“Sing me something new” Noel Gallagher1

NEW CHALLENGES

We live in the era of the aging society. Owing to increasing demographic aging and exponential demographic growth, people aged 80 years or older are projected to triple between 2020 and 2050 to 426 million.2

This unique phenomenon leads to unprecedented challenges for health systems, particularly regarding cardiovascular disease. The latter represents the leading global cause of death and disability-adjusted life years, typically affecting older age groups. Heart failure (HF) prevalence is expected to continuously increase, particularly HF with preserved ejection fraction (HFpEF), which occurs in older patients and shares several pathophysiological mechanisms with the process of physiological aging of the heart.3 Diabetes mellitus (DM) is a major cardiovascular risk factor, i.e., 45% prevalent in patients with HFpEF. Remarkably, the prevalence of DM (from 3.0% [95% CI, 2.2–3.7] to 4.1% [95% CI, 3.5–4.7]) significantly increased among young adults in the United States from 2009 to 2020, suggesting harmful lifestyle impacts in recent years.4

These data call for tragic scenarios regarding the sustainability of health care systems in the following years if a substantial step forward regarding precautionary measures will not be taken soon. Major improvements in dietary and lifestyle habits will be necessary, but more is needed. Given that most patients with initial cardiac dysfunction are asymptomatic, an early implementation of cardiovascular drugs targeting specific mechanisms to halt or revert pathological processes underlying HF would hopefully prevent cardiovascular outcomes and reduce health care costs. In this scenario, sensible and accurate imaging markers of cardiac dysfunction are essential in guiding appropriate therapy.

NEW DRUGS

Sodium–glucose cotransporter-2 inhibitors (SGLT2-i), initially proposed as glucose-lowering agents in DM, have been recently introduced as first-line drugs for patients with or without DM and HF with reduced left ventricular ejection because of tangible clinical benefits. In those patients on optimal medical therapy, implementing SGLT2-i led to a 25% additional reduction of major cardiovascular events.

Based on the favorable effects in patients with HF with reduced left ventricular ejection and the absence of reliable treatment options in patients with HFpEF, SGLT2-i have been recently tested in this scenario. EMPEROR Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) have shown that Empagliflozin and Dapagliflozin can significantly reduce the combined end point of HF-related hospitalization and cardiovascular death (−21% and −18%, respectively; the effects were mainly driven by HF-related hospitalizations). Thus, SGLT2-i are the first drug class demonstrating clinical benefits in this population. The mechanisms underlying SGLT2-i's effects on the cardiovascular system are complex and beyond the scope of this editorial.

NEW IMAGING MARKERS

Left ventricular ejection fraction (LV-EF) is the vox populi of cardiac function and is the single imaging marker most used for clinical decision-making in daily practice. Despite the significant improvement in accuracy and reproducibility brought by three-dimensional echocardiography (3DE), which does not rely on geometric assumptions in contrast with two-dimensional echocardiography (2DE), LV-EF presents intrinsic limitations for evaluating cardiac function. LV-EF reflects LV pump function but not precisely systolic function. Accordingly, many patients with HF show normal LV-EF. Two conditions may characterize these patients: (1) diastolic dysfunction but normal systolic function and (2) early systolic dysfunction not captured by LV-EF, given the low sensibility and accuracy of this parameter to detect subclinical dysfunction. Similarly, changes in heart rate, blood volume, valve regurgitations, and cardiac shunts can affect LV-EF independently of systolic function.

Therefore, alternative and novel parameters with less preload dependency are needed to estimate cardiac function better and tailor specific treatments potentially able to halt the vicious cycle of HF in an early, initial stage of cardiac dysfunction.

2DE-speckle tracking echocardiography (STE) is a strain technique that quantifies myocardial mechanisms, and global longitudinal strain (GLS), the most validated derived parameter, has rapidly become an accurate surrogate of LV systolic function used in the daily practice.5 The so-called “speckles” are acoustic markers originated by the constructive and destructive interference from ultrasound beam hitting the myocardium, resulting in a frame-by-frame trackable target thoroughly the cardiac cycle. Beyond being significantly less load-dependent than LV-EF, LV-GLS is relatively angle- and operator-independent, can identify subclinical LV dysfunction, and contributes incrementally to LV-EF to risk stratification in several cardiac diseases.5

Myocardial work (MW) is calculated as LV pressure applied over strain.6 In so doing, this technique takes into account the dynamic myocardial contraction in relationship to various loading conditions. Global work efficiency (GWE) is a derived index indicating a virtuous cardiac function, resulting from the ratio between the constructive work and the sum of constructive and wasted work: GCW/(GCW + GWW). By only requiring a noninvasive measurement of blood pressure, MW is a quick and feasible method that theoretically provides a more accurate assessment of LV systolic function than strain parameters.

In their interesting article, Russo et al7 evaluated changes in these advanced echocardiographic markers of cardiac function among 35 asymptomatic patients with well-controlled DM treated with SGLT2-i with normal LV-EF and compared with an age- and sex-matched control group. By excluding patients with poorly controlled DM, established or suspected coronary artery disease, or significant chronic kidney disease, the authors weed out patients at the highest risk of coronary artery disease, making their findings particularly captivating from the perspective of early primary prevention.

Baseline assessment revealed subclinical systolic dysfunction in the DM group (LV-GLS: 15.8 ± 8.1%; normal values >18%) in contrast to the control group (LV-GLS: 22.1 ± 1.4%; P < 0001). Patients with DM also showed lower GWE (91± 4 vs. 94± 3%; P: 0.0007) and worsened indexes of diastolic function (ie, E\E′ ratio; 8.3± 2.5 vs. 6.3± 0.9; P < 0.0001) than controls. At the six-month follow-up after SGLT-i therapy, patients with DM showed a significant improvement of LV-GLS (16.2± 2.8 vs. 18.7± 2.4%; P = 0.003) and GWE (90.3± 3.5 vs. 93.3± 3.2%; P = 0.0004), expressing early reverse remodeling. By contrast, E/e’ did not significantly change at follow-up. Advanced imaging markers allowed the authors to capture an improvement in systolic function exerted by SGLT-i at a very early stage of the natural history of DM.

FUTURE PERSPECTIVES

Multicentric studies, including larger sample sizes with appropriate follow-up, are needed to confirm the authors' results and to translate their instrumental findings into clinical benefits for patients and cost-effective strategies for health care systems.

In parallel, it would also be interesting to conduct a more comprehensive baseline imaging assessment in the same type of patients, given that the advanced echocardiographic markers used by the authors have notable flaws. In fact, 2D-STE is not completely load-independent and after-load increase parallels a decrease in STE-derived indexes. MW is somewhat load-dependent too. End-diastolic LV pressure, which reflects the preload, is not considered by MW software. This issue is particularly relevant for patients with HF and increased filling pressures, in which the pressure-strain loop area significantly changes, and MW algorithms may not be completely reliable. Moreover, alterations in LV wall thickness and morphology affect MW according to Laplace law but are not accounted for in current MW algorithms. Finally, STE and MW are based on 2DE and are limited by spatial and geometrical assumptions that oversimplify systolic function.

Regarding diastolic function, it would be interesting to confirm the lack of improvement in diastolic function registered by the authors with conventional parameters (ie, E/e’) by measuring left atrial strain-derived parameters. The latter is an emerging tool to assess diastolic dysfunction with substantial advantages over conventional indexes.5

In comparison with echocardiography, cardiovascular magnetic resonance (CMR) is poised to be a better tool to assess subclinical cardiac dysfunction, given its invaluable capability to measure cardiac chambers remodeling and tissue abnormalities that can occur early in patients with DM and HFpEF.8 CMR markers of ventricular and atrial dysfunction and features of myocardial tissue alterations that may precede functional abnormalities have considerable potential in detecting adverse cardiac remodeling in its first steps.

Multimodality imaging studies, including long-term follow-up in asymptomatic patients with well-controlled DM, are needed to investigate the potential incremental value of CMR over echocardiography in tracking favorable structural and functional changes from SGLT-i. Yet, owing to the poor availability and high costs of CMR, gatekeeping for this technique based on advanced echocardiography will remain necessary.

Finally, nonimaging biomarkers can help in the aim of early identification of subclinical myocardial damage to tailor specific treatments,9 and the usage of Artificial Intelligence may identify reliable baseline imaging and nonimaging parameters to predict long-term cardiovascular outcomes in asymptomatic patients.

Overall, Russo et al and other research groups10 are paving the way to a potential terrific interplay between advanced imaging biomarkers and SGLT-i. In an ideal scenario, the former will track the favorable effects of these impressive drugs in patients with early cardiac dysfunction. We believe the authors will go on in their brilliant purpose to achieve clinically relevant results. These findings would assist physicians in the early initiation of specific treatments for preventing cardiovascular outcomes and health care systems from withstanding the dramatic impact of novel challenges to which they will be called soon (Fig. 1).

FIGURE 1.:

Novel imaging markers, treatments, and challenges in cardiovascular diseases. CV, cardiovascular; FT, feature-tracking; LGE, late gadolinium enhancement; TTE, transthoracic echocardiography.

REFERENCES 1. Gallagher Noel. Stand by me. Be here now. Creation Records; 1997. 2. Organisation for Economic Co-operation and Development. Available at: https://www.oecd.org 3. Tini G, Cannatà A, Canepa M, et al. Is heart failure with preserved ejection fraction a ‘dementia’ of the heart? Heart Fail Rev. 2022;27:587–594. 4. Aggarwal R, Yeh RW, Joynt Maddox KE, et al. Cardiovascular risk factor prevalence, treatment, and control in US adults aged 20 to 44 Years, 2009 to March 2020. JAMA. 2023;329:899–909. 5. Mor-Avi V, Lang RM, Badano LP, et al. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications. J Am Soc Echocardiogr. 2011;24:277–313. 6. Ilardi F, D'Andrea A, D'Ascenzi F, et al. Myocardial work by echocardiography: principles and applications in clinical practice. J Clin Med. 2021;10:4521. 7. Russo V, Caracciolo D'Aquino MM, Caturano A, et al. Improvement of global longitudinal strain and myocardial work in type 2 diabetes patients on sodium-glucose cotransporter 2 inhibitors therapy. J Cardiovasc Pharmacol. 2023. [Ahead of print]. 8. Chamsi-Pasha MA, Zhan Y, Debs D, et al. CMR diastole CMR in the evaluation of diastolic dysfunction and phenotyping of HFpEF: current role and future perspectives. JACC: Cardiovasc Imaging. 2020;13:283–296. 9. Morfino P, Aimo A, Castiglione V, et al. Treatment of cardiac fibrosis: from neuro-hormonal inhibitors to CAR-T cell therapy. Heart Fail Rev. 2023;28:555–569. 10. Theofilis P, Antonopoulos AS, Katsimichas T, et al. The impact of SGLT2 inhibition on imaging markers of cardiac function: a systematic review and meta-analysis. Pharmacol Res. 2022;180:106243.