Aims
Concomitant cardiac amyloidosis (CA) in severe aortic stenosis (AS) is difficult to recognize, since both conditions are associated with concentric left ventricular thickening. We aimed to ...assess type, frequency, screening parameters, and prognostic implications of CA in AS.
Methods and results
A total of 191 consecutive AS patients (81.2 ± 7.4 years; 50.3% female) scheduled for transcatheter aortic valve replacement (TAVR) were prospectively enrolled. Overall, 81.7% underwent complete assessment including echocardiography with strain analysis, electrocardiography (ECG), cardiac magnetic resonance imaging (CMR), 99mTc‐DPD scintigraphy, serum and urine free light chain measurement, and myocardial biopsy in immunoglobulin light chain (AL)‐CA. Voltage/mass ratio (VMR; Sokolow–Lyon index on ECG/left ventricular mass index) and stroke volume index (SVi) were tested as screening parameters. Receiver operating characteristic curve, binary logistic regression, and Kaplan–Meier curve analyses were performed. CA was found in 8.4% of patients (n = 16); 15 had transthyretin (TTR)‐CA and one AL‐CA. While global longitudinal strain by echo did not reliably differentiate AS from CA‐AS area under the curve (AUC) 0.643, VMR as well as SVi showed good discriminative power (AUC 0.770 and 0.773, respectively), which was comparable to extracellular volume by CMR (AUC 0.756). Also, VMR and SVi were independently associated with CA by multivariate logistic regression analysis (P = 0.016 and P = 0.027, respectively). CA did not significantly affect survival 15.3 ± 7.9 months after TAVR (P = 0.972).
Conclusion
Both TTR‐ and AL‐CA can accompany severe AS. Parameters solely based on ECG and echocardiography allow for the identification of the majority of CA‐AS. In the present cohort, CA did not significantly worsen prognosis 15.3 months after TAVR.
RATIONALE:Mechanisms of coronary occlusion in ST-elevation acute coronary syndrome are poorly understood. We have previously reported that neutrophil (polymorphonuclear cells PMNs) accumulation in ...culprit lesion site (CLS) thrombus is a predictor of cardiovascular outcomes.
OBJECTIVE:The goal of this study was to characterize PMN activation at the CLS. We examined the relationships between CLS neutrophil extracellular traps (NETs), bacterial components as triggers of NETosis, activity of endogenous deoxyribonuclease, ST-segment resolution, and infarct size.
METHODS AND RESULTS:We analyzed coronary thrombectomies from 111 patients with ST-elevation acute coronary syndrome undergoing primary percutaneous coronary intervention. Thrombi were characterized by immunostaining, flow cytometry, bacterial profiling, and immunometric and enzymatic assays. Compared with femoral PMNs, CLS PMNs were highly activated and formed aggregates with platelets. Nucleosomes, double-stranded DNA, neutrophil elastase, myeloperoxidase, and myeloid-related protein 8/14 were increased in CLS plasma, and NETs contributed to the scaffolds of particulate coronary thrombi. Copy numbers of Streptococcus species correlated positively with dsDNA. Thrombus NET burden correlated positively with infarct size and negatively with ST-segment resolution, whereas CLS deoxyribonuclease activity correlated negatively with infarct size and positively with ST-segment resolution. Recombinant deoxyribonuclease accelerated the lysis of coronary thrombi ex vivo.
CONCLUSIONS:PMNs are highly activated in ST-elevation acute coronary syndrome and undergo NETosis at the CLS. Coronary NET burden and deoxyribonuclease activity are predictors of ST-segment resolution and myocardial infarct size.
Background
Premature myocardial infarction (≤40 years) represents a rare disease with a distinct risk factor profile and a lipid phenotype that is characterized by a predominance of elevated ...triglyceride‐rich lipoproteins. So far high‐density and low‐density lipoproteins remain the primary targets for risk stratification and treatment evaluation in coronary artery disease, but this strategy might be insensitive in patients with premature myocardial infarction.
Aim
Aim of this study was to investigate the predictive value of different lipid fractions on long‐term cardiovascular outcome in patients with premature myocardial infarction.
Methods
We prospectively enrolled 102 consecutive AMI survivors (≤40 years) in this prospective multicentre study and investigated the influence of the familial combined hypercholesterolaemia phenotype and a corresponding multimarker panel of different lipid fractions on cardiovascular outcome.
Results
Total cholesterol, non‐HDL cholesterol, remnant cholesterol and Apo B lipoprotein were significantly higher in patients experiencing MACE as compared to those who did not. The familial combined hypercholesterolaemia phenotype was associated with an unfavourable cardiovascular outcome even after adjustment for potential cofounders (adjusted HR 3.04,95% CI, 1.26‐7.34, P = 0.013). Remnant cholesterol revealed the strongest association with MACE (adj.HR 1.94, 95%CI. 1.30‐2.99, P = 0.001). Interestingly LDL and HDL revealed no significant impact on cardiovascular outcome in this study cohort.
Conclusion
Non‐HDL and remnant cholesterol are strongly associated with an unfavourable outcome in patients with premature myocardial infarction and might be the preferred treatment target for lipid‐lowering therapy.
Background
Left ventricular thrombus (LVT) is a rare but dreaded complication during the acute phase of acute coronary syndrome (ACS). However, profound data on long‐term outcome and associated ...antithrombotic treatment strategies of this highly vulnerable patient population are scarce in current literature.
Methods
Patients presenting with ACS were screened for presence of LVT and subsequently included within a prospective clinical registry. All‐cause mortality and the composite of major adverse cardiac events (MACE) and thromboembolic events were defined as primary and secondary endpoint.
Results
Within 43 patients presenting with LVT, thrombus resolution during patient follow‐up was observed in 27 individuals (62.8%). Patients that reached a resolution of LVT experienced lower incidence rates of death (−23.9%; p = .022), MACE (−37.8%; p = .005), and thromboembolic events (−35.2%; p = .008). Even after adjustment for clinical variables, thrombus resolution showed an independent inverse association with all‐cause death with a hazard ratio (HR) of 0.14 (95% CI: 0.03–0.75; p = .021) and as well with MACE with a HR of 0.22 (95% CI: 0.07–0.68; p = .008) and thromboembolic events with a HR of 0.22 (95% CI: 0.06–0.75; p = .015). Triple antithrombotic therapy (TAT) with ticagrelor/prasugrel showed a strong and independent association with thrombus resolution with an adjusted HR of 3.25 (95% CI: 1.22–8.68; p = .019) compared to other strategies.
Conclusion
The presented data indicate a poor outcome of ACS patients experiencing LVT. In terms of a personalized risk stratification, thrombus resolution has a strong protective impact on both all‐cause death and MACE with the potential to tailor treatment decisions—including an intensified antithrombotic treatment approach—in this patient population.
Background
Mitral‐ and tricuspid regurgitation are associated with significant morbidity and mortality and are increasingly treated interventionally. CardioMEMS is a transcutaneously implanted ...pressure sensor placed in the pulmonary artery that allows invasive measurement of pulmonary artery pressure and cardiac output.
Methods
This proof‐of‐concept study aimed to observe hemodynamic changes as determined by CardioMEMS after transcatheter atrioventricular valve interventions, assess the additional value of CardioMEMS on top of echocardiography, and investigate a potential effect of CardioMEMS on outcome. Patients treated with transcatheter mitral‐ or tricuspid valve interventions (mitral: TMVR, tricuspid: TTVR) or bicaval valve implantation (bi‐CAVI) were recruited. All patients were followed for 12 months.
Results
Thirty‐six patients were included (4 with CardioMEMS, 32 controls). Patients with CardioMEMS were monitored prior to intervention and 3–12 months thereafter (one received TMVR, one bi‐CAVI, one both TMVR and TTVR, and one isolated TTVR). CardioMEMS group: In both patients with TMVR and in the patient with bi‐CAVI, mean pulmonary artery pressures decreased (all p < .001) and cardiac output increased significantly (both TMVR p < .001 and bi‐CAVI p = .006) while functional parameters, echocardiography, and NT‐proBNP were difficult to interpret, unreliable, or both. Changes after TTVR remained inconclusive.
Conclusion
Invasive monitoring using CardioMEMS provides important information after mitral‐ and tricuspid valve interventions. Such data pave the way for a deeper understanding of the prerequisites for optimal patient selection and management for catheter‐based interventions.
Mitral and tricuspid regurgitation are an increasing target for transcatheter interventions but evaluation of interventional success remain difficult. Continuous monitoring of cardiac output and pulmonary artery pressures with CardioMEMs may indicate interventional success. Four patients were monitored, one received isolated TMVR, one bi‐CAVI, one both TMVR and TTVR, and one underwent isolated TTVR. In both patients with TMVR and in the patient with bi‐CAVI mean PAP decreased and CO increased significantly. Changes after TTVR remain inconclusive.
Pulmonary arterial hypertension is a severe and progressive disease characterized by a pulmonary vascular remodeling process with expansion of collateral endothelial cells and total vessel occlusion. ...Endothelial cells are believed to be at the forefront of the disease process. Vascular endothelial growth factor (VEGF) and its tyrosine kinase receptor, VEGF receptor-2 (VEGFR-2), play a central role in angiogenesis, endothelial cell protection, but also in the destabilization of endothelial barrier function. Therefore, we investigated the consequences of altered VEGF signaling in an experimental model, and looked for translational correlates of this observation in patients. We performed an endothelial cell-specific conditional deletion of the
kinase insert domain protein receptor
(
kdr
) gene, coding for VEGFR-2, in C57/BL6 mice (
Kdr
∆end
)
and held them in an environmental chamber with 10% FiO
2
or under normoxia for 6 weeks.
Kdr
knockout led to a mild PH phenotype under normoxia that worsened under hypoxia.
Kdr
∆end
mice exhibited a significant increase in pulmonary arterial wall thickness, muscularization, and VEGFR-3
+
endothelial cells obliterating the pulmonary artery vessel lumen. We observed the same proliferative vasculopathy in our rodent model as seen in patients receiving anti-angiogenic therapy. Serum VEGF-a levels were elevated both in the experimental model and in humans receiving bevacizumab. Interrupted VEGF signaling leads to a pulmonary proliferative arteriopathy in rodents after direct ablative gene manipulation of
Kdr.
Histologically, similar vascular lesions can be observed in patients receiving anti-VEGF treatment. Our findings illustrate the importance of VEGF signaling for maintenance of pulmonary vascular patency.
The aim of this work was to identify the key morphological and functional features in secondary mitral regurgitation (sMR) and their prognostic impact on outcome.
Secondary sMR in patients with heart ...failure and reduced ejection fraction typically results from distortion of the underlying cardiac architecture. The morphological components which may account for the clinical impact of sMR have not been systematically assessed or correlated with clinical outcomes.
Morphomic and functional network profiling were performed on a cohort of patients with stable heart failure optimized on guideline-based medical therapy. Principal component (PC) analysis and subsequent cluster analysis were used to condense the morphomic and functional data first into PCs with varimax rotation (PCVmax) and second into homogeneous clusters. Clusters and PCs were tested for their correlations with clinical outcomes.
Morphomic and functional data from 383 patients were profiled and subsequently condensed into PCs. PCVmax 1 describes high loadings of left atrial morphological information, and PCVmax 2 describes high loadings of left ventricular (LV) topology. Based on these components, 4 homogeneous clusters were derived. sMR was most prominent in clusters 3 and 4, with the morphological difference being left ventricular size (median end-diastolic volume 188 mL interquartile range: 160 mL-224 mL vs 315 mL 264 mL-408 mL; P < 0.001). Clusters were associated with mortality (P < 0.001), but sMR remained independently associated with mortality after adjusting for the clusters (adjusted HR: 1.42; 95% CI: 1.14–1.77; P < 0.01). The detrimental association of sMR with mortality was mainly driven by cluster 3 (HR: 2.18; 95% CI: 1.32-3.60; P = 0.002), the “small LV cavity” phenotype.
These results challenge the current perceptions that sMR in heart failure with reduced ejection fraction results exclusively from global or local LV remodeling and are suggestive of a potential role of the left atrial component. The association of sMR with mortality cannot be purely attributed to cardiac morphology alone, supporting other complementary key aspects of mitral valve closure consistent with the force balance theory. Unsupervised clustering supports the association of sMR with mortality predominantly driven by the small LV cavity phenotype, as previously suggested by a conceptional framework and termed disproportionate sMR.
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Aim
Tricuspid regurgitation secondary to heart failure (HF) is common with considerable impact on survival and hospitalization rates. Currently, insights into epidemiology, impact, and treatment of ...secondary tricuspid regurgitation (sTR) across the entire HF spectrum are lacking, yet are necessary for healthcare decision‐making.
Methods and results
This population‐based study included data from 13 469 patients with HF and sTR from the Viennese community over a 10‐year period. The primary outcome was long‐term mortality. Overall, HF with preserved ejection fraction was the most frequent (57%, n = 7733) HF subtype and the burden of comorbidities was high. Severe sTR was present in 1514 patients (11%), most common among patients with HF with reduced ejection fraction (20%, n = 496). Mortality of patients with sTR was higher than expected survival of sex‐ and age‐matched community and independent of HF subtype (moderate sTR: hazard ratio HR 6.32, 95% confidence interval CI 5.88–6.80, p < 0.001; severe sTR: HR 9.04; 95% CI 8.27–9.87, p < 0.001). In comparison to HF and no/mild sTR patients, mortality increased for moderate sTR (HR 1.58, 95% CI 1.48–1.69, p < 0.001) and for severe sTR (HR 2.19, 95% CI 2.01–2.38, p < 0.001). This effect prevailed after multivariate adjustment and was similar across all HF subtypes. In subgroup analysis, severe sTR mortality risk was more pronounced in younger patients (<70 years). Moderate and severe sTR were rarely treated (3%, n = 147), despite availability of state‐of‐the‐art facilities and universal health care.
Conclusion
Secondary tricuspid regurgitation is frequent, increasing with age and associated with excess mortality independent of HF subtype. Nevertheless, sTR is rarely treated surgically or percutaneously. With the projected increase in HF prevalence and population ageing, the data suggest a major burden for healthcare systems that needs to be adequately addressed. Low‐risk transcatheter treatment options may provide a suitable alternative.
Epidemiology, impact, and treatment of secondary tricuspid regurgitation (sTR) across the heart failure (HF) spectrum in the community setting. More than moderate sTR is frequent in all HF subtypes and significantly impacts long‐term mortality. Overall treatment utilization is low despite low access burden healthcare. CI, confidence interval; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; RCT, randomized controlled trial; TR, tricuspid regurgitation.
Aim
To investigate the long‐term clinical benefit of dual antiplatelet therapy with potent P2Y12 inhibitors compared to clopidogrel in patients with acute coronary syndrome (ACS).
Methods
In this ...prospective multicenter observational study, we enrolled 708 patients with ACS treated with clopidogrel (n = 137), ticagrelor (n = 260) or prasugrel (n = 311). Major adverse cardiac events (MACE; over 1 year) and long‐term mortality (median: 5.6 years; interquartile range IQR 4.9‐6.5 years) were assessed. Multiple electrode aggregometry (MEA) was used to measure adenosine diphosphate (ADP)‐ and arachidonic acid (AA)‐induced platelet aggregation.
Results
Type of P2Y12 inhibitor emerged as an independent predictor of long‐term mortality and MACE: patients treated with potent platelet inhibitors prasugrel or ticagrelor were at lower risk for long‐term mortality (adjusted hazard ratio HR = 0.44; 95% CI: 0.22‐0.92; P = .028) or MACE (adjusted HR = 0.38; 95% CI: 0.20‐0.73; P = .004) than those treated with clopidogrel independent from clinical risk factors. In contrast, the efficacy of clopidogrel decreased with increasing severity of ACS: platelet aggregation was 37% higher in patients with ST segment elevation myocardial infarction (STEMI) and 25% higher in patients with non‐ST elevation myocardial infarction (non‐STEMI) compared to patients with unstable angina (P = .039). Patients with diabetes achieved less potent ADP‐ and AA‐induced platelet inhibition under clopidogrel, compared to patients without diabetes (P = .045; P = .030, respectively).
Conclusion
In the setting of ACS, treatment with ticagrelor or prasugrel reduced long‐term mortality and 1‐year MACE as compared to clopidogrel.
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