Coronary plaque volume and predictors for fast plaque progression assessed by serial coronary CT angiography-A single-center observational study.

PURPOSE: The rationale of this study was to identify patients with fast progression of coronary plaque volume PV and characterize changes in PV and plaque components over time. METHOD: Total PV (TPV) was measured in 350 patients undergoing serial coronary computed tomography angiography (median scan interval 3.6 years) using semi-automated software. Plaque morphology was assessed based on attenuation values and stratified into calcified, fibrous, fibrous-fatty and low-attenuation PV for volumetric measurements. Every plaque was additionally classified as either calcified, partially calcified or non-calcified. RESULTS: In total, 812 and 955 plaques were detected in the first and second scan. Mean TPV increase was 20 % on a per-patient base (51.3 mm³ [interquartile range (IQR): 14.4, 126.7] vs. 61.6 mm³ [IQR: 16.7, 170.0]). TPV increase was driven by calcified PV (first scan: 7.6 mm³ [IQR: 0.2, 33.6] vs. second scan: 16.6 mm³ [IQR: 1.8, 62.1], p < 0.01). Forty-two patients showed fast progression of TPV, defined as >1.3 mm3 increase of TPV per month. Male sex (odds ratio 3.1, p = 0.02) and typical angina (odds ratio 3.95, p = 0.03) were identified as risk factors for fast TPV progression, while high-density lipoprotein cholesterol had a protective effect (odds ratio per 10 mg/dl increase of HDL cholesterol: 0.72, p < 0.01). Progression to >50 % stenosis at follow-up was observed in 34 of 327 (10.4 %) calcified plaques, in 13 of 401 (3.2 %) partially calcified plaques and 2 of 221 (0.9 %) non-calcified plaques (p < 0.01). CONCLUSION: Fast plaque progression was observed in male patients and patients with typical angina. High HDL cholesterol showed a protective effect.

Integrin ß1 polymorphisms and bleeding risk after coronary artery stenting.

Bleeding complications following percutaneous coronary intervention associate with increased mortality. However, the underlying molecular mechanisms are insufficiently understood. Platelet recruitment and activation at sites of vascular injury depends on the function of integrin adhesion receptors. Besides GPIIbIIIa as the most abundant integrin receptor, platelets relevantly express ß1 integrins. Experimental evidence from in vivo studies suggests a significant role of ß1 integrins in primary haemostasis. However, little is known about the clinical impact of genetic alterations of the ß1 subunit, which might contribute to bleeding complications in patients. In this study, we performed DNA sequencing of patients suffering from bleeding complications after coronary artery stenting according to TIMI or BARC classification. We isolated DNA samples from 741 patients out of a cohort from 14,160 patients recruited in seven randomized clinical trials between June 2000 and May 2011. Subsequently, Sanger sequencing was performed covering the ß1 integrin cytoplasmic activation domain (exon16) and its non-coding upstream region. Out of 764 patients suffering from bleeding complications, 741 DNA samples were successfully sequenced. Genotype variation was detected for SNP rs2153875 located within the non-coding upstream region with following allele frequency in study population: CC (7.3%), CA (35%) and AA (57.8%), which is similar to a general population cohort. Further, genotype variation in SNP rs2153875 do not associate with the frequency of TIMI or BARC classified access or non-access site bleedings. Genotype variations of the ß1 integrin activation domain do not associate with bleeding risk after PCI.

Author Correction: Yolk sac macrophage progenitors traffic to the embryo during defined stages of development.

This article contains errors in Figs. 5 and 6, for which we apologize. In Fig. 5f, the image 'E12.5 tail' was inadvertently replaced with a duplicate of the image 'E12.5 trunk' from the same panel. In Figure 6d, the image 'E9.5/OH-TAM E8.5, embryo' was inadvertently replaced with a duplicate of the image 'E10.5/ OH-TAM E8.5, embryo' from Fig. 6b. The corrected versions of these figures appear in the Author Correction associated with this Article.

Inducible disruption of the c-myb gene allows allogeneic bone marrow transplantation without irradiation.

Allogeneic bone marrow (BM) transplantation enables the in vivo functional assessment of hematopoietic cells. As pre-conditioning, ionizing radiation is commonly applied to induce BM depletion, however, it exerts adverse effects on the animal and can limit experimental outcome. Here, we provide an alternative method that harnesses conditional gene deletion to ablate c-myb and thereby deplete BM cells, hence allowing BM substitution without other pre-conditioning. The protocol results in a high level of blood chimerism after allogeneic BM transplantation, whereas immune cells in peripheral tissues such as resident macrophages are not replaced. Further, mice featuring a low chimerism after initial transplantation can undergo a second induction cycle for efficient deletion of residual BM cells without the necessity to re-apply donor cells. In summary, we present an effective c-myb-dependent genetic technique to generate BM chimeras in the absence of irradiation or other methods for pre-conditioning.

Quantification of coronary low-attenuation plaque volume for long-term prediction of cardiac events and reclassification of patients.

BACKGROUND: To investigate the incremental prognostic value of low-attenuation plaque volume (LAPV) from coronary CT angiography datasets. METHODS: Quantification of LAPV was performed using dedicated software equipped with an adaptive plaque tissue algorithm in 1577 patients with suspected CAD. A combination of death and acute coronary syndrome was defined as primary endpoint. To assess the incremental prognostic value of LAPV, parameters were added to a baseline model including clinical risk and obstructive coronary artery disease (CAD), a baseline model including clinical risk and calcium scoring (CACS) and a baseline model including clinical risk and segment involvement score (SIS). RESULTS: Patients were followed for 5.5 years either by telephone contact, mail or clinical visits. The primary endpoint occurred in 30 patients. Quantified LAPV provided incremental prognostic information beyond clinical risk and obstructive CAD (c-index 0.701 vs. 0.767, p < .001), clinical risk and CACS (c-index 0.722 vs. 0.771, p < .01) and clinical risk and SIS (c-index 0.735 vs. 0.771, p < .01. A combined approach using quantified LAPV and clinical risk significantly improved the stratification of patients into different risk categories compared to clinical risk alone (categorical net reclassification index 0.69 with 95% CI 0.27 and 0.96, p < .001). The combined approach classified 846 (53.6%) patients as low risk (annual event rate 0.04%), 439 (27.8%) patients as intermediate risk (annual event rate 0.5%) and 292 (18.5%) patients as high risk (annual event rate 0.99%). CONCLUSION: Quantification of LAPV provides incremental prognostic information beyond established CT risk patterns and permits improved stratification of patients into different risk categories.

Yolk sac macrophage progenitors traffic to the embryo during defined stages of development.

Tissue macrophages in many adult organs originate from yolk sac (YS) progenitors, which invade the developing embryo and persist by means of local self-renewal. However, the route and characteristics of YS macrophage trafficking during embryogenesis are incompletely understood. Here we show the early migration dynamics of YS-derived macrophage progenitors in vivo using fate mapping and intravital microscopy. From embryonic day 8.5 (E8.5) CX3CR1+ pre-macrophages are present in the mouse YS where they rapidly proliferate and gain access to the bloodstream to migrate towards the embryo. Trafficking of pre-macrophages and their progenitors from the YS to tissues peaks around E10.5, dramatically decreases towards E12.5 and is no longer evident from E14.5 onwards. Thus, YS progenitors use the vascular system during a restricted time window of embryogenesis to invade the growing fetus. These findings close an important gap in our understanding of the development of the innate immune system.

[Anticoagulation in patients with chronic kidney disease : Recommendations from the working group "Heart-Kidney" of the German Cardiac Society and the German Society of Nephrology]. / Antikoagulation bei Patienten mit chronischer Niereninsuffizienz : Empfehlungen der Arbeitsgemeinschaft "Herz ­ Niere" der Deutschen Gesellschaft für Kardiologie ­ Herz- und Kreislaufforschung und der Deutschen Gesellschaft für Nephrologie.

Indications for anticoagulation are thromboembolic events, prosthetic heart valves, and atrial fibrillation with a corresponding risk score. Clinical trials have excluded patients with advanced chronic kidney disease and these data cannot be always generalized to patients with chronic kidney disease. Non-vitamin K antagonist oral anticoagulants (NOACs) are mostly not recommended or are contraindicated in advanced stages of chronic kidney disease. Observational studies have shown that dialysis patients with atrial fibrillation do not profit from coumarin anticoagulants; prospective studies are lacking.

Retrospective analysis of circulatory support with the Impella CP® device in patients with therapy refractory cardiogenic shock.

BACKGROUND: In cardiogenic shock (CS) the Impella CP® device provides a fast available left ventricular circulatory support of up to 4.0L/min. However, the use of the Impella CP® device was not systematically analysed yet. METHODS: We performed a retrospective analysis of 28 consecutive patients suffering from severe therapy refractory CS treated with Impella CP®. Mortality was estimated using the SAPS II-Score. Primary outcome was 30-day survival. We compared the different aetiologies of CS and the effect of additional extracorporeal life support (ECLS). RESULTS: Aetiology of CS was acute coronary syndrome (ACS) in 15 patients, 9 patients received additional therapy with ECLS. SAPS II was 73±14, representing an estimated mortality of 87.1%. 18 patients deceased representing a 30-day survival of 36%. Comparing the different aetiologies, ACS-CS patients show a trend towards better survival. Additional therapy with ECLS did not change 30-day survival. In 3 cases, vascular complication needing surgical treatment occurred. All other patients showed no relevant complications except for the commonly seen haemolysis with consecutive need of transfusion. CONCLUSION: Our data could demonstrate that the Impella CP® application in these severely diseased patients is feasible and safe. Compared to the estimated mortality, the 30-day survival seems to be improved.

Established interventions for mitral valve regurgitation. Current evidence.

Severe mitral regurgitation (MR) is a growing medical challenge in today's aging population, leading to increased health expenditure due to the resultant morbidity and mortality. Surgery, either replacement or repair, has been the mainstay of therapy for primary MR. In high-risk or inoperable patients, treatment was limited to medical therapy until 2008. Since then, alternative percutaneous therapies have been introduced and have proven to be safe and effective in patients with secondary MR. Edge-to-edge repair with the MitraClip system is applied worldwide for primary and secondary MR. Randomized data do not support its application in low-risk patients with primary MR. Results from ongoing and future randomized trials will clarify its impact on important clinical endpoints in high-risk and inoperable patients. The Carillon device is a percutaneous indirect annuloplasty technique introduced in 2009 for secondary MR. Clinical data for the novel Cardioband system, using a different intra-atrial annuloplasty technique, have been gathered from more than 40 patients and the system recently received CE mark approval. Other percutaneous repair devices and implantable valves are under development and may be introduced into clinical practice soon. The percutaneous interventional therapy of MR is a highly dynamic field of cardiovascular medicine and has the potential to improve quality of life as well as morbidity and mortality in selected patients.

A single German center experience with intermittent inotropes for patients on the high-urgent heart transplant waiting list.

AIM: Currently, more than 900 patients with end-stage heart failure are listed for heart transplantation in Germany. All patients on the Eurotransplant high-urgent status (HU) have to be treated in intensive care units and have to be relisted every 8 weeks. Long-term continuous inotropes are associated with tachyphylaxia, arrhythmias and even increased mortality. In this retrospective analysis, we report our single center experience with HU patients treated with intermittent inotropes as a bridging therapy. METHODS AND RESULTS: 117 consecutive adult HU candidates were treated at our intensive care heart failure unit between 2008 and 2013, of whom 14 patients (12 %) were stabilized and delisted during follow-up. In the remaining 103 patients (age 42 ± 15 years), different inotropes (dobutamine, milrinone, adrenaline, noradrenaline, levosimendan) were administered based on the patient's specific characteristics. After initial recompensation, patients were weaned from inotropes as soon as possible. Thereafter, intermittent inotropes (over 3-4 days) were given as a predefined weekly (until 2011) or 8 weekly regimen (from 2011 to 2013). In 57 % of these patients, additional regimen-independent inotropic support was necessary due to hemodynamic instabilities. Fourteen patients (14 %) needed a left- or biventricular assist device; 14 patients (14 %) died while waiting and 87 (84 %) received heart transplants after 87 ± 91 days. Cumulative 3 and 12 months survival of all 103 patients was 75 and 67 %, respectively. CONCLUSION: Intermittent inotropes in HU patients are an adequate strategy as a bridge to transplant; the necessity for assist devices was low. These data provide the basis for a prospective multicenter trial of intermittent inotropes in patients on the HU waiting list.

Significant aortic regurgitation after transfemoral aortic valve implantation: patients' gender as independent risk factor.

AIM: Significant aortic regurgitation (AR) has been reported in 20% of patients undergoing transfemoral aortic valve implantation (TAVI) and has been associated with increased mortality. Depending on the population included and the type of implanted prosthesis, several anatomical and procedural factors have been linked with increased risk of post-TAVI AR. While the impact of patients' gender on this complication, is still contradictory. We sought to assess the impact of patients' gender on the risk of significant AR after TAVI. METHODS: We included 323 consecutive patients (136 men) who underwent transfemoral implantation of either self-expandable or balloon-expandable prostheses for treatment of symptomatic aortic stenosis. RESULTS: After TAVI 52 patients (16.1%) had AR grade ≥ 2/4 as evaluated by angiography. They were more frequently male (59.6% vs. 40.4%, P = 0.005), received self-expandable (94.2% vs. 63.5%, P < 0.001) and bigger size prostheses (28 ± 1.9 vs. 27.3 ± 2.1 mm, P = 0.028) and had reduced left ventricular ejection fraction (45.3% ± 14.2% vs. 51.2% ± 13%, P = 0.003) compared to patients with AR grade < 2/4 (N. = 271). In multivariate analysis, men (OR 2.13 [95% CI, 1.08-4.18]) and prosthesis type (OR 13.17 [95% CI, 3.24-57.97]) were identified as independent predictors of AR grade ≥ 2/4. CONCLUSION: Alongside with the implantation of self-expandable aortic prosthesis, male gender independently increases the risk of significant AR in patients undergoing TAVI. The question if this finding is related to gender biology itself or to gender-related aggregation of subtle anatomic characteristics needs further investigations.

Prasugrel vs clopidogrel in cardiogenic shock patients undergoing primary PCI for acute myocardial infarction. Results of the ISAR-SHOCK registry.

There is limited clinical data comparing different P2Y12-receptor inhibitors in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock. The aim of the ISAR-SHOCK registry was to compare the clinical outcome of patients treated with clopidogrel vs prasugrel in this setting. Patients (n=145) with AMI complicated by cardiogenic shock and undergoing primary PCI in two centres (Deutsches Herzzentrum München and Klinikum rechts der Isar, Technical University Munich) between January 2009 and May 2012 were included in this registry. The use of prasugrel for patients within this registry reflected co-morbidities and platelet function testing results during the acute AMI phase. Early outcome at 30-days was reported with regard to all-cause mortality, myocardial infarction (MI), stent thrombosis (ST) and bleeding events. With regard to antiplatelet treatment in the 145 cardiogenic shock patients, 50 patients were initially treated or immediately switched to prasugrel while 95 patients were treated with clopidogrel. All-cause mortality was lower in prasugrel- vs clopidogrel-treated patients (30 % vs 50.5%, HR: 0.51, 95% CI [0.29-0.92], p=0.025). No significant differences in prasugrel- vs clopidogrel-treated patients were observed for the occurrence of MI (p=0.233), ST (p=0.306) or TIMI major bleedings (p=0.571). Results of the ISAR-SHOCK registry suggest that the use of prasugrel in AMI patients complicated by cardiogenic shock might be associated with a lower mortality risk as compared to clopidogrel therapy without increasing the risk of bleeding. These findings, however, need confirmation from specifically designed randomised studies in this high-risk cohort of patients.

Contrast-induced acute kidney injury after computed tomography prior to transcatheter aortic valve implantation.

AIM: To identify independent predictors of contrast medium-induced acute kidney injury (CI-AKI) after enhanced multidetector-row computed tomography (MDCT) prior to transcatheter aortic valve implantation (TAVI) in high-risk patients. MATERIALS AND METHODS: The present single-centre study analysed retrospectively 361 patients who were assessed using MDCT prior to TAVI. CI-AKI was defined as an increase in serum creatinine (SCr) of ≥ 25% or ≥ 0.5 mg/dl in at least one sample over baseline (24 h before MDCT) and at 24, 48, and 72 h after MDCT. RESULTS: A total of 38 patients (10.5%) experienced CI-AKI. As compared to patients without CI-AKI, they presented more frequently with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2), (81.6% versus 64.4%, p = 0.045) and tended to receive higher volumes of iodinated contrast media (ICM; 55.3% versus 39%, p = 0.057). There was a significant interaction between baseline eGFR and the amount of intravenous ICM administered (pfor interaction = <0.001) identifying the amount of ICM >90 ml as independent predictive factor of CI-AKI only in patients with baseline eGFR <60 ml/min/1.73m(2) (OR 2.615; 95% CI: 1.21-5.64). CONCLUSION: One in ten elderly patients with aortic stenosis undergoing MDCT to plan a TAVI procedure experienced CI-AKI after intravenous ICM injection. Intravenous administration of <90 ml of ICM reduces this risk in patients with or without pre-existing impaired renal function. However, in the majority of patients renal function recovers before the TAVI procedure.

A comparative cohort study on personalised antiplatelet therapy in PCI-treated patients with high on-clopidogrel platelet reactivity. Results of the ISAR-HPR registry.

In clopidogrel-treated patients undergoing percutaneous coronary intervention (PCI), high platelet reactivity (HPR) is associated with a higher risk for thrombotic events including stent thrombosis (ST). A personalised therapy with selective intensification of treatment may improve HPR patients´ outcome in this setting although recent randomised trials are against this hypothesis. The aim of the ISAR-HPR registry was to assess whether clopidogrel-treated HPR patients benefit from selective intensification of P2Y12 receptor inhibition. For the registry, outcomes were compared between two cohorts. We identified 428 clopidogrel treated HPR patients (AU x min ≥468 on the Multiplate analyser) between 2007-2008 (historical control cohort) without a change of treatment based on platelet function (PF) testing results. Between 2009-2011, we identified 571 HPR patients (guided therapy cohort) and used this information for guidance and selective intensification of P2Y12 receptor directed treatment (reloading with clopidogrel, switch to prasugrel, re-testing) in a setting of routine PF testing. The primary outcome was the composite of death from any cause or ST after 30 days. Major bleeding according to TIMI criteria was also monitored. The incidence of the primary outcome was significantly lower in the guided vs the control cohort (7 [1.2%] vs 16 [3.7%] events; HR 0.32, 95% CI 0.13-0.79; p=0.009). The incidence of major bleeding was numerically but not statistically higher in the guided vs the control cohort (1.9 vs 0.7%; p=0.10). In conclusion, present findings are in support for a PF testing guided antiplatelet therapy with selective intensification of P2Y12 receptor inhibition. The issue of personalised antiplatelet treatment warrants further investigation in randomized and well-controlled clinical trials.

[Cardiological diseases]. / Kardiologische Krankheitsbilder.

Knowledge of rare but important clinical disease symptoms in cardiology is of vital importance in the daily routine as severe courses of disease as well as death may be prevented by early diagnosis, effective monitoring and timely initiation of an adequate therapy. In this article an important rhythmological disease, arrhythmogenic right ventricular cardiomyopathy, as well as two significant structural diseases, takotsubo (stress-related) cardiomyopathy and aortic aneurysm related to Marfan syndrome, as well as their implications for clinical practice will be presented.

Crossroads of coagulation and innate immunity: the case of deep vein thrombosis.

Deep vein thrombosis (DVT) is a common condition characterized by the formation of an occlusive blood clot in the venous vascular system, potentially complicated by detachment and embolization of thrombi into the lung. Recent evidence from mouse models has shed light on the sequence of events and on the cellular (innate immune cells, platelets) and molecular (hematopoietic tissue factor, nucleic acids) components involved. In response to decreased blood flow, circulating neutrophils and monocytes adhere to the activated endothelium within hours. They initiate and propagate DVT by interacting with platelets and by the exposure and activation of circulating tissue factor and FXII. Intravascular blood coagulation is also induced by extracellular nucleosomes released mainly from activated neutrophils. Interestingly, these mechanisms are closely linked to an evolutionary conserved immune defense mechanism activated in response to infections. In this review, we will give an overview of DVT and the role of innate immune pathways supporting this process. While the latter are aimed at preserving tissue integrity and function, uncontrolled blood coagulation and activation of immune cells may result in pathological thrombus formation and vascular occlusion. Understanding the molecular and cellular players triggering occlusion of large veins, and their distinction from physiological hemostasis, is important for the development of strategies to prevent and treat DVT.

[Interventional Mitral valve repair with the MitraClip® procedure. Patient selection criteria]. / Interventionelle Mitralklappenrekonstruktion mit dem MitraClip®-Verfahren. Patientenauswahlkriterien.

In current practice the MitraClip® procedure is increasingly being used for patients unsuitable or at high risk for cardiac surgery. This article initially describes the patient groups that are suitable for percutaneous edge-to-edge repair. For this purpose the echocardiographic criteria for severe mitral regurgitation are first characterized and treatment algorithms for patients with primary as well as secondary mitral regurgitation according to current guidelines are illustrated. Basic anatomical requirements for the successful implantation of a MitraClip® are described and a distinction is made between various valve morphologies ranging from optimal to unsuitable anatomical conditions. Finally, three patient groups eligible for percutaneous edge-to-edge repair considering clinical and anatomical criteria are defined: (1) optimal for MitraClip®, (2) MitraClip® could be considered and (3) MitraClip® only in exceptional cases.