Longitudinal wall motion of the common carotid artery can be assessed by velocity vector imaging

Velocity vector imaging (VVI) is novel ultrasound image analysis software, enabling simultaneous evaluation of longitudinal and radial tissue motion. This study aimed to investigate the possible usefulness of VVI in evaluating the longitudinal vessel wall movement of the common carotid artery (CCA). Sixteen healthy volunteers and 16 patients with established coronary artery disease (CAD) were included in the study. CCA was scanned and standard B-mode ultrasound images were analysed off-line with VVI. In healthy volunteers, total longitudinal displacements (tLoD) of the right and left CCA were similar, as were the movements of the near- and far wall of the right CCA. The CAD group showed significantly lower tLoD compared to the healthy volunteers (0·543 ± 0·394 versus 0·112 ± 0·074, P<0·0001). VVI is a highly feasible technique in assessing longitudinal CCA wall motion, which may be of potential relevance as a novel vascular biomarker

Moderate-to-high intensity exercise with person-centered guidance influences fatigue in older adults with rheumatoid arthritis

Fatigue is described as a dominant and disturbing symptom of rheumatoid arthritis (RA) regardless of the advances in pharmacological treatment. Fatigue is also found to correlate with depression. The objective was to evaluate the impact of moderate-to-high intensity, aerobic and resistance exercise with person-centered guidance on fatigue, anxiety and depression, in older adults with RA. Comparisons were made between older adults (&gt; 65\ua0years) with RA taking part in a 20-week moderate-to-high intensity exercise at a gym (n = 36) or in home-based exercise of light intensity (n = 38). Assessments were performed at baseline, at 20\ua0weeks, and at 52\ua0weeks. Outcomes were differences in Multidimensional Fatigue Inventory (MFI-20), Visual Analog Scale Fatigue (VAS fatigue), and Hospital Anxiety and Depression Scale (HADS). Analysis of metabolomics was also performed. The subscales “physical fatigue” and “mental fatigue” in MFI-20 and symptoms of depression using HADS depression scale improved significantly at week 20 in the exercise group compared with the control group. Exercise did not influence global fatigue rated by VAS or subscales “reduced motivation”, “reduced activity” and “general fatigue” in MFI-20. No significant change was found on the anxiety index of HADS. The improvements in physical fatigue were associated with changes in the metabolism of lipids, bile acids, the urea cycle and several sugars. Moderate-to-high intensity exercise with person-centered guidance decreased fatigue and improved symptoms of depression and were accompanied by metabolic changes in older adults with RA

Association of Coronary Microvascular Dysfunction With Heart Failure Hospitalizations and Mortality in Heart Failure With Preserved Ejection Fraction:A Follow-up in the PROMIS-HFpEF Study

Background: Coronary microvascular dysfunction (CMD) is common in heart failure with preserved ejection fraction (HFpEF). We assessed the association of CMD with hospitalization and mortality in HFpEF. Methods and Results: We assessed the 1-year outcomes in patients from the PROMIS-HFpEF study, a prospective observational study of patients with chronic stable HFpEF undergoing coronary flow reserve measurements. Outcomes were (1) time to cardiovascular (CV) death/first HF hospitalization, (2) CV death/recurrent HF hospitalizations, (3) all-cause death/first HF hospitalization, and (4) first and (5) recurrent all-cause hospitalizations. CMD was defined as coronary flow reserve of Conclusions: In this exploratory assessment of the prognostic role of CMD in HFpEF, CMD was independently associated with primarily CVand HF-specific events. The high prevalence of CMD and its CV and HF specific prognostic role suggest CMD may be a potential treatment target in HFpEF

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

Cardiac expression of the microsomal triglyceride transport protein protects the heart function during ischemia

Aims: The microsomal triglyceride transport protein (MTTP) is critical for assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins and is most abundant in the liver and intestine. Surprisingly, MTTP is also expressed in the heart. Here we tested the functional relevance of cardiac MTTP expression. Materials and methods: We combined clinical studies, advanced expression analysis of human heart biopsies and analyses in genetically modified mice lacking cardiac expression of the MTTP-A isoform of MTTP. Results: Our results indicate that lower cardiac MTTP expression in humans is associated with structural and perfusion abnormalities in patients with ischemic heart disease. MTTP-A deficiency in mice heart does not affect total MTTP expression, activity or lipid concentration in the heart. Despite this, MTTP-A deficient mice displayed impaired cardiac function after a myocardial infarction. Expression analysis of MTTP indicates that MTTP expression is linked to cardiac function and responses in the heart. Conclusions: Our results indicate that MTTP may play an important role for the heart function in conjunction to ischemic events

Synthetic mRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial

Therapeutic angiogenesis may improve outcomes in patients with coronary artery disease undergoing surgical revascularization. Angiogenic factors may promote blood vessel growth and regenerate regions of ischemic but viable myocardium. Previous clinical trials of vascular endothelial growth factor A (VEGF-A) gene therapy with DNA or viral vectors demonstrated safety but not efficacy. AZD8601 is VEGF-A165 mRNA formulated in biocompatible citrate-buffered saline and optimized for high-efficiency VEGF-A expression with minimal innate immune response. EPICCURE is an ongoing randomized, double-blind, placebo-controlled study of the safety of AZD8601 in patients with moderately decreased left ventricular function (ejection fraction 30%–50%) undergoing elective coronary artery bypass surgery. AZD8601 3 mg, 30 mg, or placebo is administered as 30 epicardial injections in a 10-min extension of cardioplegia. Injections are targeted to ischemic but viable myocardial regions in each patient using quantitative 15O-water positron emission tomography (PET) imaging (stress myocardial blood flow 0.6 mL/g/min). Improvement in regional and global myocardial blood flow quantified with 15O-water PET is an exploratory efficacy outcome, together with echocardiographic, clinical, functional, and biomarker measures. EPICCURE combines high-efficiency delivery with quantitative targeting and follow-up for robust assessment of the safety and exploratory efficacy of VEGF-A mRNA angiogenesis (ClinicalTrials.gov: NCT03370887).</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

Design and rationale of FLAVOUR: A phase IIa efficacy study of the 5-lipoxygenase activating protein antagonist AZD5718 in patients with recent myocardial infarction

levels is the primary efficacy outcome. FLAVOUR also aims to evaluate whether AZD5718 can improve coronary microvascular function, as measured by transthoracic colour Doppler-assisted coronary flow velocity reserve. Centrally pretrained study sonographers use standardized protocols and equipment. Additional outcomes include assessment of comprehensive echocardiographic parameters (including coronary flow, global strain, early diastolic strain rate and left ventricular ejection fraction), arterial stiffness, biomarkers, health-related quality of life, and safety. Specific anti-inflammatory therapies may represent novel promising treatments to reduce residual risk in patients with coronary artery disease. By combining primary pharmacodynamic and secondary cardiovascular surrogate efficacy outcomes, FLAVOUR aims to investigate the mechanistic basis and potential benefits of AZD5718 treatment in patients with coronary artery disease

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

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