Anna Perillo

BACKGROUND: Physiologic interaction between the cardiovascular and renal systems is pivotal in the understanding of disease and as a target for therapeutic interventions, as highlighted in the cardiovascular-kidney-metabolic syndrome. This study explores the association of renal blood flow, derived noninvasively from cardiac positron emission tomography–computed tomography, with cardiovascular and renal outcomes. METHODS: We evaluated the association between renal blood flow and outcomes in a retrospective cohort of 295 consecutive patients who underwent ¹³ N-ammonia positron emission tomography–computed tomography myocardial perfusion imaging between September 1, 2019, and March 1, 2020 (Brigham and Women’s Hospital, Boston). Global myocardial blood flow, myocardial flow reserve, semiquantitative coronary artery calcium, and previously validated resting renal blood flow were obtained, along with clinical and laboratory data. Patients were followed for 4.0 (interquartile range, 1.7–4.1) years for a composite cardiovascular outcome of all-cause mortality, heart failure hospitalization, or acute coronary syndrome, and a composite renal outcome of 25% reduction in estimated glomerular filtration rate or end-stage renal disease. Survival analyses were adjusted for demographic and clinical characteristics and additionally for estimated glomerular filtration rate and myocardial flow reserve. RESULTS: The population had a mean age of 65.6 years, a body mass index of 29.2 kg/m ² , and was 49% female. Overall, 36% had chronic kidney disease stage ≥3. Patients were stratified into 3 renal blood flow groups: ≥75%, 25 to 75th, and ≤25% percentile. Lower renal blood flow was significantly associated with a higher risk of cardiovascular events (adjusted hazard ratio, 5.21 [95% CI 1.53–17.75]; P =0.008; lowest versus highest quartile), and with an elevated risk of adverse renal outcomes ( P =0.026), independent of estimated glomerular filtration rate and myocardial flow reserve. CONCLUSIONS: Impaired renal blood flow is associated with cardiac and kidney events, independent of the highly prognostic estimated glomerular filtration rate and myocardial flow reserve. Simultaneous quantification of cardiac and renal perfusion by noninvasive ¹³ N-ammonia positron emission tomography–computed tomography may provide a valuable tool to interrogate pathophysiology and prognosis in the cardiovascular-kidney-metabolic syndrome.

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.

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.