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Myocardial Tissue Characterization in Heart Failure with Preserved Ejection Fraction: From Histopathology and Cardiac Magnetic Resonance Findings to Therapeutic Targets.

ABSTRACT: Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome responsible for high mortality and morbidity rates. It has an ever growing social and economic impact and a deeper knowledge of molecular and pathophysiological basis is essential for the ideal management of HFpEF patients. The association between HFpEF and traditional cardiovascular risk factors is known. However, myocardial alterations, as well as pathophysiological mechanisms involved are not completely defined. Under the definition of HFpEF there is a wide spectrum of different myocardial structural alterations. Myocardial hypertrophy and fibrosis, coronary microvascular dysfunction, oxidative stress and inflammation are only some of the main pathological detectable processes. Furthermore, there is a lack of effective pharmacological targets to improve HFpEF patients' outcomes and risk factors control is the primary and unique approach to treat those patients. Myocardial tissue characterization, through invasive and non-invasive techniques, such as endomyocardial biopsy and cardiac magnetic resonance respectively, may represent the starting point to understand the genetic, molecular and pathophysiological mechanisms underlying this complex syndrome. The correlation between histopathological findings and imaging aspects may be the future challenge for the earlier and large-scale HFpEF diagnosis, in order to plan a specific and effective treatment able to modify the disease's natural course.

SUBMITTER: Severino P

PROVIDER: S-EPMC8304780 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Myocardial Tissue Characterization in Heart Failure with Preserved Ejection Fraction: From Histopathology and Cardiac Magnetic Resonance Findings to Therapeutic Targets.

Severino Paolo P D'Amato Andrea A Prosperi Silvia S Fanisio Francesca F Birtolo Lucia Ilaria LI Costi Bettina B Netti Lucrezia L Chimenti Cristina C Lavalle Carlo C Maestrini Viviana V Mancone Massimo M Fedele Francesco F

International journal of molecular sciences 20210717 14

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome responsible for high mortality and morbidity rates. It has an ever growing social and economic impact and a deeper knowledge of molecular and pathophysiological basis is essential for the ideal management of HFpEF patients. The association between HFpEF and traditional cardiovascular risk factors is known. However, myocardial alterations, as well as pathophysiological mechanisms involved are not completely defi ...[more]

PMID: 34299270

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Project description:Background This study aimed to explore the value of cardiac magnetic resonance tissue tracking (CMR-TT) technology in evaluating heart failure with preserved ejection fraction (HFpEF) in patients with chronic myocardial infarction (CMI). Methods Between June 2016 and March 2022, we included a consecutive series of 92 patients with CMI and 40 healthy controls in this retrospective study. The CMI patients enrolled were divided into different subgroups [HFpEF-CMI group (n=54) and non- heart failure (HF)-CMI group (n=38)] according to the Heart Failure Association (HFA)-PEFF (step 1: P, pre-test assessment; step 2: E, echocardiography and natriuretic peptide score; step 3: F1, functional testing; step 4: F2, final aetiology) diagnostic algorithm. CMR scan was performed at the First Hospital of China Medical University. Quantitative measurements of myocardial damage, such as myocardial strain parameters of both ventricles derived by CMR-TT and infarct size and transmurality by late gadolinium enhancement (LGE), were assessed. One-way analysis of variance, independent samples t-test, and rank sum test were used to compare myocardial impairment among groups. Pearson or Spearman correlation coefficient was used to measure correlations between left ventricular (LV) strains and clinical and functional parameters. Logistic regression analysis and receiver operating characteristic (ROC) curve were performed to identify the best parameter for diagnosing HFpEF-CMI. Results HFpEF-CMI patients demonstrated significantly impaired LV strains and strain rates in all of the three directions (radial, circumferential and longitudinal) compared to non-HF-CMI patients and healthy controls (P<0.001 for all), whereas only global longitudinal strain (GLS) was significantly impaired in HFpEF-CMI patients vs. controls for right ventricular strain parameters (P<0.001). LV strains showed moderate correlation with N-terminal pro-brain natriuretic peptide (radial, circumferential and longitudinal strain, R=−0.401, R=0.408, R=0.407, respectively, P<0.001 for all). LV strains in the three directions (radial, circumferential and longitudinal) [area under ROC curve (AUC) =0.707, 95% confidence interval (CI): 0.603–0.797; AUC =0.708, 95% CI: 0.604–0.798; AUC =0.731, 95% CI: 0.628–0.818; respectively, P<0.01 for all] were discriminators for HFpEF-CMI and non-HF-CMI. LV strains and myocardial infarction volume were independent factors in multi-logistic regression analysis after adjusting for body mass index, age, and sex (P<0.05 for all). Conclusions CMR-TT provides clinicians with useful additional imaging parameters to facilitate the assessment of CMI patients with HFpEF. LV strain parameters can detect early cardiac insufficiency in patients with HFpEF-CMI and have potential value for discriminating between HFpEF and non-HF patients post-CMI.

Project description:BackgroundIncreased myocardial fibrosis may play a key role in heart failure with preserved ejection fraction (HFpEF) pathophysiology. The study aim was to evaluate the presence, associations, and prognostic significance of diffuse fibrosis in HFpEF patients compared to age- and sex-matched controls.MethodsWe prospectively included 118 consecutive HFpEF patients. Diffuse myocardial fibrosis was estimated by extracellular volume (ECV) quantified by cardiovascular magnetic resonance with the modified Look-Locker inversion recovery sequence. We determined an ECV age- and sex-adjusted cutoff value (33%) in 26 controls.ResultsMean ECV was significantly higher in HFpEF patients versus healthy controls (32.9 ± 4.8% vs 28.2 ± 2.4%, P < 0.001). Multivariate logistic regression showed that body mass index (BMI) (odds ratio (OR) =0.92 [0.86-0.98], P = 0.011), diabetes (OR = 2.62 [1.11-6.18], P = 0.028), and transmitral peak E wave velocity (OR = 1.02 [1.00-1.03], P = 0.022) were significantly associated with abnormal ECV value. During a median follow-up of 11 ± 6 months, the primary outcome (all-cause mortality or first heart failure hospitalization) occurred in 38 patients. In multivariate Cox regression analysis, diabetes (hazard ratio (HR) =1.98 [1.04; 3.76], P = 0.038) and hemoglobin level (HR = 0.81 [0.67; 0.98], P = 0.028) were significant predictors of composite outcome. The ECV ability to improve this model added significant prognostic information. We then developed a risk score including diabetes, hemoglobin and ECV > 33% demonstrating significant prediction of risk and validated this score in a validation cohort of 53 patients. Kaplan-Meier curves showed a significant difference according to tertiles of the probability score (P < 0.001).ConclusionAmong HFpEF patients, high ECV, likely reflecting abnormal diffuse myocardial fibrosis, was associated with a higher rate of all-cause death and first HF hospitalization in short term follow up.Trial registrationCharacterization of Heart Failure With Preserved Ejection Fraction.Trial registration numberNCT03197350 . Date of registration: 20/06/2017. This trial was retrospectively registered.

Project description:BACKGROUND:The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O2 consumption [MVO2]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O2 extraction. Lastly, we assessed whether coupling of MVO2 to EW (mechanical efficiency) was impaired in HFpEF. METHODS AND RESULTS:In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11C-acetate positron emission tomography assessing MVO2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO2, and MBF. With dobutamine, LV EW, MVO2, and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls. CONCLUSIONS:In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O2 supply relative to demand, and is associated with reserve dysfunction.

Project description:BackgroundThe noninvasive diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging. The role of left atrial (LA) functional changes in patients with HFpEF has attracted increased attention. This study aimed to evaluate LA deformation in patients with hypertension (HTN) using cardiac magnetic resonance tissue tracking and to investigate the diagnostic value of LA strain for HFpEF.MethodsThis retrospective study consecutively enrolled 24 HTN patients with HFpEF (HTN-HFpEF) and 30 patients with pure HTN based on clinical indications. Thirty age-matched healthy participants were also enrolled. All participants underwent a laboratory examination and 3.0 T cardiovascular magnetic resonance (CMR). The LA strain and strain rate, including total strain (εs), passive strain (εe), active strain (εa), peak positive strain rate (SRs), peak early negative strain rate (SRe), and peak late negative strain rate (SRa), were evaluated using CMR tissue tracking and compared among the 3 groups. Receiver operating characteristic (ROC) analysis was used to identify HFpEF. Spearman correlation was used to analyze the correlation between LA strain and brain natriuretic peptide (BNP) level.ResultsPatients with HTN-HFpEF had significantly lower εs (17.70%, IQR 14.65% to 19.70%, εe 7.83%±2.86%), εa (9.08%±3.19%), SRs (0.88±0.24 s-1), SRe (-0.60 s-1, IQR -0.90 to -0.50 s-1), and SRa (-1.10±0.47 s-1) than did patients with HTN and control participants (all P values <0.05). Compared to the control group, patients with HTN had lower εs (25.35%, IQR 21.80% to 27.25%), εe (11.49%±2.64%), SRs (1.10 s-1, IQR 1.00 to 1.48 s-1), and SRe (-1.11±0.37 s-1) (all P values <0.05). The values of εa and SRa were not significantly different between the HTN and control groups. LA total strain εs was independently associated with HFpEF (odds ratio 0.009; P<0.05) with a cutoff value of 19.55% (95% CI: 0.882-0.996), and the sensitivity and specificity were 75% and 97%, respectively. There was a good correlation between the LA strain parameters and BNP level (all P values <0.05).ConclusionsLA function impairment exists in patients with HFpEF. The LA strain parameter has potential value in diagnosing HFpEF.

Project description:Background: Heart failure with preserved ejection fraction (HFpEF) constitutes more than half of all heart failure but has few effective therapies. Recent human myocardial transcriptomics and metabolomics have revealed major differences between HFpEF, HF with reduced EF (HFrEF), and controls. How this translates at the protein level is currently unknown. Methods: Myocardial tissue from patients with HFpEF and non-failing donor controls was analyzed by data-dependent (DDA, n=10 HFpEF, n=9 controls) and data-independent (DIA, n=44 HFpEF, n=5 controls) mass spectrometry-based proteomics. Previously reported myocardial proteomic data from end-stage HFrEF and controls were also used. Differential protein expression analysis, machine learning and pathway enrichment were integrated with clinical characteristics and myocardial transcriptomics. Results: DDA-MS proteomics identified 88 significantly upregulated and 248 down-regulated proteins in HFpEF vs controls, out of 1996 identified proteins. Principal component analysis of DDA-MS proteomics found HFpEF was separated into 2 sub-groups: one being similar to controls the other quite disparate. Top proteins contributing to the separation of HFpEF subgroups were enriched in actin/myosin binding, regulation of DNA replication/repair, transcription, and translation. Downregulated proteins in HFpEF vs controls were enriched in pathways related to ribosome structure, transmembrane transporters, metabolic enzymes, and oxidative phosphorylation (OxPhos) proteins. Enriched pathways for proteins upregulated in HFpEF related to actin and phospholipid binding, growth factor signaling, kinase regulation, and glycolysis. Ingenuity pathway analysis predicted downregulation of protein translation, mitochondrial function, and glucose and fat metabolism in HFpEF. OxPhos gene (increased) versus protein (decreased) expression was discordant in HFpEF. The second DIA proteomic analysis also yielded two HFpEF sub-groups; the one most different from controls also having reduced OxPhos and protein translation pathways. A higher proportion of these patients also had severe obesity. Conclusions: Integrative proteomics, transcriptomics, and pathway analysis supports a translational defect particularly involving mitochondrial, ribosomal and protein translation proteins in HFpEF. Patients with more distinct proteomic signatures from control were more often very obese. The results support therapeutic efforts targeting metabolism, mitochondrial function, and protein translation in this subgroup.

Project description:AimsTo evaluate the prognostic validity of clinical risk factors as well as infarct characterization and myocardial deformation by cardiac magnetic resonance (CMR) in ST-elevation myocardial infarction (STEMI) patients with preserved left ventricular ejection fraction (LVEF) following primary percutaneous coronary intervention (PCI).Methods and resultsThis multicentre, individual patient-data analysis from two large CMR trials included 1247 STEMI patients. Cardiac magnetic resonance examinations were conducted 3 [interquartile range (IQR) 2-4] days after PCI. LVEF, infarct size, microvascular obstruction (MVO), and myocardial strain values were measured. Primary endpoint was defined as composite of major adverse cardiovascular events (MACE) including death, re-infarction, and congestive heart failure. A preserved LVEF (defined as LVEF ≥50%) was observed in 724 patients (=58%). In the overall cohort, 97 patients experienced a MACE event [follow-up time 12 (IQR 12-13) months], and 34 MACE events occurred in the group with preserved LVEF (5% vs. 12% incidence rate in patients with LVEF < 50%). TIMI risk score [hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.02-1.59; P = 0.03] and female gender (HR 2.24, 95% CI 1.10-4.57; P = 0.03) emerged as independent clinical determinants of MACE in the patient group with preserved LVEF. Among CMR parameters, the presence of MVO (HR 2.39, 95% CI 1.05-5.46; P = 0.04) and reduced global longitudinal strain (GLS; HR 1.12, 95% CI 1.02-1.23; P = 0.02) independently predicted MACE in the LVEF-preserved population. The addition of MVO and GLS to the clinical prognostic markers (TIMI risk score, female gender) increased (P = 0.02) the prognostic validity [AUC 0.76 (95% CI 0.73-0.79)] compared to the clinical markers alone [AUC 0.65 (0.62-0.69)].ConclusionIn contemporary treated STEMI patients showing preserved LVEF, a CMR-based risk prediction approach assessing MVO and GLS provided strong prognostic value that was incremental to clinical outcome parameters.

Project description:BackgroundHeart failure (HF) with preserved ejection fraction (HFpEF) constitutes half of all HF but lacks effective therapy. Understanding of its myocardial biology remains limited because of a paucity of heart tissue molecular analysis.MethodsWe performed RNA sequencing on right ventricular septal endomyocardial biopsies prospectively obtained from patients meeting consensus criteria for HFpEF (n=41) contrasted with right ventricular septal tissue from patients with HF with reduced ejection fraction (HFrEF, n=30) and donor controls (n=24). Principal component analysis and hierarchical clustering tested for transcriptomic distinctiveness between groups, effect of comorbidities, and differential gene expression with pathway enrichment contrasted HF groups and donor controls. Within HFpEF, non-negative matrix factorization and weighted gene coexpression analysis identified molecular subgroups, and the resulting clusters were correlated with hemodynamic and clinical data.ResultsPatients with HFpEF were more often women (59%), African American (68%), obese (median body mass index 41), and hypertensive (98%), with clinical HF characterized by 65% New York Heart Association Class III or IV, nearly all on a loop diuretic, and 70% with a HF hospitalization in the previous year. Principal component analysis separated HFpEF from HFrEF and donor controls with minimal overlap, and this persisted after adjusting for primary comorbidities: body mass index, sex, age, diabetes, and renal function. Hierarchical clustering confirmed group separation. Nearly half the significantly altered genes in HFpEF versus donor controls (1882 up, 2593 down) changed in the same direction in HFrEF; however, 5745 genes were uniquely altered between HF groups. Compared with controls, uniquely upregulated genes in HFpEF were enriched in mitochondrial adenosine triphosphate synthesis/electron transport, pathways downregulated in HFrEF. HFpEF-specific downregulated genes engaged endoplasmic reticulum stress, autophagy, and angiogenesis. Body mass index differences largely accounted for HFpEF upregulated genes, whereas neither this nor broader comorbidity adjustment altered pathways enriched in downregulated genes. Non-negative matrix factorization identified 3 HFpEF transcriptomic subgroups with distinctive pathways and clinical correlates, including a group closest to HFrEF with higher mortality, and a mostly female group with smaller hearts and proinflammatory signaling. These groupings remained after sex adjustment. Weighted gene coexpression analysis yielded analogous gene clusters and clinical groupings.ConclusionsHFpEF exhibits distinctive broad transcriptomic signatures and molecular subgroupings with particular clinical features and outcomes. The data reveal new signaling targets to consider for precision therapeutics.

Dataset Information

Myocardial Tissue Characterization in Heart Failure with Preserved Ejection Fraction: From Histopathology and Cardiac Magnetic Resonance Findings to Therapeutic Targets.

Publications

Myocardial Tissue Characterization in Heart Failure with Preserved Ejection Fraction: From Histopathology and Cardiac Magnetic Resonance Findings to Therapeutic Targets.

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