Jason D. Roh

BACKGROUND: Hypertensive disorders of pregnancy (HDP) affect over 10% of pregnancies worldwide, but their association with cardiovascular-kidney-metabolic (CKM) syndrome remains unexplored. METHODS: The present study included parous UK Biobank participants. The primary exposure was HDP history. CKM syndrome was categorized from stage 0 (no risk factors) to 4 (cardiovascular disease). Logistic regression tested the association of HDP history with CKM stage, adjusted for age, age ² , race, Townsend Deprivation Index, and smoking status. Cox models evaluated progression to stage 4, in addition, adjusting for baseline CKM stage. Replication analyses were performed in the Women Health Initiative, with CKM stage assessed at 2 study visits. RESULTS: Among 219 639 UK Biobank (mean age, 56.9 years) and 3591 Women Health Initiative participants (61.7 years at baseline, 78.1 years at the follow-up visit), 2836 (1.3%) and 304 (8.4%), respectively, had a history of HDP. In the UK Biobank, HDP history was significantly associated with higher CKM stage (adjusted odds ratio, 3.40 [95% CI, 3.12–3.71]; P P P <0.001). Replication in the Women Health Initiative produced consistent results. CONCLUSIONS: HDP history was associated with greater CKM stage and progression to advanced CKM syndrome, supporting its use as an early life predictor of adverse CKM trajectories.

Background and Aims: Peripartum cardiomyopathy (PPCM) is an idiopathic form of heart failure occurring in the peripartum phase. Elevated circulating levels of the senescence–associated–secretory–phenotype (SASP) factor Activin-A have been associated with heart failure severity in acute PPCM patients at baseline diagnosis. Here, we investigated Activin-A serum levels in the German PPCM registry in acute PPCM and during left ventricular (LV) recovery. Methods and results: Clinical data including LV ejection fraction (LVEF) and Activin-A serum levels were assessed at initial diagnosis (baseline [BL]) and during follow-up (FU) at 3 months (M) and 6M in PPCM patients from the German PPCM Registry (n = 151, mean age 33 ± 5 years) compared to postpartum healthy controls (n = 27, mean age 32 ± 5 years). Activin-A serum levels at BL were elevated (404 pg/ml; interquartile range [IQR]: 197–815, n = 151) compared to healthy postpartum controls (240 pg/ml, IQR:148–446, n = 27; P < .01) and remained persistently elevated above postpartum healthy controls at 3 M (418 pg/ml, IQR: 169–806, n = 100) and 6M-FU (520 pg/ml, IQR: 214–1131, n = 104). Activin-A levels at BL did not correlate with LVEF (Spearman r = 0.10, P = .2416, n = 139), NT-proBNP (r = 0.096, P = .2766, n = 131), CRP (r = −0.0008, P = .9933; n = 110) or PPCM biomarker plasminogen-activator-inhibitor-1 (PAI-1) (r = 0.095, P = .3273, n = 109). The majority of PPCM patients showed LV recovery 6M after initial diagnosis, indicated by improved LVEF (PPCM BL: 25%, IQR: 20–33, n = 152; 6M-FU: 52% IQR: 45–56, n = 128, P < .0001). Activin-A levels did not differ between full or incomplete LV recovery, or between patients with hypertensive pregnancy disorders. Conclusions: In PPCM patients from the German PPCM registry Activin-A serum levels were elevated at diagnosis, remained persistently high after 3M- and 6M-FU but were not associated with LV recovery.

Endurance exercise promotes adaptive growth and improved function of myocytes, which is supported by increased mitochondrial activity. In skeletal muscle, these benefits are in part transcriptionally coordinated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The importance of PGC-1α to exercise-induced adaptations in the heart has been unclear. Here we show that deleting PGC-1α specifically in cardiomyocytes prevents the expected benefits from exercise training and instead leads to heart failure after just 6 weeks of training. Consistent with this, in humans, rare genetic variants in PPARGC1A, which encodes PGC-1α, are associated with increased risk of heart failure. In this model, we identify growth differentiation factor 15 (GDF15) as a key heart-secreted mediator that contributes to this dysfunction. Blocking cardiac Gdf15 expression improves cardiac performance and exercise capacity in these mice. Finally, in human heart tissue, lower cardiomyocyte PPARGC1A expression is associated with higher GDF15 expression and reduced cardiomyocyte density. These findings uncover a crucial role for cardiomyocyte PGC-1α in enabling healthy cardiac adaptation to exercise in part through suppression of GDF15.

Cardiovascular disease (CVD) is a leading cause of maternal mortality worldwide [1,2]. The molecular mechanisms underlying de novo CVD in pregnancy are not fully understood, which has limited targeted therapeutic development. Our group’s recent article

Cardiac complications, including myocardial injury and dysfunction, are common in severe viral respiratory infections (VRI) and are associated with increased mortality^1–3. The pathophysiology of VRI-induced myocardial injury is multifactorial, but frequently involves structural damage to the heart’s microvascular network that leads to subsequent myocardial ischemia and dysfunction^4–6. Currently, there are no targeted therapies available to prevent or attenuate VRI-associated myocardial injury. Moreover, the molecular mechanisms driving the cardiac microvascular pathology in severe VRI are largely unclear. In this study, we identify increased endothelial cell (EC) activin type IIA receptor (ActRIIA) signaling as a key mediator of cardiac microvascular injury and pathologic remodeling in severe VRI. We show that genetic deletion of EC ActRIIA is sufficient to mitigate EC death and myocardial capillary loss in a murine model of severe influenza infection, which results in improved myocardial perfusion, cardiac function, and survival. We then provide proof-of-concept evidence for two novel pharmacological approaches to target EC ActRIIA pathophysiology in the treatment of VRI-induced cardiac dysfunction.

The lymphatic vasculature plays essential roles in fluid balance, immunity, and lipid transport. Chronic, low‐grade inflammation in peripheral tissues develops when lymphatic structure or function is impaired, as observed during aging. While aging has been associated with a broad range of heart pathophysiology, its effect on cardiac lymphatic vasculature has not been characterized. Here, we analyzed cardiac lymphatics in aged 20‐month‐old mice versus young 2‐month‐old mice. Aged hearts showed reduced lymphatic vascular density, more dilated vessels, and increased inflammation and fibrosis in peri‐lymphatic zones. As exercise has shown benefits in several different models of age‐related heart disease, we further investigated the effects of aerobic training on cardiac lymphatics. Eight weeks of voluntary wheel running attenuated age‐associated adverse remodeling of the cardiac lymphatics, including reversing their dilation, increasing lymph vessel density and branching, and reducing perilymphatic inflammation and fibrosis. Intravital lymphangiography demonstrated improved cardiac lymphatic flow after exercise training. Our findings illustrate that aging leads to cardiac lymphatic dysfunction, and that exercise can improve lymphatic health in aged animals.

BACKGROUND: Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic endothelial dysfunction. The pathophysiology of preeclampsia remains incompletely understood. This study used human venous endothelial cell (EC) transcriptional profiling to investigate potential novel mechanisms underlying EC dysfunction in preeclampsia. METHODS: Venous ECs were isolated from postpartum patients with severe preeclampsia and those with normotensive pregnancy using a J wire–based technique in the antecubital vein followed by CD144 (vascular endothelial cadherin) magnetic bead isolation. Venous EC transcriptomes were compared between preeclamptic and normotensive individuals. Differentially expressed genes were carried forward for genetic validation using expression quantitative trait loci from the Genotype-Tissue Expression project as exposures for vascular-specific Mendelian randomization. Functional validation of the top candidate was performed in human umbilical vein ECs using gain- and loss-of-function genetic approaches. RESULTS: Seventeen individuals with preeclampsia and 7 normotensive controls were included. Pairwise analysis yielded 14 protein-coding genes nominally differentially expressed in participants with preeclampsia. Mendelian randomization revealed a significant association between higher genetically predicted METAP1 (methionyl aminopeptidase 1) expression in aortic and tibial arterial tissues and greater risk of preeclampsia. METAP1 overexpression in human umbilical vein ECs decreased angiogenesis, with a 66% decrease in tube formation ( P =7.9×10 ⁻³ ) and 72% decrease in cell proliferation ( P =2.9×10 ⁻² ). Furthermore, METAP1 overexpression decreased VEGFA expression and increased expression of multiple preeclampsia-related genes, for example, FLT1 , INHBA , and IL1B . Conversely, METAP1 knockdown produced opposite effects on tube formation, cell proliferation, and inflammation-related gene expression. CONCLUSIONS: In a cohort of early postpartum individuals, we observed greater METAP1 expression in venous ECs of women with preeclampsia versus normotensive delivery. Mendelian randomization supported a causal relationship between greater vascular METAP1 expression and higher preeclampsia risk, and functional experiments demonstrated antiangiogenic and proinflammatory effects of METAP1 in human ECs consistent with alterations observed in preeclampsia. Ex vivo EC transcriptomics can identify novel mechanisms underlying preeclampsia pathophysiology, with implications for prevention and treatment.

Age is a major risk factor for heart failure, but one that has been historically viewed as non-modifiable. Emerging evidence suggests that the biology of aging is malleable, and can potentially be intervened upon to treat age-associated chronic diseases, such as heart failure. While aging biology represents a new frontier for therapeutic target discovery in heart failure, the challenges of translating Geroscience research to the clinic are multifold. In this review, we propose a strategy that prioritizes initial target discovery in human biology. We review the rationale for starting with human omics, which has generated important insights into the shared (patho)biology of human aging and heart failure. We then discuss how this knowledge can be leveraged to identify the mechanisms of aging biology most relevant to heart failure. Lastly, we provide examples of how this human-first Geroscience approach, when paired with rigorous functional assessments in preclinical models, is leading to early-stage clinical development of gerotherapeutic approaches for heart failure.

BACKGROUND: Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating proangiogenic and antiangiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk. METHODS: Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography within 4 weeks of delivery. A control group of premenopausal, nonpostpartum women was also included. Myocardial flow reserve, myocardial blood flow, and coronary vascular resistance were compared across groups. sFlt-1 (soluble fms-like tyrosine kinase receptor-1) and PlGF (placental growth factor) were measured at imaging. RESULTS: The primary cohort included 19 women with severe preeclampsia (imaged at a mean of 15.3 days postpartum), 5 with normotensive pregnancy (mean, 14.4 days postpartum), and 13 nonpostpartum female controls. Preeclampsia was associated with lower myocardial flow reserve (β, −0.67 [95% CI, −1.21 to −0.13]; P =0.016), lower stress myocardial blood flow (β, −0.68 [95% CI, −1.07 to −0.29] mL/min per g; P =0.001), and higher stress coronary vascular resistance (β, +12.4 [95% CI, 6.0 to 18.7] mm Hg/mL per min/g; P =0.001) versus nonpostpartum controls. Myocardial flow reserve and coronary vascular resistance after normotensive pregnancy were intermediate between preeclamptic and nonpostpartum groups. Following preeclampsia, myocardial flow reserve was positively associated with time following delivery ( P =0.008). The sFlt-1/PlGF ratio strongly correlated with rest myocardial blood flow ( r =0.71; P <0.001), independent of hemodynamics. CONCLUSIONS: In this exploratory cross-sectional study, we observed reduced coronary microvascular function in the early postpartum period following preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves coronary microcirculation. Further research is needed to establish interventions to mitigate the risk of preeclampsia-associated cardiovascular disease.