therefore essential for physicians to be aware of the more often atypical symptoms that diabetic AMI patients report.

Increase of Cardiac Autoantibodies Against Beta-2-adrenergic Receptor During Acute Cellular Heart Transplant Rejection.

BACKGROUND: Acute cellular rejection (ACR) in heart transplant (HTx) recipients may be accompanied by cardiac cell damage with subsequent exposure to cardiac autoantigens and the production of cardiac autoantibodies (aABs). This study aimed to evaluate a peptide array screening approach for cardiac aABs in HTx recipients during ACR (ACR-HTx). METHODS: In this retrospective single-center observational study, sera from 37 HTx recipients, as well as age and sex-matched healthy subjects were screened for a total of 130 cardiac aABs of partially overlapping peptide sequences directed against structural proteins using a peptide array approach. RESULTS: In ACR-HTx, troponin I (TnI) serum levels were found to be elevated. Here, we could identify aABs against beta-2-adrenergic receptor (ß-2AR: EAINCYANETCCDFFTNQAY) to be upregulated in ACR-HTx (intensities: 0.80 versus 1.31, P = 0.0413). Likewise, patients positive for ß-2AR aABs showed higher TnI serum levels during ACR compared with aAB negative patients (10.0 versus 30.0 ng/L, P = 0.0375). Surprisingly, aABs against a sequence of troponin I (TnI: QKIFDLRGKFKRPTLRRV) were found to be downregulated in ACR-HTx (intensities: 3.49 versus 1.13, P = 0.0025). A comparison in healthy subjects showed the same TnI sequence to be upregulated in non-ACR-HTx (intensities: 2.19 versus 3.49, P = 0.0205), whereas the majority of aABs were suppressed in non-ACR-HTx. CONCLUSIONS: Our study served as a feasibility analysis for a peptide array screening approach in HTx recipients during ACR and identified 2 different regulated aABs in ACR-HTx. Hence, further multicenter studies are needed to evaluate the prognostic implications of aAB testing and diagnostic or therapeutic consequences.

Association Between Acute Myocardial Infarction Symptoms and Short- and Long-term Mortality After the Event.

BACKGROUND: In this study, we investigated various acute myocardial infarction (AMI) symptoms and their associations with short-term (28 day) and long-term mortality. METHODS: The analysis was based on 5900 patients, aged 25 to 84 years, with first-time AMI recorded by the population-based Myocardial Infarction Registry Augsburg between 2010 and 2017. Median follow-up time was 3.8 years (interquartile range: 1.1-6.3). As part of a face-to-face interview, the presence (yes/no) of 11 most common AMI symptoms at the acute event was assessed. Using multivariable-adjusted logistic regression and Cox regression models, the association between various symptoms and all-cause mortality was investigated. P values of the regression models were false discovery rate adjusted. RESULTS: Pain in various body parts (chest pain, left and right shoulder/arm/hand, between shoulder blades), sweating, nausea/vomiting, dizziness and fear of death/feeling of annihilation were significantly associated with a decreased 28-day mortality after AMI. The pain symptoms and sweating were also significantly associated with a decreased long-term mortality. Shortness of breath was significantly associated with a higher long-term mortality. CONCLUSIONS: The absence of several symptoms, including typical chest discomfort (chest pain or retrosternal pressure/tightness), is associated with unfavourable outcomes after AMI. This finding has implications for patient management and public health measures designed to encourage appropriate and prompt medical consultation of patients with atypical AMI symptoms.

Reticulated Platelets Predict Cardiovascular Death and Adverse Events in Coronary Artery Disease: A Systematic Review and Meta-analysis.

BACKGROUND: The pro-thrombotic immature or reticulated platelets (RPs) are known to be elevated in high-risk patients and in different pathological settings. It has been shown that RPs correlate with an insufficient antiplatelet response to antiplatelet agents. RPs are emerging novel predictors of adverse cardiovascular events in cardiovascular disease. This study, using the totality of existing evidence, evaluated the prognostic role of RPs in patients with coronary artery disease. METHODS: We performed a systematic review and meta-analysis including trials of acute and chronic coronary syndrome reporting clinical outcomes according to RPs levels in the peripheral blood. We compared patients with elevated RPs (RPshigh) to patients without elevated RPs (RPslow). Odds ratios (ORs) and 95% CIs were used as metric of choice for treatment effects with random-effects models. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE). Secondary endpoints were cardiovascular death, myocardial infarction, ischemic stroke, urgent coronary revascularization and bleedings. RESULTS: A total of 7 studies, including 2213 patients, were included. The risk for MACCE was significantly higher in RPshigh compared to RPslow patients (OR 2.67 [1.87; 3.81], I2 = 43.8%). RPshigh were associated with cardiovascular death (OR 2.09 [1.36; 3.22], I2 = 40.4%). No associations for RPshigh were detected with the other singular components of MACCE: myocardial infarction (OR 1.73 [0.89; 3.38] I2 = 60.5%) and stroke (OR 1.72 [0.59; 4.96] I2 = 21%). The risk of bleeding did not differ between groups(OR 0.58 [0.15; 2.22] I2 = 86.1%). CONCLUSION: Elevated RPs are significantly associated with increased risk of cardiovascular events and cardiovascular death.