Biomarkers in heart failure with preserved ejection fraction

Biomarkers are widely used and studied in heart failure. Most studies have described the utility and performance of biomarkers in sub-studies of randomised clinical trials, where the vast majority of the patients suffered from heart failure with reduced ejection fraction (HFrEF), and not with preserved ejection fraction (HFpEF). As a result, there is a scarcity of data describing the levels, dynamics, clinical and biochemical correlates, and biology of biomarkers in patients suffering from HFpEF, whereas HFpEF is in fact a very frequent clinical entity. This article discusses the value of different biomarkers in HFpEF. We describe various aspects of natriuretic peptide measurements in HFpEF patients, with a focus on diagnosis, prognosis and the risk prediction of developing heart failure. Further, we will discuss several emerging biomarkers such as galectin-3 and suppression of tumorigenicity 2, and recently discovered ones such as growth differentiation factor-15 and syndecan-1.     

Animal models of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) constitutes a clinical syndrome in which the diagnostic criteria of heart failure are not accompanied by gross disturbances of systolic function, as assessed by ejection fraction. In turn, under most circumstances, diastolic function is impaired. Although it now represents over 50 % of all patients with heart failure, the mechanisms of HFpEF remain understood, precluding effective therapy. Understanding the pathophysiology of HFpEF has been restricted by both limited access to human myocardial biopsies and by the lack of animal models that fully mimic human pathology. Animal models are valuable research tools to clarify subcellular and molecular mechanisms under conditions where the comorbidities and other confounding factors can be precisely controlled. Although most of the heart failure animal models currently available represent heart failure with reduced ejection fraction, several HFpEF animal models have been proposed. However, few of these fulfil all the features present in human disease. In this review we will provide an overview of the currently available models to study HFpEF from rodents to large animals as well as present advantages and disadvantages of these models.     

Uncovering heart failure with preserved ejection fraction in patients with type 2 diabetes in primary care: time for a change

Undetected heart failure appears to be an important health problem in patients with type 2 diabetes and aged ≥ 60 years. The prevalence of previously unknown heart failure in these patients is high, steeply rises with age, and is overall higher in women than in men. The majority of the patients with newly detected heart failure have a preserved ejection fraction. A diagnostic algorithm to detect or exclude heart failure in these patients with variables from the medical files combined with items from history taking and physical examination provides a good to excellent accuracy. Annual screening appears to be cost-effective. Both unrecognised heart failure with reduced and with preserved ejection fraction were associated with a clinically relevant lower health status in patients with type 2 diabetes. Also the prognosis of these patients was worse than of those without heart failure. Existing disease-management programs for type 2 diabetes pay insufficient attention to early detection of cardiovascular diseases, including heart failure. We conclude that more attention is needed for detection of heart failure in older patients with type 2 diabetes.     

Heart failure with preserved ejection fraction in women: the Dutch Queen of Hearts program

Heart failure (HF) poses a heavy burden on patients, their families and society. The syndrome of HF comes in two types: with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). The latter is on the increase and predominantly present in women, especially the older ones. There is an urgent need for mortality-reducing drugs in HFpEF, a disease affecting around 5 % of those aged 65 years and over. HFpEF develops in patients with risk factors and comorbidities such as obesity, hypertension, diabetes, COPD, but also preeclampsia. These conditions are likely to drive microvascular disease with involvement of the coronary microvasculature, which may eventually evolve into HFpEF. Currently, the diagnosis of HFPEF relies mainly on echocardiography. There are no biomarkers that can help diagnose female microvascular disease or facilitate the diagnosis of (early stages of) HFpEF. Recently a Dutch consortium was initiated, Queen of Hearts, with support from the Netherlands Heart Foundation, with the aim to discover and validate biomarkers for diastolic dysfunction and HFpEF in women. These biomarkers come from innovative blood-derived sources such as extracellular vesicles and circulating cells. Within the Queen of Hearts consortium, we will pursue female biomarkers that have the potential for further evolution in assays with point of care capabilities. As a spin-off, the consortium will gain knowledge on gender-specific pathology of HFpEF, possibly opening up novel treatment options.     

Proteomic profiling of epicardial fat in heart failure with preserved versus reduced and mildly reduced ejection fraction

In order to explore the proteomic signatures of epicardial adipose tissue (EAT) related to the mechanism of heart failure with reduced and mildly reduced ejection fraction (HFrEF/HFmrEF) and heart failure (HF) with preserved ejection fraction (HFpEF), a comprehensive proteomic analysis of EAT was made in HFrEF/HFmrEF (n = 5) and HFpEF (n = 5) patients with liquid chromatography–tandem mass spectrometry experiments. The selected differential proteins were verified between HFrEF/HFmrEF (n = 20) and HFpEF (n = 40) by ELISA (enzyme-linked immunosorbent assay). A total of 599 EAT proteins were significantly different in expression between HFrEF/HFmrEF and HFpEF. Among the 599 proteins, 58 proteins increased in HFrEF/HFmrEF compared to HFpEF, whereas 541 proteins decreased in HFrEF/HFmrEF. Of these proteins, TGM2 in EAT was down-regulated in HFrEF/HFmrEF patients and was confirmed to decrease in circulating plasma of the HFrEF/HFmrEF group (p = 0.019). Multivariate logistic regression analysis confirmed plasma TGM2 could be an independent predictor of HFrEF/HFmrEF (p = 0.033). Receiver operating curve analysis indicated that the combination of TGM2 and Gensini score improved the diagnostic value of HFrEF/HFmrEF (p = 0.002). In summary, for the first time, we described the proteome in EAT in both HFpEF and HFrEF/HFmrEF and identified a comprehensive dimension of potential targets for the mechanism behind the EF spectrum. Exploring the role of EAT may offer potential targets for preventive intervention of HF.     

Usefulness of parathyroid hormone as a predictor of heart failure with preserved ejection fraction

Objective: To investigate the relation between parathyroid hormone (PTH) and heart failure with preserved ejection fraction (HF-PEF) in outpatients.

Methods: One hundred consecutive patients who had preserved left ventricular (LV) ejection fraction and heart failure (HF) symptoms, were enrolled. Echocardiography, assessing the diastolic functions was performed. Blood samples were collected for intact PTH and brain natriuretic peptide (BNP).

Results: Significant correlations between PTH level and predictors of advanced HF-PEF were found (p < 0.05). PTH level and left atrium diameter were found to be independent predictors of DHF.

Conclusion: Measurement of serum PTH provides complementary information for the diagnosis and prognosis of HF-PEF.     

Telmisartan ameliorates cardiac fibrosis and diastolic function in cardiorenal heart failure with preserved ejection fraction

Chronic kidney disease (CKD) is a major contributor to the development of heart failure with preserved ejection fraction (HFpEF), whereas the underlying mechanism of cardiorenal HFpEF is still elusive. The aim of this study was to investigate the role of cardiac fibrosis in a rat model of cardiorenal HFpEF and explore whether treatment with Telmisartan, an inhibitor of renin-angiotensin-aldosterone system (RAAS), can ameliorate cardiac fibrosis and preserve diastolic function in cardiorenal HFpEF. Male rats were subjected to 5/6 subtotal nephrectomy (SNX) or sham operation (Sham), and rats were allowed four weeks to recover and form a stable condition of CKD. Telmisartan or vehicle was then administered p.o. (8 mg/kg/d) for 12 weeks. Blood pressure, brain natriuretic peptide (BNP), echocardiography, and cardiac magnetic resonance imaging were acquired to evaluate cardiac structural and functional alterations. Histopathological staining, real-time polymerase chain reaction (PCR) and western blot were performed to evaluate cardiac remodeling. SNX rats showed an HFpEF phenotype with increased BNP, decreased early to late diastolic transmitral flow velocity (E/A) ratio, increased left ventricular (LV) hypertrophy and preserved ejection fraction (EF). Pathology revealed increased cardiac fibrosis in cardiorenal HFpEF rats compared with the Sham group, while chronic treatment with Telmisartan significantly decreased cardiac fibrosis, accompanied by reduced markers of fibrosis (collagen I and collagen III) and profibrotic cytokines (α-smooth muscle actin, transforming growth factor-β1, and connective tissue growth factor). In addition, myocardial inflammation was decreased after Telmisartan treatment, which was in a linear correlation with cardiac fibrosis. Telmisartan also reversed LV hypertrophy and E/A ratio, indicating that Telmisartan can improve LV remodeling and diastolic function in cardiorenal HFpEF. In conclusion, cardiac fibrosis is central to the pathology of cardiorenal HFpEF, and RAAS modulation with Telmisartan is capable of alleviating cardiac fibrosis and preserving diastolic dysfunction in this rat model.     

伊伐布雷定治疗高龄老年射血分数中间值心衰患者的疗效观察

目的 评价伊伐布雷定治疗高龄老年射血分数中间值心衰(HFmrEF)患者的临床疗效.方法 选择我院治疗的120例高龄老年HFmrEF患者,按随机数字表法分为观察组和对照组各60例,对照组给予规范化抗心衰治疗,观察组在此基础上加用伊伐布雷定治疗.随访6个月后,比较两组治疗前后静息心率(RHR)、氨基末端脑钠肽前体(NT-p...     

Chronic low‐grade inflammation in heart failure with preserved ejection fraction

Heart failure (HF) with preserved ejection fraction (HFpEF) is currently the predominant form of HF with a dramatic increase in risk with age. Low‐grade inflammation, as occurs with aging (termed “inflammaging”), is a common feature of HFpEF pathology. Suppression of proinflammatory pathways has been associated with attenuated HFpEF disease severity and better outcomes. From this perspective, inflammasome signaling plays a central role in mediating chronic inflammation and cardiovascular disease progression. However, the causal link between the inflammasome‐immune signaling axis on the age‐dependent progression of HFpEF remains conjectural. In this review, we summarize the current understanding of the role of inflammatory pathways in age‐dependent cardiac function decline. We will also evaluate recent advances and evidence regarding the inflammatory pathway in the pathophysiology of HFpEF, with special attention to inflammasome signaling.     

Asymmetrical myocardial expression of natriuretic peptides in pacing-induced heart failure

High-frequency pacing of the left ventricle (LV) free wall causes a dyssynchronous pattern of contraction that leads to progressive heart failure (HF) with pronounced differences in regional contractility. Aim of this study was to evaluate possible changes in brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) mRNA expression in the anterior/anterior lateral region (pacing site, PS) as compared to the infero-septal region (opposite site, OS) and to explore possible association between the contractiling pattern and biomarker expression. Cardiac tissue was collected from minipigs with pacing-induced HF (n = 8) and without (control, n = 6). The samples were selectively harvested from the anterior left ventricular (LV) wall, PS, and from an area remote to the pacing-site, OS. BNP and CNP mRNA expression was evaluated by semi-quantitative polymerase chain reaction (PCR). A significant difference in BNP expression was found in the PS between HF animals and controls (BNP/GAPDH: 0.65 ± 0.11 vs. 0.35 ± 0.04, p = 0.02), but not in the OS (BNP/GAPDH: 0.36 ± 0.05, ns vs. controls). CNP expression was not different compared to controls, although higher levels were observed in the PS and in the OS with respect to the controls (CNP/GAPDH: controls 0.089 ± 0.036, PS 0.289 ± 0.23, OS 0.54 ± 0.16). This finding was in tune with an increase of CNP tissue concentration (controls: 0.69 ± 0.13; PS = 1.56 ± 0.19; OS = 1.70 ± 0.42 pg/mg protein; p = 0.039 controls vs. OS). Higher BNP mRNA expression in the PS is consistent with a reduction in contractile function in this region, while higher CNP mRNA expression in the OS suggests the presence of concomitant endothelial dysfunction in the remote region.     

Early calcium handling imbalance in pressure overload-induced heart failure with nearly normal left ventricular ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a common clinical syndrome associated with high morbidity and mortality. Therapeutic options are limited due to a lack of knowledge of the pathology and its evolution. We investigated the cellular phenotype and Ca²⁺ handling in hearts recapitulating HFpEF criteria. HFpEF was induced in a portion of male Wistar rats four weeks after abdominal aortic banding. These animals had nearly normal ejection fraction and presented elevated blood pressure, lung congestion, concentric hypertrophy, increased LV mass, wall stiffness, impaired active relaxation and passive filling of the left ventricle, enlarged left atrium, and cardiomyocyte hypertrophy. Left ventricular cell contraction was stronger and the Ca²⁺ transient larger. Ca²⁺ cycling was modified with a RyR2 mediated Ca²⁺ leak from the sarcoplasmic reticulum and impaired Ca²⁺ extrusion through the Sodium/Calcium exchanger (NCX), which promoted an increase in diastolic Ca²⁺. The Sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase (SERCA2a) and NCX protein levels were unchanged. The phospholamban (PLN) to SERCA2a ratio was augmented in favor of an inhibitory effect on the SERCA2a activity. Conversely, PLN phosphorylation at the calmodulin-dependent kinase II (CaMKII)-specific site (PLN-Thr17), which promotes SERCA2A activity, was increased as well, suggesting an adaptive compensation of Ca²⁺ cycling. Altogether our findings show that cardiac remodeling in hearts with a HFpEF status differs from that known for heart failure with reduced ejection fraction. These data also underscore the interdependence between systolic and diastolic “adaptations” of Ca²⁺ cycling with complex compensative interactions between Ca²⁺ handling partner and regulatory proteins.     

Association of serum total bilirubin levels with diastolic dysfunction in heart failure with preserved ejection fraction

Background

Left ventricular diastolic dysfunction is one of the main characteristics of heart failure patients with a preserved left ventricular ejection fraction. As bilirubin is regarded as an important endogenous antioxidant molecule, serum total bilirubin levels were compared between heart failure patients with a preserved left ventricular ejection fraction and normal controls in this study. We recruited 327 heart failure patients with a preserved left ventricular ejection fraction and 200 healthy controls. Patients were divided into 4 subgroups by their comprehensive echocardiographic manifestations, 1-mild, 2-moderate, 3-severe (reversible restrictive), 4-severe (fixed restrictive). Total bilirubin levels were compared using stepwise multiple regressions adjusted for selected factors.

Results

After adjusting for gender, age, smoking, systolic blood pressure, diastolic blood pressure, total cholesterol and triglyceride, serum total bilirubin levels were significantly lower in the heart failure group compared with the control group (P < 0.01). Patients in the subgroup (4-severe) showed significantly (P < 0.05) lower levels of total bilirubin when compared with the subgroup (1-mild).

Conclusions

TB level was negatively correlated with left ventricular diastolic dysfunction in heart failure patients with a preserved left ventricular ejection fraction, which might provide a new insight into the complicated mechanisms of heart failure with a preserved left ventricular ejection fraction.     

Immunoreactive forms of natriuretic peptides in ovine brain: response to heart failure

In order to elucidate how brain natriuretic peptides (NPs) are affected by experimentally induced heart failure, we have measured the immunoreactive (IR) levels of the NP in extracts from 10 regions of ovine brain, including pituitary, and clarified their molecular forms using high performance liquid chromatography (HPLC). Using species-specific radioimmunoassay (RIA), atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were all detected in extracts taken from control animals and sheep that had undergone rapid ventricular pacing for 7 days to induce heart failure. CNP was the most abundant NP as assessed by specific RIA, and the pituitary contained the highest IR levels for all three NP. Compared with control animals, the pituitary content of BNP in animals with heart failure was reduced by 40% (control, 0.26±0.02 pmol/g wet weight versus heart failure 0.16±0.01; P<0.01, n=7). No other significant changes were observed. The molecular forms of ANP and CNP in whole brain extracts as assessed by HPLC were proANP and CNP22, CNP53 and proCNP, respectively. BNP in pituitary extracts was assessed to be primarily proBNP with a minor component of mature BNP26.     

慢性充血性心力衰竭血浆血管活性水平及临床意义

目的：探讨慢性心力衰竭患者血浆B型利钠肽（BNP）、心钠素（ANF）、胱抑素C（CysC）的水平及临床意义。方法：选择70例CHF患者,按NYHA分级;20例健康者作为对照。采用放射免疫法检查BNP和ANF水平;采用免疫比浊法检查CysC。比较不同心衰等级以及不同BNP水平的上述指标的变化。结果：CHF患者血浆BNP、ANF、CysC水平与对照比较显著升高（P〈0．05）,并随NYHA等级增高而升高（P〈0．05）。与BNP〈400pg／ml组比较,400pg／ml≤BNP〈800pg／ml组和BNP≥800pg／ml组心力衰竭患者Cr、BUN水平显著增高（P〈0．05）;相反地,HDL水平显著降低。结论：血浆B型利钠肽（BNP）、心钠素（ANF）及胱抑素c参与．了CHF的发生发展过程．联合测定箕合号的变化．对CHF患者的诊断、评估及詹．险分层具有一定的临床意义．     

A comparison of clinical outcomes following atrial fibrillation ablation for heart failure patients with preserved or reduced left ventricular function: A systematic review and meta-analysis

BackgroundThis review aims to determine if patients who undergo atrial fibrillation (AF) ablation with heart failure with preserved ejection fraction (HFpEF) do better, or worse or the same compared to patients with heart failure with reduced ejection fraction (HFrEF).MethodsA search of MEDLINE and EMBASE was performed using the search terms: “atrial fibrillation”, “ablation” and terms related to HFpEF and HFrEF in order to identify studies that evaluated one or more of i) AF recurrence, ii) periprocedural complications and iii) adverse outcomes at follow up for patients with HFpEF and HFrEF who underwent AF ablation. Data was extracted from included studies and statistically pooled to evaluate adverse events and AF recurrence.Results5 studies were included in this review and the sample size of the studies ranged from 91 to 521 patients with heart failure. There was no significant difference in the pooled rate for no AF or symptom recurrence after AF ablation comparing patients with HFpEF vs HFrEF (RR 1.07 95%CI 0.86–1.33, p = 0.15). The most common complications were access site complications/haematoma/bleeding which occurred in similar proportion in each group; HFpEF (3.1%) and HFrEF (3.1%). In terms of repeat ablations, two studies were pooled to yield a rate of 78/455 (17.1%) for HFpEF vs 24/279 (8.6%) for HFrEF (p = 0.001.ConclusionsHeart failure patients with preserved or reduced ejection fraction have similar risk of AF or symptom recurrence after AF ablation but two studies suggest that patients with HFpEF are more likely to have repeat ablations.     

Efficacy and safety of atrial fibrillation ablation in heart failure patients with left ventricular ejection fraction less than 50%

IntroductionThe efficacy of catheter ablation in patients with low cardiac function has been previously reported; however, only a few studies have included mid-range ejection fraction (mrEF). This study aimed to evaluate the efficacy and safety of atrial fibrillation (AF) ablation in patients with left ventricular ejection fraction (LVEF) < 50%.MethodsThis study retrospectively analyzed 79 patients (reduced ejection fraction [rEF]/mrEF, 38/41; paroxysmal/persistent, 37/42; heart failure hospitalizations within one year before ablation, 36 [45.6%]) who underwent the first ablation procedure at our hospital from April 2017 to December 2021. Radiofrequency ablation and cryoablation were performed for 69 and 10 patients, respectively.ResultsComplications included pacemaker implantation for postoperative sick sinus syndrome in one patient and inguinal hematoma in one patient. Regarding efficacy, there were significant postoperative improvements in echocardiographic data, blood test values, and diuretic use. After a mean follow-up of 60 months, 86.1% patients had no AF recurrence. There were 9 heart failure hospitalizations (11.4%) and 5 all-cause deaths (6.3%); no significant differences were found between the rEF and mrEF groups. No significant predictors of AF recurrence were found in preoperative patient characteristics.ConclusionAF ablation in patients with LVEF <50% significantly improved cardiac and renal functions with few complications, resulting in a high non-recurrence rate and reduced heart failure.     

慢性充血性心力衰竭血浆血管活性水平及临床意义

目的:探讨慢性心力衰竭患者血浆B型利钠肽(BNP)、心钠素(ANF)、胱抑素C(CysC)的水平及临床意义。方法:选择70例CHF患者,按NA分级;20例健康者作为对照。采用放射免疫法检查BNP和ANF水平;采用免疫比浊法检查Cys C。比较不同心衰等级以及不同BNP水平的上述指标的变化。结果:CHF患者血浆BNP、ANF、CysC水平与对照比较显著升高(P<0.05),并随NYHA等级增高而升高(P<0.05)。与BNP<400pg/ml组比较,400pg/ml≤BNP<800pg/ml组和BNP≥800pg/ml组心力衰竭患者Cr、BUN水平显著增高(P<0.05);相反地,HDL水平显著降低。结论:血浆B型利钠肽(BNP)、心钠素(ANF)及胱抑素C参与了CHF的发生发展过程,联合测定其含量的变化,对CHF患者的诊断、评估及危险分层具有一定的临床意义。     

Lipoprotein-associated phospholipase A2 activity in patients with preserved left ventricular ejection fraction

Background: A significant proportion of heart failure (HF) patients have preserved ejection fraction (EF). Considering that inflammation and oxidative stress are involved in HF evolution, we investigated lipoprotein-associated phospholipase A2 (LpPLA2), an enzyme involved in these pathophysiologic processes in relation to EF.

Methods and results: The study included 208 HF patients and 20 healthy controls. HF patients with preserved EF (HFpEF) represented 42.31% of all HF patients. LpPLA2 activity was significantly increased in HF patients when compared with controls and was higher in HFpEF than in HF with reduced EF patients (HFrEF). The incidence of left ventricular hypertrophy was higher in HFpEF than in HFrEF (EF < 50).

Conclusion: Confirming its role as a marker of vascular inflammation, LpPLA2 seems to be a biomarker constantly correlated with HF, regardless of etiology. Elevated plasma values of LpPLA2 in HFpEF are consistent with the exacerbated inflammatory status.     

How to diagnose heart failure with preserved ejection fraction: the value of invasive stress testing

Heart failure with preserved ejection fraction (HFpEF) is a growing healthcare burden worldwide and its prevalence is increasing. Diagnosing HFpEF is challenging and relies upon the presence of symptoms and/or signs of heart failure, preserved left ventricular systolic function, and evidence of diastolic dysfunction. Current diagnostic algorithms mainly rely on echocardiography (E/e’) and biomarkers (NT-proBNP). However, only a minority of patients with HFpEF are identified, and especially HFpEF patients at an early stage of the disease are easily missed. We propose to incorporate invasive stress testing, by means of right heart catheterisation at rest and during exercise, and accurate assessment of right ventricular function, by means of cardiac magnetic resonance imaging. These additions to the current diagnostic work-up will improve diagnostic sensitivity and accurate staging of HFpEF patients.