Sex differences in proteomic correlates of coronary microvascular dysfunction among patients with heart failure and preserved ejection fraction

Aims: Little information is available on sex differences in coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF). We investigated sex-specific proteomic profiles associated with CMD in patients with HFpEF. Methods and results: Using the prospective multinational PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in HFpEF; n = 182; 54.6% women), we compared clinical and biomarker correlates of CMD (defined as coronary flow reserve [CFR] <2.5) between men and women with HFpEF. We used lasso penalized regression to analyse 242 biomarkers from high-throughput proximity extension assays, adjusting for age, body mass index, creatinine, smoking and study site. The prevalence of CMD was similarly high in men and women with HFpEF (77% vs. 70%; p = 0.27). Proteomic correlates of CFR differed by sex, with 10 versus 16 non-overlapping biomarkers independently associated with CFR in men versus women, respectively. In men, proteomic correlates of CFR included chemokine ligand 20, brain natriuretic peptide, proteinase 3, transglutaminase 2, pregnancy-associated plasma protein A and tumour necrosis factor receptor superfamily member 14. Among women, the strongest proteomic correlates with CFR were insulin-like growth factor-binding protein 1, phage shock protein D, CUB domain-containing protein 1, prostasin, decorin, FMS-like tyrosine kinase 3, ligand growth differentiation factor 15, spondin-1, delta/notch-like epidermal growth factor-related receptor and tumour necrosis factor receptor superfamily member 13B. Pathway analyses suggested that CMD was related to the inflammation-mediated chemokine and cytokine signalling pathway among men with HFpEF, and the P13-kinase and transforming growth factor-beta signalling pathway among women with HFpEF. Conclusion: While the prevalence of CMD among men and women with HFpEF is similar, the drivers of microvascular dysfunction may differ by sex. The current inflammatory paradigm of CMD in HFpEF potentially predominates in men, while derangement in ventricular remodelling and fibrosis may play a more important role in women

Disproportionate left atrial myopathy in heart failure with preserved ejection fraction among participants of the PROMIS-HFpEF study

Impaired left atrial (LA) function in heart failure with preserved ejection fraction (HFpEF) is associated with adverse outcomes. A subgroup of HFpEF may have LA myopathy out of proportion to left ventricular (LV) dysfunction; therefore, we sought to characterize HFpEF patients with disproportionate LA myopathy. In the prospective, multicenter, Prevalence of Microvascular Dysfunction in HFpEF study, we defined disproportionate LA myopathy based on degree of LA reservoir strain abnormality in relation to LV myopathy (LV global longitudinal strain [GLS]) by calculating the residuals from a linear regression of LA reservoir strain and LV GLS. We evaluated associations of disproportionate LA myopathy with hemodynamics and performed a plasma proteomic analysis to identify proteins associated with disproportionate LA myopathy; proteins were validated in an independent sample. Disproportionate LA myopathy correlated with better LV diastolic function but was associated with lower stroke volume reserve after passive leg raise independent of atrial fibrillation (AF). Additionally, disproportionate LA myopathy was associated with higher pulmonary artery systolic pressure, higher pulmonary vascular resistance, and lower coronary flow reserve. Of 248 proteins, we identified and validated 5 proteins (involved in cardiomyocyte stretch, extracellular matrix remodeling, and inflammation) that were associated with disproportionate LA myopathy independent of AF. In HFpEF, LA myopathy may exist out of proportion to LV myopathy. Disproportionate LA myopathy is a distinct HFpEF subtype associated with worse hemodynamics and a distinct proteomic signature, independent of AF

Generalizability of HFA-PEFF and H2FPEF Diagnostic Algorithms and Associations With Heart Failure Indices and Proteomic Biomarkers: Insights From PROMIS-HFpEF

BackgroundDiagnosing heart failure with preserved ejection fraction (HFpEF) remains challenging. We aimed to evaluate the generalizability of the HFA-PEFF (Heart Failure Association Pre-test assessment, Echocardiography & natriuretic peptide, Functional testing, Final etiology) and weighted H2FPEF (Heavy, 2 or more Hypertensive drugs, atrial Fibrillation, Pulmonary hypertension, Elder age > 60, elevated Filling pressures) diagnostic algorithms and associations with HF severity, coronary microvascular dysfunction and proteomic biomarkers.Methods and ResultsDiagnostic likelihood of HFpEF was calculated in the prospective, multinational PROMIS-HFpEF (Prevalence of microvascular dysfunction in HFpEF) cohort using current European Society of Cardiology recommendations, HFA-PEFF and H2FPEF algorithms. Associations between the 2 algorithms and left atrial function, Doppler-based coronary flow reserve, 6-minute walk test, quality of life, and proteomic biomarkers were investigated. Of 181 patients with an EF of ≥50%, 129 (71%) and 94 (52%) fulfilled criteria for high likelihood HFpEF as per HFA-PEFF and H2FPEF, and 28% and 46% were classified as intermediate likelihood, requiring additional hemodynamic testing. High likelihood HFpEF patients were older with higher prevalence of atrial fibrillation and lower global longitudinal strain and left atrial reservoir strain (P ConclusionsAlthough the HFA-PEFF and H2FPEF scores were associated with measures of HF severity and biomarkers related to HFpEF, they demonstrated a modest and differential ability to identify HFpEF noninvasively, necessitating additional functional testing to confirm the diagnosis.</p

Análisis general de sistemas productivos claves y sus indicadores a nivel nacional en el contexto de crecimiento verde

El concepto de crecimiento verde fue incluido en el Plan Nacional de Desarrollo 2014-2018 “Todos por un Nuevo País” con el objetivo de buscar el desarrollo económico sostenible, la competitividad y la reducción de vulnerabilidades al cambio climático. En este informe se busca dar a conocer el estado actual de los indicadores de crecimiento verde para diferentes sistemas productivos agropecuarios en Colombia e identificar las opciones tecnológicas que permitan mejorar dichos indicadores con el fin de incrementar la productividad de la tierra sin afectar los demás indicadores de crecimiento verde. Para lograr esto se han propuesto en este estudio cinco fases que van desde la fase de preparación, un análisis general a nivel nacional, un análisis detallado a nivel regional, un análisis de barreras para la implementación de medidas y recomendaciones. Este reporte corresponde a la fase dos del estudio sobre análisis general. La línea base de expansión en área proyectada para los cinco sistemas productivos, la construcción y estimación de los indicadores a nivel nacional para cada uno de los sistemas productivos y una lista de opciones tecnológicas que pueden contribuir al crecimiento verde en estos sistemas productivos. Posteriormente se estimará el potencial que tiene cada tecnología sobre los indicadores de crecimiento verde. En este estudio también se incluye la metodología y resultados sobre el proceso de priorización de los sistemas productivos. The concept of green growth was included in the National Development Plan 2014-2018 "All for a New Country" with the objective of seeking sustainable economic development, competitiveness and the reduction of vulnerabilities in climate change. This report seeks to publicize the current status of green growth indicators for different agricultural production systems in Colombia and identify the technological options that allow improving the indicators in order to increase the productivity of the land without affecting the other indicators of green growth To achieve this, five phases have been improved in this study, ranging from the preparation phase, a general analysis at the national level, detailed analysis at the regional level, an analysis of barriers to the implementation of measures and recommendations. This report corresponds to the phase of the study on general analysis. The baseline projected in this area for the five productive systems, the construction and the estimation of the indicators at national level for each one of the productive systems and a list of technological options that can contribute to the green growth in these productive systems. Subsequently, the potential of each technology on green growth indicators will be estimated. This study also includes the methodology and results on the process of prioritization of productive systems.The concept of green growth was included in the National Development Plan 2014-2018 "All for a New Country" with the objective of seeking sustainable economic development, competitiveness and the reduction of vulnerabilities in climate change. This report seeks to publicize the current status of green growth indicators for different agricultural production systems in Colombia and identify the technological options that allow improving the indicators in order to increase the productivity of the land without affecting the other indicators of green growth To achieve this, five phases have been improved in this study, ranging from the preparation phase, a general analysis at the national level, detailed analysis at the regional level, an analysis of barriers to the implementation of measures and recommendations. This report corresponds to the phase of the study on general analysis. The baseline projected in this area for the five productive systems, the construction and the estimation of the indicators at national level for each one of the productive systems and a list of technological options that can contribute to the green growth in these productive systems. Subsequently, the potential of each technology on green growth indicators will be estimated. This study also includes the methodology and results on the process of prioritization of productive systems

Sex differences in proteomic correlates of coronary microvascular dysfunction among patients with heart failure and preserved ejection fraction

Aims Little information is available on sex differences in coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF). We investigated sex-specific proteomic profiles associated with CMD in patients with HFpEF. Methods and results Using the prospective multinational PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in HFpEF; n = 182; 54.6% women), we compared clinical and biomarker correlates of CMD (defined as coronary flow reserve [CFR] Conclusion While the prevalence of CMD among men and women with HFpEF is similar, the drivers of microvascular dysfunction may differ by sex. The current inflammatory paradigm of CMD in HFpEF potentially predominates in men, while derangement in ventricular remodelling and fibrosis may play a more important role in women.</p

Disproportionate left atrial myopathy in heart failure with preserved ejection fraction among participants of the PROMIS-HFpEF study

Impaired left atrial (LA) function in heart failure with preserved ejection fraction (HFpEF) is associated with adverse outcomes. A subgroup of HFpEF may have LA myopathy out of proportion to left ventricular (LV) dysfunction; therefore, we sought to characterize HFpEF patients with disproportionate LA myopathy. In the prospective, multicenter, Prevalence of Microvascular Dysfunction in HFpEF study, we defined disproportionate LA myopathy based on degree of LA reservoir strain abnormality in relation to LV myopathy (LV global longitudinal strain [GLS]) by calculating the residuals from a linear regression of LA reservoir strain and LV GLS. We evaluated associations of disproportionate LA myopathy with hemodynamics and performed a plasma proteomic analysis to identify proteins associated with disproportionate LA myopathy; proteins were validated in an independent sample. Disproportionate LA myopathy correlated with better LV diastolic function but was associated with lower stroke volume reserve after passive leg raise independent of atrial fibrillation (AF). Additionally, disproportionate LA myopathy was associated with higher pulmonary artery systolic pressure, higher pulmonary vascular resistance, and lower coronary flow reserve. Of 248 proteins, we identified and validated 5 proteins (involved in cardiomyocyte stretch, extracellular matrix remodeling, and inflammation) that were associated with disproportionate LA myopathy independent of AF. In HFpEF, LA myopathy may exist out of proportion to LV myopathy. Disproportionate LA myopathy is a distinct HFpEF subtype associated with worse hemodynamics and a distinct proteomic signature, independent of AF

Artificial intelligence-enabled fully automated detection of cardiac amyloidosis using electrocardiograms and echocardiograms.

Patients with rare conditions such as cardiac amyloidosis (CA) are difficult to identify, given the similarity of disease manifestations to more prevalent disorders. The deployment of approved therapies for CA has been limited by delayed diagnosis of this disease. Artificial intelligence (AI) could enable detection of rare diseases. Here we present a pipeline for CA detection using AI models with electrocardiograms (ECG) or echocardiograms as inputs. These models, trained and validated on 3 and 5 academic medical centers (AMC) respectively, detect CA with C-statistics of 0.85-0.91 for ECG and 0.89-1.00 for&nbsp;echocardiography. Simulating deployment on 2 AMCs indicated a positive predictive value (PPV) for the ECG model of 3-4% at 52-71% recall. Pre-screening with ECG enhance the echocardiography model performance at 67% recall from PPV of 33% to PPV of 74-77%. In conclusion, we developed an automated strategy to augment CA detection, which should be generalizable to other rare cardiac diseases

Generalizability of HFA-PEFF and H2FPEF Diagnostic Algorithms and Associations With Heart Failure Indices and Proteomic Biomarkers: Insights From PROMIS-HFpEF

10.1016/j.cardfail.2021.02.005Journal of Cardiac Failure277756-76

Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF

Aims To date, clinical evidence of microvascular dysfunction in patients with heart failure (HF) with preserved ejection fraction (HFpEF) has been limited. We aimed to investigate the prevalence of coronary microvascular dysfunction (CMD) and its association with systemic endothelial dysfunction, HF severity, and myocardial dysfunction in a well defined, multi-centre HFpEF population. Methods and results This prospective multinational multi-centre observational study enrolled patients fulfilling strict criteria for HFpEF according to current guidelines. Those with known unrevascularized macrovascular coronary artery disease (CAD) were excluded. Coronary flow reserve (CFR) was measured with adenosine stress transthoracic Doppler echocardiography. Systemic endothelial function [reactive hyperaemia index (RHI)] was measured by peripheral arterial tonometry. Among 202 patients with HFpEF, 151 [75% (95% confidence interval 69-81%)] had CMD (defined as CFR <2.5). Patients with CMD had a higher prevalence of current or prior smoking (70% vs. 43%; P = 0.0006) and atrial fibrillation (58% vs. 25%; P = 0.004) compared with those without CMD. Worse CFR was associated with higher urinary albumin-to-creatinine ratio (UACR) and NTproBNP, and lower RHI, tricuspid annular plane systolic excursion, and right ventricular (RV) free wall strain after adjustment for age, sex, body mass index, atrial fibrillation, diabetes, revascularized CAD, smoking, left ventricular mass, and study site (P <0.05 for all associations). Conclusions PROMIS-HFpEF is the first prospective multi-centre, multinational study to demonstrate a high prevalence of CMD in HFpEF in the absence of unrevascularized macrovascular CAD, and to show its association with systemic endothelial dysfunction (RHI, UACR) as well as markers of HF severity (NTproBNP and RV dysfunction). Microvascular dysfunction may be a promising therapeutic target in HFpEF