Urokinase versus Alteplase in Patients with Intermediate–High-Risk Pulmonary Embolism Treated with Ultrasound-Accelerated Endovascular Thrombolysis

Background. Ultrasound-accelerated thrombolysis (USAT) is a safe and effective treatment for patients with intermediate–high-risk pulmonary embolism (PE). In all studies investigating USAT in the setting of PE, the recombinant tissue-plasminogen activator (rt-PA) alteplase or actilyse was used. Currently, there is a shortage of alteplase (Alteplase, Boehringer Ingelheim) in Europe. It is unknown whether the efficacy of urokinase (UK) is comparable with alteplase for USAT in patients with PE. Methods. Patients with intermediate–high-risk PE undergoing USAT with urokinase and alteplase were included in this study. One-to-one nearest neighbour matching was performed to account for baseline differences. We identified one patient treated with USAT and UK (n = 9) for each patient treated with USAT and alteplase (n = 9). Results. A total of 56 patients underwent USAT. The treatment was successful in all patients. The propensity score matched the identified nine pairs of patients. There were no statistically significant differences in the change in right ventricle-to-left ventricle (RV/LV) ratio (0.4 ± 0.3 versus 0.5 ± 0.4, p = 0.54), systolic pulmonary artery pressure (17.3 ± 8.0 versus 18.1 ± 8.1, p = 0.17), or improvement of RV function (5.8 ± 3.8 versus 5.1 ± 2.6, p = 1.0). The complication rates were comparable (11% in both groups, p = 0.55). There were no deaths in hospital or during 90 days in either group. Conclusions. In this case-matched comparison, the short-term clinical and echocardiographic outcomes showed comparable results between USAT–UK and USAT–rt-PA

Tailored antiplatelet therapy can overcome clopidogrel and aspirin resistance - The BOchum CLopidogrel and Aspirin Plan (BOCLA-Plan) to improve antiplatelet therapy

<p>Abstract</p> <p>Background</p> <p>Dual antiplatelet therapy using acetylsalicylic acid (ASA, aspirin) and clopidogrel is of great importance following coronary stenting. However, the variable platelet inhibitory effectiveness compromises the antithrombotic advantages provided by dual antiplatelet therapy. The aim of this single-center prospective study was to reduce the low response incidence of dual antiplatelet therapy with ASA and clopidogrel according to a prespecified therapy algorithm.</p> <p>Methods</p> <p>Platelet function testing using whole blood aggregometry (Chronolog 590) was performed 48 hours following coronary stenting (for either acute coronary syndromes or stable coronary artery disease) on 504 patients. The antiplatelet therapy included a loading dose of 600 mg clopidogrel and 500 mg ASA, followed by 75 mg clopidogrel and 100 mg ASA once daily. Clopidogrel low responders (CLR: >5 ohm; adenosine diphosphate (ADP) 5 μM) and/or ASA low responders (ALR: >0 ohm; arachidonic acid 10 μM) were treated according to a structured therapy plan: in the case of CLR, the maintenance + dose was doubled (repeated loading dose followed by 150 mg daily), and when still ineffective ticlopidine or prasugrel, if available and not contraindicated, were used. ALR was treated by increasing the dose to 300 mg in a first step or to 500 mg ASA when the first modification did not take effect sufficiently. In addition, ADP receptor antagonist 2-methylthioadenosine 5'-monophosphate triethylammonium salt (MeSAMP) testing and ASA incubation were performed to rule out either a platelet ADP-receptor defect or an ASA pharmacokinetic resistance.</p> <p>Results</p> <p>Of the total cohort of 504 patients, we detected 30.8% clopidogrel low-responders and 19.4% aspirin low-responders. For ALR, with a dose adjustment of 300 mg ASA daily, 94.6% of ALR were effectively treated and the residual 5.4% by administration of daily dosages of 500 mg ASA. This means that after modification of the ASA maintenance dose, all initial ALRs had an adequate antiplatelet response.</p> <p>The results for clopidogrel revealed that 69% of the CLR were treated effectively by increasing the clopidogrel dose to 150 mg daily. When prasugrel was not available or contraindicated, 12.7% of the remaining low responders showed an adequate result after being switched to ticlopidine. Consequently, by applying the therapy algorithm, we were able to reduce the CLR prevalence by 86.6%. On including prasugrel in the therapy plan, we were finally able to eliminate thienopyridine low response. In addition, no ADP receptor defect was found in this study as a potential reason for CLR.</p> <p>We identified the following factors associated with both CLR and ALR status: acute coronary syndromes, positive troponin values as well as diabetes mellitus and elevated HbA_1Cvalues and a higher platelet count. Furthermore, our data revealed for CLR elevated C-reactive protein values and a high PREDICT-score (including an age >65 years, acute coronary syndrome, diabetes mellitus, renal failure, and reduced left ventricular function) as risk factors. The following factors correlated with the risk of ASA low response: patients with elevated hemoglobin, serum creatinine and C-reactive protein values. In addition, medication with nitrates reduced the risk of being CLR. As also holds true for CLR, we found the PREDICT-score to be correlated to the risk of being ALR. However, by far the strongest risk factor for CLR or ALR was the fact of dual resistance.</p> <p>Conclusion</p> <p>Following a structured therapy plan based on a "test and treat" strategy, the prevalence of clopidogrel or aspirin low response can be significantly reduced and the risk of inadequate dual antiplatelet therapy minimized.</p> <p>Trial Registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01212302">NCT01212302</a> (Clinicaltrials.gov)</p

A randomized comparison of 5 versus 12 hours per day of cardiac contractility modulation treatment for heart failure patients: A preliminary report

Background: Cardiac contractility modulation (CCM) signals are non-excitatory electrical signals delivered during the absolute refractory period intended to improve contraction and cardiac function. Clinical trials have shown that CCM treatment significantly improves exercise tolerance and quality of life in symptomatic heart failure patients. Studies with CCM therapy typically include CCM delivery for 3, 5 or 7 h per day, although other configurations are also commonly used. Each has been associated with improved outcomes in heart failure, but it is not clear whether different application durations are associated with the various degrees of benefit. The purpose of the current pilot evaluation study was to evaluate the quality of life, exercise tolerance, and cardiac function, over a 6-month period when CCM was delivered for 5 h/day vs. 12 h/day. Increasing the daily CCM therapy duration is safe and as good as the standard CCM periods of application per day. Methods: This single center pilot evaluation study involved 19 medically refractory symptomatic patients with heart failure and reduced left ventricular function who underwent implantation of an Optimizer™ system (Impulse Dynamics, Orangeburg, NY, USA). Patients were randomized into one of two treatment groups; 5 h/day CCM treatment or 12 h/day CCM treatment. Subjects and evaluating physicians were blinded to the study group. Subjects returned to the hospital after 12 and 24 weeks. Efficacy evaluations included changes from baseline to 24 weeks in Minnesota Living With Heart Failure Questionnaire score (MLWHFQ), maximal oxygen consumption in the cardio-pulmonary stress test (peak VO2), New York Heart Association classification (NYHA), 6-min walk distance (6MWD), and ejection fraction (EF). Results: At the end of 24 weeks, clinical improvement was observed in the entire cohort in all efficacy measures (mean change from baseline of –17.1 in MLWHFQ, –0.86 in NYHA, and improvement trend of 1.48 mL O2/kg/min in peak VO2, 31.3 m in 6MWD, and 2.25% in EF). There were no significant differences, either clinically or statistically, between the groups receiving CCM for 5 h/day vs. 12 h/day. Three subjects were voluntarily withdrawn before completing the study. One subject died from pneumonia after 125 days, and 6 serious adverse events were reported, none of which was classified as related to either the device or the procedure. Conclusions: Together with previously reported experience with CCM, delivery of CCM therapy is equally safe and appears similarly effective over the range of shorter (5 h) to longer (12 h) daily periods of application. Given the small sample size, further studies are warranted.

713-4 Inhibition of Vascular Superoxide Production in Hypercholesterolemic Rabbit Aorta by L-Arginine Contributes to Restored Endothelium-dependent Relaxation

Chronic oral administration of L-arginine (L-ARG) has been shown to enhance endothelial function in cholesterol (CHOL)-fed rabbits and to reduce atherogenesis. We investigated whether modulation of endogenous NO production (as assessed by urinary NO3-excretion) by L-ARG and the inhibitor of NO synthesis, L-NAME, affects vascular superoxide (O2-) production in hypercholesterolemic rabbits. Phorbol-myristate-acetate (PMA)-stimulated O2-production from isolated aortic rings was increased in rabbits given CHOL (+159±28%) or CHOL + L-NAME (+149±37%) as compared to controls (-22±7%), and endothelium-dependent relaxations by acetylcholine were diminished in both groups. In aortic rings from rabbits given CHOL + L-ARG, PMA-induced O2-production was restored to control levels (+14±17%; p&lt;0.05), and endothelium-dependent cholinergic relaxations were also partly restored. Urinary NO3-excretion decreased in all animals fed a CHOL-enriched diet (p&lt;0.01). As NO inactivated by O2-is also oxidized to NO3-, this indicates a decreased endothelial production of NO. NO3-excretion was further decreased by L-NAME (p&lt;0.05 vs. CHOL), and partly restored by L-ARG (p&lt;0.05). We conclude that both a decreased production of NO and an enhanced breakdown of NO by O2-contribute to the diminished biological activity of endothelial NO in hypercholesterolemia. L-ARG restores endothelial function by enhancing NO formation and by protecting NO from early breakdown by O2-

a prospective cohort study

Background The effects of target temperature management (TTM) on the heart aren’t thoroughly studied yet. Several studies showed the prolongation of various ECG parameters including Tpeak-Tend-time under TTM. Our study’s goal is to evaluate the acute and long-term outcome of these prolongations. Methods In this study we included patients with successful resuscitation after cardiac arrest who were admitted to the Charité Virchow Klinikum Berlin or the Heart and Vascular Centre of the Ruhr University Bochum between February 2006 and July 2013 (Berlin) or May 2014 to November 2015 (Bochum). For analysis, one ECG during TTM was recorded after reaching the target temperature (33–34 °C) or in the first 6 h of TTM. If possible, another ECG was taken after TTM. The patients were being followed until February 2016. Primary endpoint was ventricular arrhythmia during TTM, secondary endpoints were death and hospitalization due to cardiovascular diseases during follow-up. Results One hundred fifty-eight patients were successfully resuscitated in the study period of which 95 patients had usable data (e.g. ECGs without artifacts). During TTM significant changes for different parameters of ventricular de- and repolarization were noted: QRS (103.2 ± 23.7 vs. 95.3 ± 18.1; p = 0.003),QT (405.8 ± 76.4 vs. 373.8 ± 75.0; p = 0.01), QTc (474.9 ± 59.7 vs. 431.0 ± 56.8; p < 0.001), JT (302.8 ± 69.4 vs. 278.5 ± 75.2; p = 0.043), JTc (354.3 ± 60.2 vs. 318.7 ± 59.1; p = 0.001). 13.7% of the patients had ventricular arrhythmias during TTM, however these patients showed no difference regarding their ECG parameters in comparison to those were no ventricular arrhythmias occurred. We were able to follow 69 Patients over an average period of 35 ± 31 months. The 14 (21.5%) patients who died during the follow-up had significant prolongations of the TpTe-time in the ECGs without TTM (103.9 ± 47.2 vs. 75.8 ± 28.6; p = 0.023). Conclusion Our results show a significant prolongation of ventricular repolarization during TH. However, there was no significant difference between the ECG parameters of those who developed a ventricular arrhythmia and those who did not. The temporary prolongation of the repolarization during TTM seems to be less important for the prognosis of the patient. Whereas the prolongation of the repolarization in the basal ECG is associated with a higher mortality in our study

Cardiomyopathies in Children: Genetics, Pathomechanisms and Therapeutic Strategies

Despite great advances in cardiovascular medicine, cardiomyopathies in children still are challenging for pediatricians as well as cardiologists. Pediatric cardiomyopathies can manifest in diverse phenotypes but are often life-threatening and have a poor prognosis. However, many therapeutic options available for adult patients do not apply for children, leaving a very limited portfolio to attenuate disease progression to avoid or postpone heart transplantation. Childhood cardiomyopathies can arise from different etiologies, but genetic defects such as mutations, for example, in sarcomeric proteins, which are pivotal for the contractile function, are common. This leads to the demand to identify new variants found by genetic screening as pathogenic and furthermore to allow a prognosis or risk assessment for related carriers, thus increasing the need to uncover molecular pathomechanisms of such mutations. This chapter aims to highlight the unique characteristics of pediatric cardiomyopathies in contrast to adult forms, including etiology, pathophysiology, genetics, as well as molecular mechanisms. We will also tackle currents options, challenges, and perspectives in diagnosis and treatment of pediatric cardiomyopathies

Oxidative stress and inflammation distinctly drive molecular mechanisms of diastolic dysfunction and remodeling in female and male heart failure with preserved ejection fraction rats

Heart failure with preserved ejection fraction (HFpEF) is a complex cardiovascular insufficiency syndrome presenting with an ejection fraction (EF) of greater than 50% along with different proinflammatory and metabolic co-morbidities. Despite previous work provided key insights into our understanding of HFpEF, effective treatments are still limited. In the current study we attempted to unravel the molecular basis of sex-dependent differences in HFpEF pathology. We analyzed left ventricular samples from 1-year-old female and male transgenic (TG) rats homozygous for the rat Ren-2 renin gene (mRen2) characterized with hypertension and diastolic dysfunction and compared it to age-matched female and male wild type rats (WT) served as control. Cardiomyocytes from female and male TG rats exhibited an elevated titin-based stiffness (Fpassive), which was corrected to control level upon treatment with reduced glutathione indicating titin oxidation. This was accompanied with high levels of oxidative stress in TG rats with more prominent effects in female group. In vitro supplementation with heat shock proteins (HSPs) reversed the elevated Fpassive indicating restoration of their cytoprotective function. Furthermore, the TG group exhibited high levels of proinflammatory cytokines with significant alterations in apoptotic and autophagy pathways in both sexes. Distinct alterations in the expression of several proteins between both sexes suggest their differential impact on disease development and necessitate distinct treatment options. Hence, our data suggested that oxidative stress and inflammation distinctly drive diastolic dysfunction and remodeling in female and male rats with HFpEF and that the sex-dependent mechanisms contribute to HF pathology

Modulation of Titin-Based Stiffness in Hypertrophic Cardiomyopathy via Protein Kinase D

L