Exposome in ischaemic heart disease: beyond traditional risk factors.

Ischaemic heart disease represents the leading cause of morbidity and mortality, typically induced by the detrimental effects of risk factors on the cardiovascular system. Although preventive interventions tackling conventional risk factors have helped to reduce the incidence of ischaemic heart disease, it remains a major cause of death worldwide. Thus, attention is now shifting to non-traditional risk factors in the built, natural, and social environments that collectively contribute substantially to the disease burden and perpetuate residual risk. Of importance, these complex factors interact non-linearly and in unpredictable ways to often enhance the detrimental effects attributable to a single or collection of these factors. For this reason, a new paradigm called the 'exposome' has recently been introduced by epidemiologists in order to define the totality of exposure to these new risk factors. The purpose of this review is to outline how these emerging risk factors may interact and contribute to the occurrence of ischaemic heart disease, with a particular attention on the impact of long-term exposure to different environmental pollutants, socioeconomic and psychological factors, along with infectious diseases such as influenza and COVID-19. Moreover, potential mitigation strategies for both individuals and communities will be discussed.

Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence.

Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.

Sodium-glucose cotransporter 2 inhibitors and the cancer patient: from diabetes to cardioprotection and beyond.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class initially designed and approved for treatment of diabetes mellitus, have been shown to exert pleiotropic metabolic and direct cardioprotective and nephroprotective effects that extend beyond their glucose-lowering action. These properties prompted their use in two frequently intertwined conditions, heart failure and chronic kidney disease. Their unique mechanism of action makes SGLT2i an attractive option also to lower the rate of cardiac events and improve overall survival of oncological patients with preexisting cardiovascular risk and/or candidate to receive cardiotoxic therapies. This review will cover biological foundations and clinical evidence for SGLT2i modulating myocardial function and metabolism, with a focus on their possible use as cardioprotective agents in the cardio-oncology settings. Furthermore, we will explore recently emerged SGLT2i effects on hematopoiesis and immune system, carrying the potential of attenuating tumor growth and chemotherapy-induced cytopenias.

Cardio-oncology rehabilitation: are we ready?

Cardio-oncology rehabilitation (CORE) is not only an essential component of cancer rehabilitation but also a pillar of preventive cardio-oncology. Cardio-oncology rehabilitation is a comprehensive model based on a multitargeted approach and its efficacy has been widely documented; when compared with an 'exercise only' programme, comprehensive CORE demonstrates a better outcome. It involves nutritional counselling, psychological support, and cardiovascular (CV) risk assessment, and it is directed to a very demanding population with a heavy burden of CV diseases driven by physical inactivity, cancer therapy-induced metabolic derangements, and cancer therapy-related CV toxicities. Despite its usefulness, CORE is still underused in cancer patients and we are still at the dawning of remote models of rehabilitation (tele-rehabilitation). Not all CORE is created equally: a careful screening procedure to identify patients who will benefit the most from CORE and a multidisciplinary customized approach are mandatory to achieve a better outcome for cancer survivors throughout their cancer journey. The aim of this paper is to provide an updated review of CORE not only for cardiologists dealing with this peculiar population of patients but also for oncologists, primary care providers, patients, and caregivers. This multidisciplinary team should help cancer patients to maintain a healthy and active life before, during, and after cancer treatment, in order to improve quality of life and to fight health inequities.

Left Ventricular-Arterial Coupling and Vascular Function in Childhood Cancer Survivors Exposed to Anthracycline Chemotherapy.

Background: Cardiovascular (CV) diseases are a cause of increased long-term morbidity and mortality in childhood cancer survivors (CCSs) treated with anthracyclines. These drugs may affect not only the heart, but also the vascular system. Left ventricular-arterial coupling (LVAC) represents a reliable parameter of altered ventricular and vascular performance, with validated prognostic value and never investigated in this setting. Aim of this study was to assess, in CCSs and matched controls, LVAC changes, performed with different echocardiographic modalities, and their relationship with endothelial function. Methods: Twenty survivors treated with anthracyclines for childhood malignancies and a matched control group of 20 healthy subjects were enrolled. Arterial elastance (Ea), end-systolic elastance (Ees), Ea/Ees ratio, as well as three-dimensional (3D) LVAC (assessed by measurement of End Systolic Volume [ESV]/Stroke Volume [SV] ratio) were performed at rest. Endothelial function was evaluated by measurement of flow-mediated dilatation (FMD) of the brachial artery. Results: 3D SV and 3D ESV/SV ratio resulted respectively significantly lower and higher in CCSs than in controls, while Ea, Ees and Ea/Ees ratio were not different among groups. A positive correlation between 3D ESV/SV ratio and cumulative anthracycline doses, as well as with time after drug exposure were also found. Mean FMD was similar in CCSs and controls (8.45 ± 1.79 versus 9.41 ± 3.41, p = 0.34). Conclusions: In conclusion, conventional LVAC parameters were not shown to be significantly different between CCSs and controls; however, 3D SV and LVAC were significantly impaired in our population. In these patients, endothelial function was comparable to controls. Larger validation studies are therefore needed.

Cardiac Anthracycline Accumulation and B-Type Natriuretic Peptide to Define Risk and Predictors of Cancer Treatment-Related Early Diastolic Dysfunction.

Diastolic dysfunction (DD) was reported to precede heart failure (HF) in patients with cancer who were treated with chemotherapy. We aimed at defining risk versus dose relationships and risk predictors in patients with cancer treated mainly with anthracyclines. Data from 67 patients without comorbidities (60 treated with anthracyclines, 7 with nonanthracycline chemotherapy) were retrospectively incorporated in a mathematical function that correlated DD risk with experimental indices of anthracycline accumulation in human myocardium. Risk was calculated for all patients and for subgroups stratified by intertreatment levels of the endogenous cardiac relaxant agent, B-type natriuretic peptide (BNP). Grade I DD (impaired relaxation) occurred in 14 of 67 patients, and 5% risk doses were much lower for DD than HF (mg of anthracycline/m2: 210 vs. 470 or 190 vs. 450 for all patients or anthracycline-treated patients in isolation, respectively; P ≤ 0.01 for DD vs. HF). Patients with transient BNP elevations showed the lowest 5% risk dose (150 mg/m2), whereas patients with persistent elevations showed the highest risk dose (280 mg/m2; P < 0.05). Patients with or without DD were similar for systemic and cardiac exposure to anthracyclines; however, high-risk patients with transient BNP elevations and DD were older and presented at baseline with lower indices of transmitral flow. In conclusion, DD risk develops after lower anthracycline doses than HF and intertreatment levels of BNP help to identify patients with high or low DD risk. These findings are of potential value to monitor or treat the patient with cancer at risk of DD. SIGNIFICANCE STATEMENT: DD is an early manifestation of cardiotoxicity from anthracyclines and nonanthracycline chemotherapeutics. We show that merging preclinical characterization of cardiac anthracycline accumulation with clinical data from patients treated primarily with anthracyclines identifies DD risk from very low anthracycline doses. DD risk is associated with older age, baseline diastolic indices toward the lower limit of normal, and transient intertreatment elevations of the endogenous cardiac relaxant agent, BNP. These findings have numerous pharmacological implications.

Microvascular complications identify a specific coronary atherosclerotic phenotype in patients with type 2 diabetes mellitus.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are considered as a homogeneous cohort of patients. However, the specific role of diabetic microvascular complications (DMC), in determining the features of coronary plaques is poorly known. We investigated whether the presence of DMC may identify a different phenotype of patients associated to specific clinical, angiographic, optical coherence tomography (OCT) features and different prognosis. METHODS: We prospectively enrolled consecutive T2DM patients with obstructive coronary artery disease (CAD) at their first coronary event. Patients were stratified according to the presence or absence of DMC, including diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy. OCT assessment of the culprit vessel was performed in a subgroup of patients. The incidence of major adverse cardiac events (MACEs) was assessed at follow-up. RESULTS: We enrolled 320 T2DM patients (mean age 70.3 ± 8.8 years; 234 [73.1%] men, 40% acute coronary syndrome, 60% chronic coronary syndrome). Patients with DMC (172 [53.75%]) presented a different clinical and biochemical profile and, of importance, a higher prevalence of multivessel CAD (109 [63.4%] vs. 68 [45.9%], p = 0.002). At OCT analysis, DMC was associated to a higher prevalence of large calcifications and healed plaques and to a lower prevalence of lipid plaques. Finally, MACEs rate was significantly higher (25 [14.5%] vs. 12 [8.1%], p = 0.007) in DMC patients, mainly driven by a higher rate of planned revascularizations, and DMC predicted the occurrence of MACEs (mean follow-up 33.4 ± 15.6 months). CONCLUSIONS: The presence of DMC identifies a distinct diabetic population with more severe CAD but with a more stable pattern of coronary atherosclerosis.

Predictors of Early or Delayed Diastolic Dysfunction After Anthracycline-Based or Nonanthracycline Chemotherapy: A Pharmacological Appraisal.

Diastolic dysfunction (DD) is an early manifestation of cancer drug cardiotoxicity. Anthracyclines are considered as more cardiotoxic than other chemotherapeutics, but previous studies have shown that both anthracycline-based and nonanthracycline chemotherapy can cause an early DD, detected 1 week after the end of chemotherapy. Here we characterized if DD also occurred in a delayed form, detected 6 months after chemotherapy. Sixty-seven comorbidity-free patients were examined. DD was diagnosed by echocardiography and cardiac biomarkers. Early or delayed DD occurred in 26 or 13 patients, respectively, sharing a pattern of grade I DD (impaired relaxation at echocardiography) or elevated B-type natriuretic peptide. Binary logistic analysis showed that age, gender, and type of chemotherapy (anthracycline-based vs. nonanthracycline) did not independently increase the probability of early or delayed DD. Early DD was predicted by the patient's cardiovascular profile and in particular by diastolic indices that were in ranges of normality but showed measurable discrepancies from mean control values. Delayed DD was not predicted by the patient's cardiovascular profile but was predicted by postchemotherapy adjuvant treatments (e.g., chest radiation or hormone therapy). Early and delayed DD were accompanied by moderate left ventricular ejection fraction decrements. These findings show that anthracycline-based and nonanthracycline chemotherapy can induce early or delayed DD, which are governed by different patient- or treatment- related factors. Pharmacologic interventions that prevent DD or mitigate its progression toward a more serious cardiac dysfunction should be considered. SIGNIFICANCE STATEMENT: Predictors of early or delayed diastolic dysfunction (DD) were investigated in patients with cancer treated with anthracycline-based or nonanthracycline chemotherapy. The type of chemotherapy did not predict the risk of DD. Early DD was predicted by the patient's cardiovascular profile. Delayed DD was predicted by the adjuvant treatments the patient received after chemotherapy. These findings show that any chemotherapeutic can cause DD; however, the trajectories of DD are differently influenced by patients' characteristics or postchemotherapy exposure to additional cardiotoxic hits.

Sodium-Glucose Cotransporter Inhibitors Reduce Mortality and Morbidity in Patients With Heart Failure: Evidence From a Meta-Analysis of Randomized Trials.

BACKGROUND: Recent trials demonstrated the clinical efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with heart failure (HF), regardless of the presence or absence of type 2 diabetes. These data may allow the use of this innovative drug class in clinical routine for treating these patients. STUDY QUESTION: We aimed at further clarifying the role of SGLT2i in patients with diagnosis of HF, capitalizing on pooled sample size and heightened power for clinically relevant safety and efficacy outcomes. DATA SOURCES: We conducted a systematic search of PubMed, reference lists of relevant articles, and Medline database from inception until March 1, 2021. STUDY DESIGN: This meta-analysis was completed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched for randomized trials that evaluated the cardiovascular effects of SGLT2i in patients with HF. Three investigators independently assessed study eligibility, extracted the data, and assessed risk of bias. Hazard ratios and 95% confidence intervals (CIs) were pooled and meta-analyzed using a random-effect model. Numbers needed to treat (NNT) with the relative 95% CIs were also calculated. The primary outcome was a composite of HF hospitalization or an urgent visit for worsening HF and cardiovascular death. RESULTS: Three trials were included in the study. Overall, treatment with SGLT2i was associated with a lower risk of the primary composite outcome [hazard ratios 0.73, 95% CI (0.67-0.80), NNT = 11.3]. Similarly, there was a significantly reduced risk of cardiovascular death, all-cause death, HF hospitalization and need for urgent treatment for HF, and HF hospitalization. CONCLUSIONS: Therefore, the available evidence supports the routine use of these drugs as standard-of-care, also given the highly favorable NNTs.

Sex-Related Differences in Dilated Cardiomyopathy with a Focus on Cardiac Dysfunction in Oncology.

PURPOSE OF REVIEW: The aim of this report is to describe the main aspects of sex-related differences in non-ischemic dilated cardiomyopathies (DCM), focusing on chemotherapy-induced heart failure (HF) and investigating the possible therapeutic implications and clinical management applications in the era of personalized medicine. RECENT FINDINGS: In cardio-oncology, molecular and multimodality imaging studies confirm that sex differences do exist, affecting the therapeutic cardioprotective strategies and, therefore, the long-term outcomes. Interestingly, compelling evidences suggest that sex-specific characteristics in drug toxicity might predict differences in the therapeutic response, most likely due to the tangled interplay between cancer and HF, which probably share common underlying mechanisms. Cardiovascular diseases show many sex-related differences in prevalence, etiology, phenotype expression, and outcomes. Complex molecular mechanisms underlie this diverse pathological manifestations, from sex-determined differential gene expression to sex hormone interaction with their receptors in the heart. Non-ischemic DCM is an umbrella definition that incorporates several etiologies, including chemotherapy-induced cardiomyopathies. The role of sex as a risk factor for cardiotoxicity is poorly explored. However, understanding the various features of disease manifestation and outcomes is of paramount importance for a prompt and tailored evaluation.

Anthracycline Cardiotoxicity in Adult Cancer Patients: JACC: CardioOncology State-of-the-Art Review.

Since their introduction in the 1960s, anthracyclines have been a significant breakthrough in oncology, introducing dramatic changes in the treatment of solid and hematologic malignancies. Although new-generation targeted drugs and cellular therapies are revolutionizing contemporary oncology, anthracyclines remain the cornerstone of treatment for lymphomas, acute leukemias, and soft tissue sarcomas. However, their clinical application is limited by a dose-dependent cardiotoxicity that can reduce cardiac performance and eventually lead to overt heart failure. The field of cardio-oncology has emerged to safeguard the cardiovascular health of cancer patients receiving these therapies. It focuses on controlling risk factors, implementing preventive strategies, ensuring appropriate surveillance, and managing complications. This state-of-the-art review summarizes the current indications for anthracyclines in modern oncology, explores recent evidence on pathophysiology and epidemiology, and discusses advances in cardioprotection measures in the anthracycline-treated patient. Additionally, it highlights key clinical challenges and research gaps in this area.

Anthracyclines, Diastolic Dysfunction and the road to Heart Failure in Cancer survivors: An untold story.

Many cardiovascular diseases are characterized by diastolic dysfunction, which associates with worse clinical outcomes like overall mortality and hospitalization for heart failure (HF). Diastolic dysfunction has also been suspected to represent an early manifestation of cardiotoxicity induced by cancer drugs, with most of the information deriving from patients treated with anthracyclines; however, the prognostic implications of diastolic dysfunction in the anthracycline-treated patient have remained poorly explored or neglected. Here the molecular, pathophysiologic and diagnostic aspects of anthracycline-related diastolic dysfunction are reviewed in the light of HF incidence and phenotype in cancer survivors. We describe that the trajectories of diastolic dysfunction toward HF are influenced by a constellation of patient- or treatment- related factors, such as comorbidities and exposure to other cardiotoxic drugs or treatments, but also by prospective novel opportunities to treat diastolic dysfunction. The importance of a research-oriented multidimensional approach to patient surveillance or treatment is discussed within the framework of what appears to be a distinct pathophysiologic entity that develops early during anthracycline treatment and gradually worsens over the years.

Atherosclerotic Coronary Plaque Features in Patients With Chronic Obstructive Pulmonary Disease and Acute Coronary Syndrome.

Previous studies reported a robust relation between chronic obstructive pulmonary disease (COPD) and coronary artery disease (CAD). Systemic inflammation has been proposed as possible pathogenetic mechanism linking these 2 entities, although data on atherosclerotic coronary features in COPD patients are lacking. We studied atherosclerotic coronary plaque features in COPD patients presenting with acute coronary syndrome (ACS) using optical coherence tomography (OCT). ACS patients who underwent intracoronary OCT imaging of the culprit vessel were enrolled. Coronary plaque characteristics and OCT-defined macrophage infiltration (MØI) were assessed by OCT. ACS patients were divided into 2 groups according to the presence of an established diagnosis of COPD, and plaque features at the culprit site and along the culprit vessel were compared between the groups. Of 146 ACS patients (mean age:66.1 ± 12.7 years, 109 men), 47 (32.2%) had COPD. Patients with COPD had significantly higher prevalence of MØI (78.7% vs 54.5%, p = 0.005) and thin cap fibroatheroma (TCFA) (48.9% vs 22.2%, p = 0.001) at the culprit site. In the multivariate logistic regression, COPD was independently associated with MØI (odds ratio [OR] 21.209, 95% confidence interval [CI] 1.679 to 267.910, p = 0.018) and TCFA at the culprit site (OR 5.345, 95% CI 1.386 to 20.616, p = 0.015). Similarly, COPD was independently associated with both MØI (OR 3.570, 95% CI 1.472 to 8.658, p = 0.005) and TCFA (OR 4.088, 95% CI 1.584 to 10.554, p = 0.004) along the culprit vessel. In conclusion, in ACS patients who underwent OCT imaging of the culprit vessel, COPD was an independent predictor of plaque inflammation and vulnerability. These results may suggest that a higher inflammatory milieu in COPD patients might enhance local coronary inflammation, promoting CAD development and plaque vulnerability.

Short-term air pollution exposure and mechanisms of plaque instability in acute coronary syndromes: An optical coherence tomography study.

BACKGROUND AND AIMS: Air pollution is emerging as an important risk factor for acute coronary syndrome (ACS). In this study, we investigated the association between short-term air pollution exposure and mechanisms of coronary plaque instability evaluated by optical coherence tomography (OCT) imaging in ACS patients. METHODS: Patients with ACS undergoing OCT imaging were retrospectively selected. Mechanism of culprit lesion instability was classified as plaque rupture (PR) or intact fibrous cap (IFC) by OCT. Based on each case's home address, the mean daily exposures to several pollutants, including particulate matter 2.5 (PM2.5), on the same day of ACS and in the immediate days (up to 6 days) prior to the index ACS, were collected. RESULTS: 139 ACS patients were included [69 (49.6%) had PR and 70 (50.4%) IFC]. Patients with PR, compared to those with IFC, had higher PM2.5 exposure levels on the same day of ACS, without differences in the immediate 6 days before index ACS. At multivariate analysis, PM2.5 exposure on the same day of ACS was the only independent predictor of PR [OR = 1.912 per SD (8.6 µg/m3), CI95 % (1.087-3.364), p = 0.025]. Patients with PR presented a steady increase in PM2.5 daily exposure levels in the days preceding the occurrence of ACS, with a peak the day of ACS (p for trend = 0.042) CONCLUSIONS: This study demonstrates for the first time that a higher short-term PM2.5 exposure, on the same day of ACS, is associated with an increased risk of PR as a pathobiological mechanism of coronary plaque instability.

Current use of echocardiography in cardio-oncology: nationwide real-world data from an ANMCO/SIECVI joint survey.

Aims: The need for cardio-oncology competencies is constantly growing, and with the establishment of cardio-oncology services, cardiovascular imaging, particularly transthoracic echocardiography (TTE), has become pivotal in patients' management. However, care pathways for oncologic patients largely depend on local health structures' resources. This survey from Associazione Italiana Medici Cardiologi Ospedalieri and the Italian Society of Echocardiography and Cardiovascular Imaging aimed at investigating the use of echocardiography in cardio-oncology services and knowledge levels on cancer patients' care. Methods and results: Data were obtained via an electronic survey based on a structured questionnaire uploaded to the promoting societies' websites. Responses came from 159 centres with echocardiography. According to one-third of participating centres, workload related to cancer patients represented >30% of the total requests. The most common TTE indication (85%) was left ventricular ejection fraction (LVEF) evaluation. Many centres (55%) still assessed LVEF solely by bidimensional method or visual estimation in case of inadequate acoustic windows. At the same time, almost 40% of centres reported routinely using global longitudinal strain when feasible. We further performed a sub-analysis according to the presence (33%) or absence (77%) of dedicated cardio-oncologists, revealing significant differences in cardiovascular surveillance strategies and cardiotoxicity management. Conclusion: This survey on echocardiography practice for cancer patients reveals a significant gap between actual clinical practice and standards proposed by recommendations, underlying the need for stronger partnerships between cardiologists and oncologists and dedicated, well-structured cardio-oncology services.

Inflammation and acute cardiotoxicity in adult hematological patients treated with CAR-T cells: results from a pilot proof-of-concept study.

AIMS: Chimeric Antigen Receptor-T (CAR-T) cell infusion is a rapidly evolving antitumor therapy; however, cardiovascular (CV) complications, likely associated with cytokine release syndrome (CRS) and systemic inflammation, have been reported to occur. The CARdio-Tox study aimed at elucidating incidence and determinants of cardiotoxicity related to CAR-T cell therapy. METHODS: Patients with blood malignancies candidate to CAR-T cells were prospectively evaluated by echocardiography at baseline and 7 and 30 days after infusion. The study endpoints were i) incidence of cancer therapy-related cardiac dysfunction (CTRCD), CTRCD were also balanced for any grade CRS, but CTRCD occurred of Cardiology Guidelines on Cardio-Oncology (decrements of left ventricular ejection fraction (LVEF) or global longitudinal strain (GLS) and/or elevations of cardiac biomarkers (high sensitivity troponin I, natriuretic peptides) and ii), correlations of echocardiographic metrics with inflammatory biomarkers. RESULTS: Incidence of CTRCD was high at 7 days (59,3%), particularly in subjects with CRS. The integrated definition of CTRCD allowed the identification of the majority of cases (50%). Moreover, early LVEF and GLS decrements were inversely correlated with fibrinogen and interleukin-2 receptor levels (p always ≤ 0.01). CONCLUSIONS: There is a high incidence of early CTRCD in patients treated with CAR-T cells, and a link between CTRCD and inflammation can be demonstrated. Dedicated patient monitoring protocols are advised.

Echocardiographic left atrial stiffness index predicts high left ventricular filling pressures in patients with acute heart failure: an observational study.

BACKGROUND: In acute heart failure (AHF) patients, non-invasive estimation of left ventricular filling pressures (LVFPs) appears crucial to guide management. Although poorly investigated, left atrial (LA) mechanics play a pivotal role in this setting. This report sought to assess the correlation of echocardiographic LA stiffness index with invasive LVFPs and its diagnostic accuracy as compared to other parameters used in clinical practice. METHODS: In this observational, prospective study, 104 patients with suspected acute coronary syndrome and signs/symptoms of AHF were enrolled. Available invasive estimation of LVFPs was required. Comprehensive echocardiography was performed for all patients, including LA reservoir strain (LARS). LA stiffness index was derived by speckle-tracking analysis and Tissue Doppler imaging as early diastolic transmitral inflow velocity/mitral annulus early diastolic velocity [E/e']/LARS. RESULTS: Invasively measured LVFPs showed a strong correlation with LA stiffness index (Spearman ρ = 0.773, p < 0.0001), as well as with LARS and E/e'. Receiver operating characteristic (ROC) curve analysis was used to demonstrate better accuracy performed by LA stiffness index than average E/e', LA volume or LARS alone, in predicting high LVFPs. Guideline-recommended assessment of diastolic function was finally compared to LARS and LA stiffness index performances in an independent population group; we were hence able to obtain a LA stiffness threshold of 0.48 with a positive predictive value of 91.7% and a negative predictive value of 88.9% in identifying patients with high LVFPs. CONCLUSIONS: For the first time, diagnostic performance of LA stiffness index has been investigated in a heterogeneous AHF population, providing correlations with invasively measured LVFPs and comparisons with established diastolic function metrics.