Inflammation-Based Scores as a Common Tool for Prognostic Assessment in Heart Failure or Cancer.

Background: Inflammation-based scores are widely tested in cancer and have been evaluated in cardiovascular diseases including heart failure. Objectives: We investigated the impact of established inflammation-based scores on disease severity and survival in patients with stable heart failure with reduced ejection fraction (HFrEF) paralleling results to an intra-institutional cohort of treatment naïve cancer patients. Methods: HFrEF and cancer patients were prospectively enrolled. The neutrophil-to-lymphocyte-ratio (NLR), the monocyte-to-lymphocyte-ratio (MLR), the platelet-to-lymphocyte-ratio (PLR), and the prognostic nutritional index (PNI) at index day were calculated. Association of scores with disease severity and impact on overall survival was determined. Interaction analysis was performed for the different populations. Results: Between 2011 and 2017, a total of 818 patients (443 HFrEF and 375 cancer patients) were enrolled. In HFrEF, there was a strong association between all scores and disease severity reflected by NT-proBNP and NYHA class (p ≤ 0.001 for all). In oncologic patients, association with tumor stage was significant for the PNI only (p = 0.035). In both disease entities, all scores were associated with all-cause mortality (p ≤ 0.014 for all scores). Kaplan-Meier analysis confirmed the discriminatory power of all scores in the HFrEF and the oncologic study population, respectively (log-rank p ≤ 0.026 for all scores). A significant interaction with disease (HFrEF vs. cancer) was observed for PNI (p interaction = 0.013) or PLR (p interaction = 0.005), respectively, with higher increase in risk per inflammatory score increment for HFrEF. Conclusion: In crude models, the inflammatory scores NLR, MLR, PLR, and PNI are associated with severity of disease in HFrEF and with survival in HFrEF similarly to cancer patients. For PNI and PLR, the association with increase in risk per increment was even stronger in HFrEF than in malignant disease.

Secondary mitral regurgitation-Insights from microRNA assessment.

BACKGROUND: While secondary mitral regurgitation (sMR) is associated with adverse outcome in heart failure with reduced ejection fraction (HFrEF), key pathophysiologic mechanisms remain poorly understood and might be elucidated by microRNAs (miRNA/miR), that were recently related to cardiac remodelling. This study sought to assess (i) the differences of miRNA profiles in patients with severe sMR compared to matched disease controls, (ii) the correlation between circulating miRNAs and surrogates of sMR severity as well as (iii) the prognostic implications of miRNA levels in severe sMR. MATERIALS AND METHODS: Sixty-six HFrEF patients were included, of these 44 patients with severe sMR 2:1 matched to HFrEF controls with no/mild sMR. A comprehensive set of miRNAs (miR-21, miR-29a, miR-122, miR-132, miR-133a, miR-let7i) were measured and correlated to echocardiographic sMR severity. RESULTS: miRNA patterns differed distinctly between patients with severe sMR and HFrEF controls (P < .05). Among the panel of assessed miRNAs, miR-133a correlated most strongly with surrogates of sMR severity (r = -0.41, P = .001 with sMR vena contracta width). Interestingly, elevated levels of miR-133 were associated with an increased risk for cardiovascular death and/or HF hospitalizations with and adjusted HR of 1.85 (95% CI 1.24-2.76, P = .003). CONCLUSIONS: This study unveils distinct pathophysiologic maladaptions at a cellular level in patients with severe sMR compared to no/mild sMR by showing significant differences in miRNA profiles and correlations with sMR severity, supporting the concept that sMR drives cardiac remodelling in heart failure. Moreover, the increased risk for adverse outcome in HFrEF patients with severe sMR conveyed by miR-133a might indicate irreversible myocardial damage.

Quantitative Hybrid Cardiac [18F]FDG-PET-MRI Images for Assessment of Cardiac Repair by Preconditioned Cardiosphere-Derived Cells.

Cardiosphere-derived cells (CDCs) are progenitor cells derived from heart tissue and have shown promising results in preclinical models. APOSEC, the secretome of irradiated peripheral blood mononuclear cells, has decreased infarct size in acute and chronic experimental myocardial infarction (MI). We enhanced the effect of CDCs with APOSEC preconditioning (apoCDC) and investigated the reparative effect in a translational pig model of reperfused MI. Supernatants of CDCs, assessed by proteomic analysis, revealed reduced production of extracellular matrix proteins after in vitro APOSEC preconditioning. In a porcine model of catheter-based reperfused anterior acute MI (AMI), CDCs with (apoCDC, n = 8) or without APOSEC preconditioning (CDC, n = 6) were infused intracoronary, 15 min after the start of reperfusion. Untreated AMI animals (n = 7) and sham procedures (n = 5) functioned as controls. 2-deoxy-2-(18 F)-fluoro-D-glucose-positron emission tomography-magnetic resonance imaging ([18F]FDG-PET-MRI), with late enhancement after 1 month, showed reduced scar volume and lower transmurality of the infarcted area in CDC and apoCDC compared to AMI controls. Segmental quantitative PET images displayed indicated more residual viability in apoCDC. The left-ventricle (LV) ejection fraction was improved nonsignificantly to 45.8% ± 8.6% for apoCDC and 43.5% ± 7.1% for CDCs compared to 38.5% ± 4.4% for untreated AMI. Quantitative hybrid [18F]FDG-PET-MRI demonstrated improved metabolic and functional recovery after CDC administration, whereas apoCDCs induced preservation of viability of the infarcted area.

A Unifying Concept for the Quantitative Assessment of Secondary Mitral Regurgitation.

BACKGROUND: Diverging guideline definitions for the quantitative assessment of severe secondary mitral regurgitation (sMR) reflect the lacking link of the sMR spectrum to mortality and has introduced a source of uncertainty and continuing debate. OBJECTIVES: The current study aimed to define improved risk-thresholds specifically tailored to the complex nature of sMR that provide a unifying solution to the ongoing guideline-controversy. METHODS: This study enrolled 423 heart failure patients under guideline-directed medical therapy and assessed sMR by effective regurgitant orifice area (EROA), regurgitant volume (RegVol), and regurgitant fraction (RegFrac). RESULTS: Measures of sMR severity were consistently associated with 5-year mortality with a hazard ratio of 1.42 for a 1-SD increase (95% confidence interval [CI]: 1.25 to 1.63; p < 0.001) for EROA, 1.37 (95% CI: 1.20 to 1.56; p < 0.001) for RegVol, and 1.50 (95% CI: 1.30 to 1.73; p < 0.001) for RegFrac. Results remained statistically significant after bootstrap- or clinical confounder-based adjustment. Spline-curve analyses showed a linearly increasing risk enabling the ability to stratify into low-risk (EROA <20 mm2 and RegVol <30 ml), intermediate-risk (EROA 20 to 29 mm2 and RegVol 30 to 44 ml), and high-risk (EROA ≥30 mm2 and RegVol ≥45 ml) groups. In the intermediate-risk group, a RegFrac ≥50% as indicator for hemodynamic severe sMR was associated with poor outcome (p = 0.017). A unifying concept based on combined assessment of the EROA, the RegVol, and the RegFrac showed a significantly better discrimination compared with the currently established algorithms. CONCLUSIONS: Risk-based thresholds tailored to the pathophysiological concept of sMR provide a unifying solution to the ongoing guideline controversy. An algorithm based on the combined assessment of the unifying cutoffs for EROA, RegVol, and RegFrac improves risk prediction compared with currently established grading.

Natural History of Functional Tricuspid Regurgitation: Implications of Quantitative Doppler Assessment.

OBJECTIVES: This study sought to define the relationship between functional tricuspid regurgitation (TR) and mortality in patients with heart failure with reduced ejection fraction (HFrEF); and to establish the prognostic value of quantitative measures of TR severity (i.e., effective regurgitant orifice area [EROA] and regurgitant volume). BACKGROUND: The significance of TR in chronic heart failure is controversial. Earlier studies have shown an independent impact of TR on mortality, whereas more recent evidence suggests myocardial impairment to be the driving force of mortality rather than TR itself. Earlier studies have used qualitative measures of TR severity, hence the prognostic value of more quantitative measures of TR severity (i.e., EROA and regurgitant volumes) remains unclear. METHODS: We enrolled 382 patients with HFrEF on guideline-directed medical therapy and assessed TR EROA and regurgitant volume by Doppler/2-dimensional echocardiography. All-cause mortality was defined as the primary study endpoint. RESULTS: TR severity was associated with the HFrEF phenotype with more symptoms (p = 0.004), higher neurohumoral activation (p < 0.001), progressive right-ventricular dilatation (p < 0.001), and impaired function (p < 0.001). Cox regression showed a strong association between quantitative measures of TR with mortality (all p < 0.001). Quantitative metrics of TR severity were consistently associated with mortality with a hazard ratio of 1.009 (95% confidence interval: 1.004 to 1.013; p < 0.001) per 0.01 cm2 increase of the EROA and of 1.013 (95% confidence interval: 1.007 to 1.020; p < 0.001) per 1-ml increase in regurgitant volume. Results remained unchanged after bootstrap- or clinical confounder-based adjustment. A spline curve pattern illustrates the association with mortality with thresholds for the EROA ≥0.2 cm2, and the regurgitant volume ≥20 ml with sustained excess mortality thereafter. CONCLUSIONS: This large-scale outcome study demonstrates the prognostic value of quantitative Doppler-echocardiographic measures of TR severity in HFrEF. The thresholds for EROA and TR regurgitant volume associated with mortality in our study fall within current ranges defining nonsevere TR. This may potentially impact therapeutic decision making, particularly timing of intervention.

In vivo MRI and ex vivo histological assessment of the cardioprotection induced by ischemic preconditioning, postconditioning and remote conditioning in a closed-chest porcine model of reperfused acute myocardial infarction: importance of microvasculature.

BACKGROUND: Cardioprotective value of ischemic post- (IPostC), remote (RIC) conditioning in acute myocardial infarction (AMI) is unclear in clinical trials. To evaluate cardioprotection, most translational animal studies and clinical trials utilize necrotic tissue referred to the area at risk (AAR) by magnetic resonance imaging (MRI). However, determination of AAR by MRI' may not be accurate, since MRI-indices of microvascular damage, i.e., myocardial edema and microvascular obstruction (MVO), may be affected by cardioprotection independently from myocardial necrosis. Therefore, we assessed the effect of IPostC, RIC conditioning and ischemic preconditioning (IPreC; positive control) on myocardial necrosis, edema and MVO in a clinically relevant, closed-chest pig model of AMI. METHODS AND RESULTS: Acute myocardial infarction was induced by a 90-min balloon occlusion of the left anterior descending coronary artery (LAD) in domestic juvenile female pigs. IPostC (6 × 30 s ischemia/reperfusion after 90-min occlusion) and RIC (4 × 5 min hind limb ischemia/reperfusion during 90-min LAD occlusion) did not reduce myocardial necrosis as assessed by late gadolinium enhancement 3 days after reperfusion and by ex vivo triphenyltetrazolium chloride staining 3 h after reperfusion, however, the positive control, IPreC (3 × 5 min ischemia/reperfusion before 90-min LAD occlusion) did. IPostC and RIC attenuated myocardial edema as measured by cardiac T2-weighted MRI 3 days after reperfusion, however, AAR measured by Evans blue staining was not different among groups, which confirms that myocardial edema is not a measure of AAR, IPostC and IPreC but not RIC decreased MVO. CONCLUSION: We conclude that IPostC and RIC interventions may protect the coronary microvasculature even without reducing myocardial necrosis.

Long-term outcome and risk assessment in premature acute myocardial infarction: A 10-year follow-up study.

BACKGROUND: Premature acute myocardial infarction (AMI) is a rare disease carrying significant morbidity and mortality. Existing data on outcome in these patients is based on retrospective analysis of angiographic reports or refer to time periods with incomparable treatment regimes, making them unusable for risk assessment in times of widespread use of reperfusion therapy. Aim of this study was to assess the outcome of premature AMI in a prospectively recruited study population enrolled in the times of modern reperfusion therapy. METHODS: We included 102 consecutive AMI survivors (≤40years) in this prospective multicentre study. Outcome was assessed via retrieval query of the Austrian Death Registry and the centralized patient management system of Vienna. RESULTS: During a median follow up time of 10.3years (IQR:8.9-11.1), 23% of all patients experienced MACE, of those 6% died, 17% experienced re-AMI and 5% patients an ischemic stroke. Furthermore, forty patients underwent cardiac re-catheterization and twenty-five needed recurrent revascularization. MACE were associated among the classic cardiovascular risk factors with elevated levels of HbA1c (adj. HR 1.32; 95%CI 1.06-1.64; P=0.012), total cholesterol (adj. HR 2.16; 95%CI 1.27-3.48; P=0.004), and c-reactive protein (adj. HR 1.67; 95%CI 1.29-2.17; P=0-003) for an increase of 1-standard deviation. CONCLUSION: Although myocardial re-infarction was the driving force of morbidity in premature myocardial infarction, we observed an excellent long-term survival opposed to previous reports. We found that persistence risk factors rather than the clinical risk profile at baseline influences the outcome in these patients, emphasizing the importance of secondary prevention in young patients after AMI.