Open research questions in Cardiovascular Function and Risk Factors

What the literature leaves open

• Acknowledgments There are four extensions that are logical extensions of the existing pipeline. Prospective Chinese anthracycline cohort (i). A The authors thank the creators of the EchoNet-Dynamic and CAMUS datasets for making their high-quality data publicly available for open scientific research.

  China-calibration-ready echocardiographic feature modeling for LVEF-derived dysfunction classification: a surrogate-label proof-of-concept · 2026 · DOI

• Whether discordant recovery between LV and LA function carries distinct prognostic implications in patients treated with ARNI-based therapy remains unknown.

  Persistent Atrial Myopathy Despite Ventricular Recovery: Prognostic Significance of Discordant LV-LA Strain Patterns in HFrEF · 2026 · DOI

• BackgroundGlobal longitudinal strain (GLS) and speckle-tracking-derived left ventricular ejection fraction (LVEF) are increasingly used to assess systolic function, but no consensus cut-off exists for identifying reduced LVEF as defined by cardiac magnetic resonance (CMR), the imaging reference standard.

  Diagnostic Accuracy of Global Longitudinal Strain and Speckle-Tracking-Derived Ejection Fraction for the Detection of Reduced Left Ventricular Ejection Fraction on Cardiac Magnetic Resonance: A Secondary Diagnostic Accuracy Analysis · 2026 · DOI

• Statistical analysis was further limited by the lack of adjustment for these factors, as well as for the medical comorbidities of each individual, for patient demographics, BSA-indexed SV, AVA indexed to BSA, and LVEF.

  The Effect of Antihypertensive Medication Classes on the Hemodynamic Severity Parameters of Classical and Paradoxical Low-Flow, Low-Gradient Aortic Stenosis · 2026 · DOI

• Keywords 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Hill force–velocity dependence; Patient-specific modelling; Myocardial mechanics; Left ventricular hypertrophy; Hypertension Hill’s force–velocity relationship is a fundamental property of myocardial contraction, yet its mechanical role in patient-specific left ventricular hypertrophy (LVH) remains underexplored.

  Patient-specific left ventricular hypertrophy under severe hypertension: mechanistic insights from Hill-type computational simulations · 2026 · DOI

• Reliance on SEC for thrombotic risk assessment reflects limitations in identifying the pre-thrombotic state, particularly due to the lack of standardized biomarkers for routine clinical use.

  Early activation of Virchow’s triad in feline hypertrophic cardiomyopathy: beyond spontaneous echo contrast and insights into translational thromboembolism · 2026 · DOI

• With the rising global prevalence of HFpEF, optimizing risk stratification and clinical management has become a top priority in cardiovascular research. To the best of our knowledge, the present study is among the first to systematically evaluate the combined association of LAD and EAT with HFpEF in patients with SA. Our findings highlight that both parameters are independently associated with the condition and closely related to disease severity in this patient population. risk and refine stratification In clinical practice, intensified monitoring of LAD and EAT in SA patients is warranted. When integrated with established biomarkers such as NT-proBNP, these imaging metrics could facilitate personalized help management strategies. From a therapeutic standpoint, emerging agents such as SGLT2 inhibitors and GLP-1 receptor agonists— known for their beneficial effects on cardiac metabolism and for EAT reducing accumulation and adverse LA remodeling (34, 35). Future research investigate whether early pharmacological intervention targeting these pathways can alter the clinical trajectory of patients with both SA and HFpEF.

  Predictive value of left atrial diameter and epicardial adipose tissue in sleep apnea and heart failure with preserved ejection fraction · 2026 · DOI

• However, the impact of anemia on outcomes in patients with HFpEF remains unclear. Although the exact pathogenesis of anemia in heart failure patients remains unclear, previous studies suggest that hemodilution, reduced erythropoietin production (particularly in those with chronic kidney disease), and impaired iron supply are likely contributing factors. [12,13] However, other studies have shown inconsistent findings. While anemia is associated with poor outcomes in heart failure with reduced ejection fraction (HFrEF), its prognostic significance in heart failure with preserved ejection fraction (HFpEF) remains debated.

  SEVERE ANEMIA PRESENTING AS HEART FAILURE WITH PRESERVED EJECTION FRACTION · 2026 · DOI

• The prevention paradigm emphasised by contemporary hypertension guidelines is urgent given the scale of the problem. An estimated 1.4 billion adults aged 30–79 years worldwide had hypertension in 2024 with only a minority having their BP controlled. In parallel, the global obesity crisis with over 890 million adults living with obesity in 2022 is accelerating the incidence of hypertension and cardiometabolic disease, particularly in younger populations. In this context, a key future challenge is designing hypertension pathways that integrate lifestyle and weight-focused prevention with targeted imaging and specialist input, rather than defaulting to resourceintensive investigations for all. Public and patient-facing initiatives will remain central to this strategy. Blood Pressure UK is the UK’s leading patient-focused charity dedicated to improving BP awareness and control, and its campaigns aim to identify the “missing millions” living with undiagnosed hypertension through opportunistic and home BP checks. In 2006, the European Society of Hypertension (ESH) developed the Hypertension Excellence Centre programme, to recognise clinical institutions providing the highest level of care for patients with hypertension, with over 120 centres certified to date. Complementing this initiative, the British and Irish Hypertension Society (BIHS) has described the rationale for specialist referral centres in the UK and is developing a Hypertension Specialist Accreditation Scheme to recognise both centres and individual clinicians with advanced expertise in hypertension. Such models could support standardised pathways for complex hypertension, improve access to work-up and provide a platform for training, audit and multicentre research in HHD. Beyond service development, the next phase of progress in HHD will depend on coordinated research priorities. The BIHS, in collaboration with the British Heart Foundation Clinical Research Collaborative (BHF CRC), has recently articulated national research priorities in hypertension, emphasising earlier-life disease, precision phenotyping, integration of digital health tools, and improved risk prediction beyond clinic BP alone. These priorities align closely with the need to better characterise hypertension-mediated cardiac damage in younger adults and to understand trajectories of structural remodelling over the life course. In this context, the forthcoming joint BIHS–UK Kidney Association (UKKA) RaDaR registry initiative for prospective data collection in individuals with hypertension under the age of 40 represents a significant opportunity [93, 94].

  Echocardiographic assessment in arterial hypertension: a contemporary narrative review · 2026 · DOI

• This review is narrative and integrative rather than a preregistered systematic review, and we did not pool estimates. The main limitation is heterogeneity across the underlying studies. Cohorts differed by setting (hospitalized, post-discharge, outpatient, trial), HFpEF definitions and diagnostic work-up, phenotype distributions, and endpoints. As a result, numerical performance metrics are not fully comparable, and transportability across contexts is constrained. Reporting was inconsistent. Discrimination was frequently provided, whereas calibration was variably assessed and rarely standardized. Effect measures were reported on different scales, and robust external validation and within-cohort headto-head comparisons were limited. In addition, several tools discussed as prognostic tools (e.g., H2FPEF and HFA-PEFF) were originally designed for diagnostic evaluation; therefore, prognostic use represents off-label repurposing and may be sensitive to missing components and local phenotype mix. Finally, the focus on clinician-usable scores may underrepresent higher-dimensional models that 70 A. Draghici and G.-A. Dan 9 could improve prediction but require infrastructure and recalibration before routine implementation.

  Clinical Prognostic Scoring Systems in Heart Failure with Preserved Ejection Fraction: An Integrative Review of Risk Prediction Models · 2026 · DOI

• exercise and Head-to-head comparisons often favor H2FPEF over the HFA-PEFF algorithm when step-3 (stress) testing is unavailable, likely because H2FPEF can be computed from routine clinical data and resting echocardiography alone [14]. HFA-PEFF comprises Heart Failure Association-led pre-test assessment, echocardiography and natriuretic peptides, functional testing, and final etiologic classification. As summarized in Table 2, the apparent prognostic separation of these diagnostic frameworks is strongly conditioned by feasibility. Still, HFA-PEFF has prognostic value when natriuretic peptide data and stress-echocardiography components are obtained. Practical barriers and variable discrimination across settings may limit its use as a stand-alone tool. In a hospitalized HFpEF cohort, the H2FPEF score correlated inversely with peak left-atrial strain and identified a higher risk of death or HF hospitalization, suggesting that H2FPEF continues to track atrial remodeling and carries prognostic information when stress testing is not feasible. Przewłocka-Kośmala et al. studied patients with exertional dyspnea and suspected HFpEF. In that head-to-head comparison, discrimination was similar for MAGGIC, H2FPEF, and step-2 HFA-PEFF (Harrell’s C = 0.637, 0.644, and 0.638, respectively), whereas incorporating step-3 exercise data improved discrimination (Harrell’s C = 0.715). This finding is setting-dependent (suspected HFpEF physiology cohort) and constrained by eligibility, because only patients in sinus rhythm were included (see Supplementary Table 2 and Supplementary Table 3). IMAGING AND FUNCTIONAL CONGESTION METRICS they Echo-anchored tools are often appealing in target filling pressures, HFpEF because pulmonary hypertension, and systemic congestion, which are processes that are tightly linked to decompensation and subsequent hospital admission. The MEDIA score, based on pulmonary artery systolic pressure, inferior vena cava collapsibility, E/e′, and lateral s′, offers a compact way to translate a multiparametric echocardiogram into a structured risk estimate. Its reported performance differs by setting. In acute HFpEF, higher scores are more strongly associated with short-term mortality. In stable outpatients, the signal shifts hospitalization heart-failure toward (Supplementary Table 2 and Supplementary Table 3). This pattern suggests settingdependent prognostic meaning. future Because HFpEF events are closely linked to congestion, markers of residual hemodynamic burden at discharge carry prognostic weight. Lung 6 Prognostic Scoring Systems in Heart Failure with Preserved Ejection Fraction 67 ultrasound (LUS) B-lines quantify pulmonary congestion. In acute HFpEF, a high B-line burden at discharge predicts 6-month rehospitalization or death and, in several analyses, outperforms admission measures. These results come primarily from early post-discharge windows and discharge-based protocols, so they should not be compared directly with admission-based scores or longer follow-up cohorts. Combining discharge LUS with BNP (B-type natriuretic peptide) and diastolic parameters further improves classification. A simple Bline count (using a Youden cut-point of 22 B-lines) can function as an imaging-based risk metric that complements global scores (e.g., GWTG-HF, MAGGIC) and HFpEF-specific instruments (MEDIA) with utility in the vulnerable post-discharge window. LUS behaves more like a modifiable risk state than a static label, which may explain its incremental value when measured at discharge rather than at presentation (Table 2).

  Clinical Prognostic Scoring Systems in Heart Failure with Preserved Ejection Fraction: An Integrative Review of Risk Prediction Models · 2026 · DOI

• magnetic 19. Ommen SR, Ho CY, Asif IM, Balaji S, Burke MA, Day SM, et al. 2024 AHA/ACC guideline of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2024;83:2324–2405. the management for 20. Bissell MM, Raimondi F, Ait Ali L, Allen BD, Barker AJ, Bolger A, et al. 4D flow resonance cardiovascular J consensus Cardiovasc Magn Reson. 2023;25:40. statement: 2023 update.

  Association of Myocardial T1/T2 Mapping Abnormalities With Late Gadolinium Enhancement and Left Ventricular Function · 2026 · DOI

• However, the extent of left ventricular outflow tract gradient (LVOTG) reduction after PESA varies considerably among patients, and reliable echocardiographic predictors of procedural efficacy remain unclear.

  Impact of Anterior Mitral Leaflet Length on the Efficacy of Intracardiac Echocardiography-Guided Endocardial Septal Ablation for HOCM · 2026 · DOI

• By performing credibly in a cardiology-based real-world setting, CHART exposed a previously under-recognised workflow gap between the nominal availability of echocardiography and timely access to structural cardiac assessment in routine care.

  Beyond Agreement: a real-world study of the workflow gap between echocardiography and timely structural cardiac assessmentHow a Validation Study Exposed a Hidden Gap in Cardiac Care · 2026 · DOI

• Abstract Single-beat (SB) approaches for estimating the end-systolic pressure–volume relationship (ESPVR) from a single pressure–volume ( P – V ) loop are widely used in experimental and clinical research, yet their structural foundations remain insufficiently formalized.

  Structural identifiability of single-beat estimation of the ventricular end-systolic pressure–volume relationship · 2026 · DOI

• Key strengths of this study include its extended follow- up, a relatively large and population- based cohort and a high participation rate. Standardised echocardiographic evaluation and the use of sex- specific, prognostically validated LAE thresholds strengthen the reliability and clinical relevance of our findings. The prospective design, with baseline risk factor measurement in early midlife, also supports a clear temporal relationship between BMI and subsequent LAE. However, several limitations should also be considered. Baseline and follow- up BMI were each assessed at a single time point, which does not capture intermediate changes in weight over the 26- year period. Although analyses of BMI change between baseline and follow- up were performed, the absence of repeated interim measurements may have underestimated cumulative exposure or temporal variability. The data did not include information on cardiovascular drug classes in the individual participant. The association of lower heart rate with LAE could therefore not be adjusted for use of beta blockers. Different instruments were used for clinic BP measurement at baseline and follow- up, and we cannot exclude that this may have influenced the difference in BP. Furthermore, 24- hour BP monitoring was not performed. Residual confounding from unmeasured factors cannot be excluded. Data on prevalent atrial fibrillation at baseline was lacking. Still, the prevalence of atrial fibrillation is low in the general population among individuals in their early forties,30 and the possibility of potential reverse causation is low. Finally, the cohort was predominantly of Northern European descent, which may limit the generalisability of the findings. The study did not include three- dimensional echocardiography or cardiac MRI, which are considered more accurate methods for the measurement of LA size. Because both LA size and BMI are indexed to height squared, this may have led to partial attenuation of true associations. Taken together, these strengths and limitations suggest that while replication in more diverse populations and with more refined cardiac imaging may add value, our results are robust and provide a novel, sex- specific understanding of how increased weight in midlife may predispose to LAE later in life.

  Sex-specific associations between midlife body mass index and later-life left atrial enlargement in the Hordaland health study · 2026 · DOI

• Journal of Cardiovascular Imaging (2026) 34:10 Page 9 of 10 using local acquisition practices and a predefined execu- tion environment; generalizability to other centers, ven- dors, and workflow ecosystems remains to be established.

  Fully automated artificial intelligence–based echocardiographic analysis substantially reduces workflow time while preserving measurement accuracy: a pilot study · 2026 · DOI

• Roque Oca Pernas1* María Navallas Irujo5, Ana García Durán6, Alex Pérez Casares7 and Flavio Zuccarino3,5, Nerea Hormaza Aguirre2, Marcos Mestas Nuñes3, Ana Capelastegui…

  How should we interpret excessive left ventricular trabeculation? Update on controversies from the cardiac imaging perspective · 2026 · DOI

• Despite the novel findings of this study, several limitations should be acknowledged. First, the study exclusion criteria resulted in a relatively selected cohort, which may limit the applicability of the findings and derived strain cut-offs to broader TAVI populations with more heterogeneous disease phenotypes. Second, a comparison with 2D CT strain would enhance the validity of the findings. Third, limited clinical follow-up and a relatively small, selected study population precluded evaluation of the incremental prognostic value of CTderived 3D strain, representing an important area for future research that should concurrently consider CT- and TTEderived 2D strain. Fourth, a comparison of circumferential and radial strain measurements between CT and TTE is needed. Fifth, right heart catheterisation (RHC) was not performed to confirm PH and its mechanism. Although RHC is not routinely performed during TAVI work-up and TTE reflects guidelinebased practice for non-invasive PH assessment in severe AS, TTE is inherently susceptible to misclassification, particularly when pulmonary pressures are estimated as absolute mmHg to Doppler values, owing assessment, TR severity, and loading conditions. For this reason, we elected a priori to utilise categorisation of PH probability to mitigate misclassification. Therefore, strain cut-off values derived from ROC analysis should be interpreted as thresholds for identifying a high echocardiographic probability of PH, rather than specific pulmonary pressure values. Sixth, although the administered DLP was comparable to other studies performing CT strain analysis (23), future work should focus on reducing radiation exposure. Seventh, to promote a wider clinical adoption of CT-derived myocardial strain, future studies should prospectively compare time between techniques. For reference, although not formally quantified in strain measurement limitations related inherent to the present study, our CT methodology required approximately 5 min per chamber per case on a computer with 12 central processing unit cores. Eighth, the modest sample size and specific selection criteria contributed to inter-group differences in myocardial volumes, EFs, and certain clinical characteristics, which limited the feasibility of multivariable analyses. Therefore, the important question of whether CT-derived strain provides independent predictive value beyond established biomarkers such as myocardial volumes and EF for detecting extra-valvular remodelling associated with PH in severe AS warrants further investigation. Larger studies the spectrum of extra-valvular remodelling are needed to assess the utility of multi-chamber 3D CT strain as a risk-stratification tool before TAVI.

  Multi-chamber three-dimensional myocardial strain assessment by computed tomography: a comparison with speckle tracking echocardiography and association with pulmonary hypertension in severe aortic stenosis · 2026 · DOI

• AI is not expected to replace clinicians but will function as a “second reader,” augmenting clinical expertise. Future developments will likely focus on integration with multimodal imaging, real-time decision support systems, personalized risk prediction models, and wider accessibility in low-resource settings. As technology evolves, AI will play a pivotal role in supporting both cardiologists and nonspecialists in delivering high-quality cardiac care.

  Artificial Intelligence in Echocardiography: Transforming Cardiac Imaging · 2026 · DOI

• The first limitation is that the sample size was relatively small. Thus, the study may have been underpowered to exclude an effect of RWMA on the trending ability of single-wall autoMAPSE. However, the concordance rates in the four patterns of RWMA suggest that any unde- tected effect of RWMA on trending ability is relatively small. Second, the septal wall autoMAPSE did not show adequate trending ability (concordance rate 88%). How- ever, a single observation in the other direction would have tipped the results to meet the threshold due to the small sample size. Notably, the same septal wall had ade- quate trending ability when assessed by single-wall man- ual MAPSE. It may, therefore, be possible that the septal wall autoMAPSE can be used if no other walls are visible. Nevertheless, the findings of this study, together with previous studies suggesting limited monitoring feasibility Yu et al. Intensive Care Medicine Experimental (2026) 14:44 Page 8 of 10 in this wall [7, 9], suggest that the septal wall MAPSE should not be the wall-of-choice, especially in patients undergoing cardiac surgery. Third, our data did not allow comparison of changes in MAPSE versus those of global longitudinal strain. However, the two parameters are highly correlated [36], and MAPSE was even found to have superior prognostic abilities compared to global lon- gitudinal strain in a head-to-head comparison using car- diac magnetic resonance imaging in a cardiology cohort [37]. Finally, the subjective visual analysis of RWMA was performed by two echocardiographic researchers and not by expert cardiologists. However, visual analysis has suboptimal reproducibility even among experts [38, 39]. There are currently no gold standards for RWMA anal- ysis, and the method used in this study is the current clinical standard in perioperative and critical care echo- cardiography. We did not use ultrasound contrast agents to optimize RWMA assessment, as the present study is a secondary analysis of already-obtained data. Novel meth- ods for more accurate quantification of regional function are underway, but none have yet reached clinical appli- cation [21, 40]. Given the uncertainty of the assessment of RWMA and the lack of a gold standard, our approach using a third independent observer to settle the disagree- ment between the first two yielded a consistent agree- ment among at least two observers.

  Automatic monitoring of single-wall MAPSE by transesophageal echocardiography for tracking global left ventricular function irrespective of regional hypokinesia: a secondary analysis · 2026 · DOI

• The paper documents improvements in diastolic performance (E/A ratio, e' velocity) but does not investigate the neurohormonal and metabolic mechanisms regulating these cardiac changes. Studies measuring circulating biomarkers (e.g., natriuretic peptides, inflammatory cytokines, adipokines) alongside echocardiographic diastolic parameters would elucidate the pathophysiology of obesity-induced cardiac remodeling reversal.

  Echocardiographic Assessment of Left Ventricular Mass Regression and Functional Changes after Bariatric Surgery · 2026 · DOI

• The research involved a small population size, which restricts the generalizability of echocardiographic findings regarding structural and functional cardiac changes after bariatric surgery. Future studies should recruit larger, more heterogeneous patient cohorts to validate whether E/A ratio improvements and LV mass regression are consistent across diverse obesity phenotypes.

  Echocardiographic Assessment of Left Ventricular Mass Regression and Functional Changes after Bariatric Surgery · 2026 · DOI

• The study notes that follow-up duration was restricted, limiting analysis of long-term cardiac remodeling patterns after bariatric surgery. Research with extended follow-up periods (≥2-5 years post-surgery) is needed to characterize the temporal dynamics of diastolic performance improvement and LV mass regression sustained over time.

  Echocardiographic Assessment of Left Ventricular Mass Regression and Functional Changes after Bariatric Surgery · 2026 · DOI

• The authors report that LV mass index was not calculated in their analysis of cardiac remodeling after bariatric surgery. Inclusion of indexed LV mass measurements (normalized to body surface area) is needed to better quantify left ventricular mass regression independent of body size changes.

  Echocardiographic Assessment of Left Ventricular Mass Regression and Functional Changes after Bariatric Surgery · 2026 · DOI

Most-cited papers in Cardiovascular Function and Risk Factors

• The Limited Reliability of Physical Signs for Estimating Hemodynamics in Chronic Heart Failure · JAMA · 1989 · 1,002 citations
• Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes · New England Journal of Medicine · 2024 · 628 citations
• 2023 Focused Update of the 2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure · European Journal of Heart Failure · 2024 · 396 citations
• Prognostic Value of Echocardiographically Assessed Right Ventricular Dysfunction in Patients With Pulmonary Embolism · Archives of Internal Medicine · 2004 · 243 citations
• The assessment of left ventricular diastolic function: guidance and recommendations from the British Society of Echocardiography · Echo Research and Practice · 2024 · 127 citations
• Comparative study on the predictive value of TG/HDL-C, TyG and TyG-BMI indices for 5-year mortality in critically ill patients with chronic heart failure: a retrospective study · Cardiovascular Diabetology · 2024 · 118 citations
• Indole-3-Propionic Acid Protects Against Heart Failure With Preserved Ejection Fraction · Circulation Research · 2024 · 117 citations
• Effect of Semaglutide on Cardiac Structure and Function in Patients With Obesity-Related Heart Failure · Journal of the American College of Cardiology · 2024 · 115 citations
• Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial · Nature Medicine · 2024 · 112 citations
• Update on obesity, the obesity paradox, and obesity management in heart failure · Progress in Cardiovascular Diseases · 2024 · 105 citations

Most recent work

• Strain measures of the left ventricle and left atrium are composite measures of left heart geometry and function · medRxiv · 2026
• Predictive accuracy of left atrial strain parameters for risk of atrial fibrillation recurrence: a systematic review and meta-analysis · Frontiers in Medicine · 2026
• Echocardiographic prediction of functional coronary stenosis: global longitudinal strain as a key determinant of quantitative flow ratio · Internal and Emergency Medicine · 2026
• Association of organ dysfunction trajectories and major adverse cardiovascular events using clinical obesity in UK Biobank · Frontiers in Endocrinology · 2026
• skNAC is a Key Driver of Cardiomyocyte Integrity Against Pathological Cardiac Hypertrophy and Heart Failure · bioRxiv · 2026
• Association Between Predicting Risk of Cardiovascular Disease Events (PREVENT) Risk Scores and Subclinical Cardiovascular Disease: Insights From the Project Baseline Health Study · Journal of the American Heart Association · 2026
• Cardiac Lipid Metabolism: Cells, Metabolites, and Rhythms · Circulation Research · 2026
• The role of artificial intelligence in early detection and risk prediction of ischemic heart disease · Annals of Medicine & Surgery · 2026
• Revolutionizing Heart Failure Management With Artificial Intelligence: A Narrative Review of Diagnostic, Prognostic, and Therapeutic Innovations · Health Science Reports · 2026
• Evaluating left ventricular function and myocardial fibrosis in hypertrophic obstructive cardiomyopathy with corrected myocardial work · Echo Research & Practice · 2026

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