This review summarizes mechanistic, preclinical, and emerging clinical evidence on whether glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) may modify aortic disorders. In addition to metabolic effects, GLP-1 RAs have anti-inflammatory, antioxidant, and antiatherogenic properties and reduce major cardiovascular events in large trials. Since inflammation and extracellular matrix remodeling contribute to aortic valve calcification, root dilation, aneurysm growth, and aorto-occlusive disease, GLP-1 RAs may offer a unified therapeutic approach. A narrative review was performed using animal studies, population data, and cardiovascular outcome trials published up to May 2025, focusing on mechanisms, disease outcomes, and translational gaps. In vitro and rodent studies show that GLP-1 RAs inhibit IL-1β, TNF-α, and matrix metalloproteinases, preserve elastin structure, and promote M2 macrophage activity, slowing both thoracic and abdominal aneurysm growth. Similar antiosteogenic signaling may reduce valve calcification, though clinical validation is lacking. Observational data and post hoc analyses report fewer adverse limb events and improved walking distance in peripheral artery disease, suggesting benefit in aorto-occlusive syndromes. However, evidence for aortic regurgitation is currently absent. Overall, mechanistic and early clinical findings support GLP-1 RAs as potential disease-modifying agents along the aortic tree. Further imaging-based studies in calcific valve disease and aneurysms and trials focused on peripheral artery disease are now warranted. If confirmed, these agents could extend their benefits beyond metabolic disease to patients at risk of serious aortic complications.

Diastolic dysfunction and delayed ventricular repolarization are typically observed in the elderly, but whether these defects are intimately associated with the progressive manifestation of the aging myopathy remains to be determined. In this regard, aging in experimental animals is coupled with increased late Na+ current (I-Na,I-L) in cardiomyocytes, raising the possibility that I-Na,I-L conditions the modality of electrical recovery and myocardial relaxation of the aged heart. For this purpose, aging male and female wild-type (WT) C57Bl/6 mice were studied together with genetically engineered mice with phosphomimetic (gain of function, GoF) or ablated (loss of function, LoF) mutations of the sodium channel Nav1.5 at Ser571 associated with, respectively, increased and stabilized I-Na,I-L. At similar to 18 mo of age, WT mice developed prolonged duration of the QT interval of the electrocardiogram and impaired diastolic left ventricular (LV) filling, defects that were reversed by I-Na,I-L inhibition. Prolonged repolarization and impaired LV filling occurred prematurely in adult (similar to 5 mo) GoF mutant mice, whereas these alterations were largely attenuated in aging LoF mutant animals. Ca2+ transient decay and kinetics of myocyte shortening/relengthening were delayed in aged (similar to 24 mo) WT myocytes, with respect to adult cells. In contrast, delayed Ca2+ transients and contractile dynamics occurred at adult stage in GoF myocytes and further deteriorated in old age. Conversely, myocyte mechanics were minimally affected in aging LoF cells. Collectively, these results document that Nav1.5 phosphorylation at Ser571 and the late Na+ current modulate the modality of myocyte relaxation, constituting the mechanism linking delayed ventricular repolarization and diastolic dysfunction. NEW & NOTEWORTHY We have investigated the impact of the late Na current (I-Na,I-L) on cardiac and myocyte function with aging by using genetically engineered animals with enhanced or stabilized I-Na,I-L, due to phosphomimetic or phosphoablated mutations of Nav1.5. Our findings support the notion that phosphorylation of Nav1.5 at Ser571 prolongs myocardial repolarization and impairs diastolic function, contributing to the manifestations of the aging myopathy.

Approximately one third of the population in the US has metabolic syndrome (MetS), a condition associated with increased risk for coronary artery disease and myocardial infarction. But whether MetS alters properties of the myocardium before the occurrence of ischemic insults remains to be fully elucidated. For this purpose, MetS was induced in C57Bl/6 female mice with a dietary paradigm recapitulating Western-style alimentary habits in humans. Animals on regular chow were used as control (Ctrl). Cardiac function was assessed by echocardiography and myocytes were studied under field stimulation, following enzymatic dissociation. From 3-12 months on the diet, MetS mice had increased body weight, impaired glucose metabolism, augmented left ventricular (LV) mass, but preserved cardiac function, with respect to Ctrl mice. Using ECGs, heart rate variability was attenuated in MetS mice, suggesting that metabolic disorders alter cardiac sympathovagal balance. At the cellular level, LV myocytes from MetS mice had increased volume (+24%), enhanced fractional cell shortening (+42%), and faster kinetics of relaxation (-27%), with respect to Ctrl myocytes. Because cAMP and protein Kinase A (PKA) modulates myocardial contractility upon activation of G-protein coupled receptors, including beta-adrenergic receptors (B-AR), levels of these molecules were assessed by ELISA assay. Consistent with enhanced cell shortening and faster relaxation, levels of cAMP and PKA activity were, respectively, 1.8-fold and 1.9-fold larger in MetS myocytes, in comparison to Ctrl cells. Interestingly, inhibition of PKA with H-89 reduced cell shortening (-30%) and delayed kinetics of relaxation (+50%) in MetS myocytes but had no major effects on Ctrl cells. To establish the contribution of the cAMP/PKA signaling in the functional behavior of the heart with MetS, mice were treated with the B-AR blocker propranolol. Under this condition, MetS mice had reduced ejection fraction and impaired indices of diastolic function, with respect to Ctrl animals. Interestingly, myocytes obtained from Ctrl and MetS mice treated with the B-AR blocker had comparable cell shortening and kinetics of relaxation. Collectively, these results indicate that metabolic syndrome alters the functional properties of the myocytes and heart by affecting cAMP homeostasis. These properties may increase myocardial oxygen demand predisposing the heart to ischemic insults.

Metabolic syndrome (MetS) increases the risk of coronary artery disease, but effects of this condition on the working myocardium remain to be fully elucidated. In the present study we evaluated the consequences of diet-induced metabolic disorders on cardiac function and myocyte performance using female mice fed with Western diet. Animals maintained on regular chow were used as control (Ctrl). Mice on the Western diet (WesD) had increased body weight, impaired glucose metabolism, preserved diastolic and systolic function, but increased left ventricular (LV) mass, with respect to Ctrl animals. Moreover, WesD mice had reduced heart rate variability (HRV), indicative of altered cardiac sympathovagal balance. Myocytes from WesD mice had increased volume, enhanced cell mechanics, and faster kinetics of contraction and relaxation. Moreover, levels of cAMP and protein kinase A (PKA) activity were enhanced in WesD myocytes, and interventions aimed at stabilizing cAMP/PKA abrogated functional differences between Ctrl and WesD cells. Interestingly, in vivo β-adrenergic receptor (β-AR) blockade normalized the mechanical properties of WesD myocytes and revealed defective cardiac function in WesD mice, with respect to Ctrl. Collectively, these results indicate that metabolic disorders induced by Western diet enhance the cAMP/PKA signaling pathway, a possible adaptation required to maintain cardiac function.

Diastolic dysfunction and delayed ventricular repolarization are observed in the elderly, but whether these defects are intimately associated in the progressive manifestation of the aging myopathy remains to be determined. Interestingly, aging in experimental animals is coupled with increased late Na current (INaL) in cardiomyocytes, raising the possibility that INaL conditions the modality of electrical recovery and relaxation of the aged heart. Thus, male wild-type (WT) and genetically engineered mice with phosphomimetic (gain-of-function, GoF) or ablated (loss-of-function, LoF) mutations of the sodium channel Nav1.5 at Ser571, a phosphorylation site mediating INaL enhancement, were studied. With respect to WT mice at ~5 months of age (m), animals at ~18 m had 20% prolongation of the QT interval of the electrocardiogram and declined diastolic left ventricular filling, consisting of a 23% increase in isovolumic relaxation time (IVRT). These defects were reversed by INaL inhibition with GS967. Prolonged repolarization and impaired LV filling occurred prematurely in GoF mice (QT, +20%; IVRT, +8%, at ~5 m vs. WT), whereas age-related alterations were largely attenuated in LoF animals. At ~24 months, QT interval was not different in WT (66±4 ms) and GoF (70±5 ms) mice but was shorter in LoF (64±5 ms) animals, with respect to GoF. Similarly, IVRT was comparable in WT (22±2 ms) and GoF (22±2 ms) mice, but shorter in LoF (18±3 ms). In field stimulated cells, with respect to WT myocytes at ~5 m, WT cells at ~24 m had prolonged time to peak (+26%) and time to 50% relaxation (+44%). Delayed cell contraction/relaxation was apparent in GoF myocytes at ~5 m (+12% and +27%, with respect to WT), and further deteriorated with age. In contrast, LoF myocytes at ~5 m had contractile kinetics comparable to adult WT cells, and modest alterations occurred in cells at ~24 m. Importantly, inhibition of INaL was effective in correcting kinetics of cell mechanics in old WT mice and adult and old GoF animals but had no effect in LoF myocytes and WT cells at ~5 months. Collectively, these results document that the late Na+ current modulates the modality of myocyte relaxation, constituting the mechanism linking delayed ventricular repolarization and diastolic dysfunction in the elderly.

Heart rate variability (HRV) is an index of cardiovascular health and reflects the ability of the heart to modify beating rate in response to neurohumoral factors. Alterations of HRV have been reported in patients with myocardial infarction (MI), but whether experimental models of ischemic disease recapitulate features of HRV observed in human remains to be clarified. HRV was evaluated in female mice using electrocardiograms collected in the conscious, restrained state using a tunnel device. Naïve mice and animals after permanent coronary artery ligation (MI) were studied. HRV was assessed using time-domain, frequency-domain, and non-linear parameters. By echocardiography, all infarcted animals presented akinetic anterior LV free wall and, respect to naïve mice, a 1.8-fold increase in LV diameter and a 64% reduction in ejection fraction. At 3 to ~30 days after MI, RR interval duration was preserved with respect to non-infarcted mice, whereas standard deviation of RR interval duration (SDRR), was reduced by 61-70% at 3 days to ~30 days after MI. Standard deviation of instantaneous (SD1) and long-term (SD2) RR interval variability, indicative of parasympathetic and sympathetic influence, respectively, were derived from Poincaré plots of RR i and RR i+1 intervals. SD1 and SD2 were reduced after MI (64-73% and 61-70%, respectively). Moreover, by frequency-domain analysis, the contribution of high- (1.5-5 Hz), low- (0.15-1.5 Hz), and very low-frequency (0-0.15 Hz) components of RR interval oscillations were assessed. High-frequency components, which are under the influence of the sympathetic nervous system, were not affected after MI; low-frequency oscillations, attributed to baroreflex-mediated modulation of heart rate, were reduced at 3 and 7 days after MI, whereas very low-frequency components, attributed to the modulatory action of the renin-angiotensin system, thermoregulation, and, partly, parasympathetic activity, were reduced from 3-30 days after MI. Moreover, the ratio between low and high frequency components, indicative of sympathovagal balance, was reduced after MI. In conclusion, myocardial infarction in rodent results in altered heart rate variability, which appears to be secondary, in part, to altered autonomic regulation.