Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer's disease.

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12 years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline.

Tau Mediates Synergistic Influence of Vascular Risk and Aß on Cognitive Decline.

OBJECTIVE: Elevated vascular risk and beta-amyloid (Aß) burden have been synergistically associated with cognitive decline in preclinical Alzheimer's disease (AD), although the underlying mechanisms remain unclear. We examined whether accelerated longitudinal tau accumulation mediates the vascular risk-Aß interaction on cognitive decline. METHODS: We included 175 cognitively unimpaired older adults (age 70.5 ± 8.0 years). Baseline vascular risk was quantified using the office-based Framingham Heart Study general cardiovascular disease risk score (FHS-CVD). Baseline Aß burden was measured with Pittsburgh Compound-B positron emission tomography (PET). Tau burden was measured longitudinally (3.6 ± 1.5 years) with Flortaucipir PET, focusing on inferior temporal cortex (ITC). Cognition was assessed longitudinally (7.0 ± 2.0 years) using the Preclinical Alzheimer's Cognitive Composite. Linear mixed effects models examined the interactive effects of baseline vascular risk and Aß on longitudinal ITC tau. Additionally, moderated mediation was used to determine whether tau accumulation mediated the FHS-CVD*Aß effect on cognitive decline. RESULTS: We observed a significant interaction between elevated baseline FHS-CVD and Aß on greater ITC tau accumulation (p = 0.004), even in individuals with Aß burden below the conventional threshold for amyloid positivity. Examining individual vascular risk factors, we found elevated systolic blood pressure and body mass index showed independent interactions with Aß on longitudinal tau (both p < 0.0001). ITC tau accumulation mediated 33% of the interactive association of FHS-CVD and Aß on cognitive decline. INTERPRETATION: Vascular risks interact with subthreshold levels of Aß to promote cognitive decline, partially by accelerating early neocortical tau accumulation. Our findings support vascular risk reduction, especially treating hypertension and obesity, to attenuate Aß-related tau pathology and reduce late-life cognitive decline. ANN NEUROL 2022;92:745-755.

Cyclic guanosine monophosphate and 10-year change in left ventricular mass: the Multi-Ethnic Study of Atherosclerosis (MESA).

Purpose: Cyclic guanosine monophosphate (cGMP) is a second messenger for natriuretic peptide (NP) and nitric oxide pathways; its enhancement a target for heart failure and cardiovascular disease (CVD). We evaluated whether plasma cGMP was associated with change in left ventricular mass (LVM) among individuals free of CVD and if this differed by sex.Methods and Results: In 611 men and 612 women aged 45-84 years with plasma cGMP measured at baseline and cardiac MRI performed at baseline and 10 years later, we tested associations of cGMP [log-transformed, per 1 SD increment] with LVM, adjusting for CVD risk factors and N-terminal pro-B-type-NP (NT-proBNP). Participants had mean (SD) age of 63.1(8.5) years and cGMP 4.8(2.6) pmol/mL. Cross-sectionally, higher cGMP was associated with lesser LVM, non-lin- early. In contrast, longitudinally, higher cGMP was associated with increase in LVM [1.70g (0.61, 2.78)] over 10 years. Higher cGMP was associated with greater LVM change in men [2.68g (1.57, 3.79)] but not women [0.24g ((-0.92, 1.39); p-interaction < 0.001].Conclusion: In conclusion, in a community-based cohort, higher cGMP levels were associated with increase in LVM over 10 years independent of CVD risk factors and NT-proBNP in men, perhaps reflecting compensatory changes. Further studies are needed to understand mechanistic roles of cGMP in LV remodelling and associated sex differences.

Vascular Risk and ß-Amyloid Are Synergistically Associated with Cortical Tau.

OBJECTIVE: Neuropathological studies have demonstrated that cerebrovascular disease and Alzheimer disease (AD) pathology frequently co-occur in older adults. The extent to which cerebrovascular disease influences the progression of AD pathology remains unclear. Leveraging newly available positron emission tomography (PET) imaging, we examined whether a well-validated measure of systemic vascular risk and ß-amyloid (Aß) burden have an interactive association with regional tau burden. METHODS: Vascular risk was quantified at baseline in 152 clinically normal older adults (mean age = 73.5 ± 6.1 years) with the office-based Framingham Heart Study cardiovascular disease risk algorithm (FHS-CVD). We acquired Aß (11 C-Pittsburgh compound B) and tau (18 F-flortaucipir) PET imaging on the same participants. Aß PET was performed at baseline; tau PET was acquired on average 2.98 ± 1.1 years later. Tau was measured in the entorhinal cortex (EC), an early site of tau deposition, and in the inferior temporal cortex (ITC), an early site of neocortical tau accumulation associated with AD. Linear regression models examined FHS-CVD and Aß as interactive predictors of tau deposition, adjusting for age, sex, APOE ε4 status, and the time interval between baseline and the tau PET scan. RESULTS: We observed a significant interaction between FHS-CVD and Aß burden on subsequently measured ITC tau (p < 0.001), whereby combined higher FHS-CVD and elevated Aß burden was associated with increased tau. The interaction was not significant for EC tau (p = 0.16). INTERPRETATION: Elevated vascular risk may influence tau burden when coupled with high Aß burden. These results suggest a potential link between vascular risk and tau pathology in preclinical AD. Ann Neurol 2019; 1-8 ANN NEUROL 2019;85:272-279.

Multiparity is associated with poorer cardiovascular health among women from the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Multiparity is associated with a greater risk of incident cardiovascular disease. However, the relationship of parity with cardiovascular health, as measured by the American Heart Association Life's Simple 7 metrics, is uncertain. OBJECTIVE: We aimed to examine the association between parity and ideal cardiovascular health among 3430 women, aged 45-84 years, free of clinical cardiovascular disease enrolled in the Multi-Ethnic Study of Atherosclerosis. STUDY DESIGN: The Multi-Ethnic Study of Atherosclerosis is a prospective cohort study that recruited middle-aged to older women and men from 6 centers in the United States between 2000 and 2002. The study population comprised 38% White, 28% Black, 23% Hispanic, and 11% Chinese American subjects. Parity (total number of live births) was self-reported and categorized as 0, 1-2, 3-4 and ≥5. The Life's Simple 7 metrics, defined according to American Heart Association criteria, include health behaviors (smoking, physical activity, body mass index, diet) and health factors (blood pressure, total cholesterol, and blood glucose). We categorized each metric into ideal (2 points), intermediate (1 point), and poor (0 points). A total cardiovascular health score of 0-8 was considered inadequate; 9-10, average; and 11-14, optimal. We used multinomial logistic regression to examine the cross-sectional association between parity and the cardiovascular health score, adjusted for sociodemographics, field site, hormone therapy, and menopause. RESULTS: The mean (standard deviation) age was 62 (10) years. The mean (standard deviation) cardiovascular health score was lower with higher parity (8.9 [2.3], 8.7 [2.3], 8.5 [2.2], and 7.8 [2.0] for 0, 1-2, 3-4, and ≥5 live births, respectively). In comparison to inadequate cardiovascular health scores, the adjusted odds of average cardiovascular health scores were significantly lower for all parity categories relative to nulliparity (prevalence odds ratios [OR] for parity of 1-2, 0.64 [95% confidence interval 0.49-0.83]; 3-4, 0.65 [0.49-0.86]; ≥5, 0.64 [0.45-0.91]). Women with ≥5 live births had a lower prevalence of optimal cardiovascular health scores (OR 0.50 [0.30-0.83]). In the fully adjusted models, the association between parity and each Life's Simple 7 metric was only statistically significant for body mass index. Women with ≥5 live births had lower prevalence of ideal body mass index (OR 0.52 [0.35-0.80]). In addition, the test for interaction showed that the association between parity and cardiovascular health was not modified by race/ethnicity (P = .81 for average cardiovascular health scores and P = .20 for optimal cardiovascular health scores). CONCLUSION: Multiparity was associated with poorer cardiovascular health, especially for women with ≥5 live births. More research is required to explore the mechanisms by which parity may worsen cardiovascular health.

Identifying longitudinal cognitive resilience from cross-sectional amyloid, tau, and neurodegeneration.

BACKGROUND: Leveraging Alzheimer's disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo. Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR. METHODS: We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aß, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women). RESULTS: The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline. CONCLUSION: These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity.

Nucleus accumbens response to incentive stimuli anticipation in children of alcoholics: relationships with precursive behavioral risk and lifetime alcohol use.

Children of alcoholics (COAs) are at elevated risk to develop alcohol and other substance use disorders. The neurobiological underpinnings of this heightened vulnerability are presently not well understood. This study investigated whether, in humans, COAs have different functioning of the mesolimbic reward circuitry beyond previous substance use confounds and examined potential group differences in neural response in relation to alcohol use and behavioral risk. We studied 20 18- to 22-year-old COAs and 20 controls, developmentally well characterized for substance use and selected to match on sex, age, IQ, lifetime substance use and associated problems, and precursive (ages 12-14 years) externalizing behavioral risk. None met criteria for Diagnostic and Statistical Manual of Mental Disorders IV diagnosis. Neural responses to anticipation of reward and loss were assessed using functional magnetic resonance imaging during a monetary incentive delay task. Overall, COAs showed reduced ventral striatum activation during anticipation of monetary reward and loss compared with controls. However, additional analysis revealed that blunted nucleus accumbens (NAcc) response was only observed in COAs who have not demonstrated any problem drinking behavior. In addition, uniquely in COAs, NAcc activation was positively correlated with precursive externalizing risk, as well as current and lifetime alcohol consumption. These findings suggest a multilevel developmental process whereby lower precursive behavioral risk appears protective of later problem alcohol use in COAs, which is further associated with a blunted NAcc response to incentive anticipation, potentially reflecting a resilience mechanism. Moreover, the results suggest that a close association between motivational responses, alcohol consumption, and behavioral risk may underlie addiction vulnerability in COAs.

Alterations in white matter microstructure in women recovered from anorexia nervosa.

OBJECTIVE: A recent study of ill individuals with anorexia nervosa (AN) reported microstructural alterations in white matter integrity including lower fractional anisotropy and higher mean diffusivity. This study was designed to determine whether such alterations exist in long-term recovered AN individuals and to examine potential associations with underlying AN traits. METHOD: Twelve adult women recovered from restricting-type AN and 10 control women were studied using diffusion tensor imaging. RESULTS: Overall, there was no significant fractional anisotropy alteration in recovered AN, in contrast to a prior study reporting lower fractional anisotropy in ill AN. Further, recovered AN showed lower mean diffusivity in frontal, parietal and cingulum white matter relative to control women, contrary to elevated mean diffusivity previously reported in ill AN. Lower longitudinal diffusivity in recovered AN was associated with higher harm avoidance. However, more severe illness history was associated with worse white matter integrity after recovery in the same direction as reported in prior work. DISCUSSION: Our findings suggest that fractional anisotropy in recovered AN is not different from controls, however, a novel pattern of lower mean diffusivity was evidenced in recovered AN, and this alteration was associated with harm avoidance. Notably, severity of illness history may have long-term consequences, emphasizing the importance of aggressive treatment.

Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results.

ALLO-715 is a first-in-class, allogeneic, anti-BCMA CAR T cell therapy engineered to abrogate graft-versus-host disease and minimize CAR T rejection. We evaluated escalating doses of ALLO-715 after lymphodepletion with an anti-CD52 antibody (ALLO-647)-containing regimen in 43 patients with relapsed/refractory multiple myeloma as part A of the ongoing first-in-human phase 1 UNIVERSAL trial. Primary objectives included determination of the safety and tolerability of ALLO-715 and the safety profile of the ALLO-647-containing lymphodepletion regimen. Key secondary endpoints were response rate and duration of response. Grade ≥3 adverse events were reported in 38 (88.0%) of patients. Cytokine release syndrome was observed in 24 patients (55.8%), with 1 grade ≥3 event (2.3%) and neurotoxicity in 6 patients (14%), with no grade ≥3 events. Infections occurred in 23 patients (53.5%), with 10 (23.3%) of grade ≥3. Overall, 24 patients (55.8%) had a response. Among patients treated with 320 × 106 CAR+ T cells and a fludarabine-, cyclophosphamide- and ALLO-647-based lymphodepletion regimen (n = 24), 17 (70.8%) had a response including 11 (45.8%) with very good partial response or better and 6 (25%) with a complete response/stringent complete response. The median duration of response was 8.3 months. These initial results support the feasibility and safety of allogeneic CAR T cell therapy for myeloma.

Association of Age at Menopause and Hormone Therapy Use With Tau and ß-Amyloid Positron Emission Tomography.

Importance: Postmenopausal females represent around 70% of all individuals with Alzheimer disease. Previous literature shows elevated levels of tau in cognitively unimpaired postmenopausal females compared with age-matched males, particularly in the setting of high ß-amyloid (Aß). The biological mechanisms associated with higher tau deposition in female individuals remain elusive. Objective: To examine the extent to which sex, age at menopause, and hormone therapy (HT) use are associated with regional tau at a given level of Aß, both measured with positron emission tomography (PET). Design, Setting, and Participants: This cross-sectional study included participants enrolled in the Wisconsin Registry for Alzheimer Prevention. Cognitively unimpaired males and females with at least 1 18F-MK-6240 and 11C-Pittsburgh compound B PET scan were analyzed. Data were collected between November 2006 and May 2021. Exposures: Premature menopause (menopause at younger than 40 years), early menopause (menopause at age 40-45 years), and regular menopause (menopause at older than 45 years) and HT user (current/past use) and HT nonuser (no current/past use). Exposures were self-reported. Main Outcomes and Measures: Seven tau PET regions that show sex differences across temporal, parietal, and occipital lobes. Primary analyses examined the interaction of sex, age at menopause or HT, and Aß PET on regional tau PET in a series of linear regressions. Secondary analyses investigated the influence of HT timing in association with age at menopause on regional tau PET. Results: Of 292 cognitively unimpaired individuals, there were 193 females (66.1%) and 99 males (33.9%). The mean (range) age at tau scan was 67 (49-80) years, 52 (19%) had abnormal Aß, and 106 (36.3%) were APOEε4 carriers. There were 98 female HT users (52.2%) (past/current). Female sex (standardized ß = -0.41; 95% CI, -0.97 to -0.32; P < .001), earlier age at menopause (standardized ß = -0.38; 95% CI, -0.14 to -0.09; P < .001), and HT use (standardized ß = 0.31; 95% CI, 0.40-1.20; P = .008) were associated with higher regional tau PET in individuals with elevated Aß compared with male sex, later age at menopause, and HT nonuse. Affected regions included medial and lateral regions of the temporal and occipital lobes. Late initiation of HT (>5 years following age at menopause) was associated with higher tau PET compared with early initiation (ß = 0.49; 95% CI, 0.27-0.43; P = .001). Conclusions and Relevance: In this study, females exhibited higher tau compared with age-matched males, particularly in the setting of elevated Aß. In females, earlier age at menopause and late initiation of HT were associated with increased tau vulnerability especially when neocortical Aß elevated. These observational findings suggest that subgroups of female individuals may be at higher risk of pathological burden.

Characterization and fate of telomerase-expressing epithelia during kidney repair.

After acute kidney injury, mice with short telomeres develop increased damage with reduced proliferative capacity, which suggests an important role for telomere length in kidney repair. The enzyme telomerase reverse transcriptase (mTert) regulates telomere length; embryonic stem cells and certain adult stem cells express mTert, but whether cells in the adult kidney express mTert and whether these cells play a role in renal repair are unknown. Here, we found that telomerase protein and mRNA were highly enriched in renal papilla, a proposed niche of kidney stem cells. Using mTert-GFP reporter mice, we detected mTert in a subset of papillary epithelial cells comprising the collecting duct predominantly but also the loop of Henle. Approximately 5% of mTert-GFP(+) cells were label retaining, a characteristic of stem cells. mTert mRNA levels increased in renal papilla after ischemia-reperfusion injury, but genetically labeled mTert-expressing papillary cells neither divided nor migrated out of the renal papilla during kidney repair. In summary, these data suggest that cells expressing telomerase reverse transcriptase are not a progenitor-cell population, and they do not play a direct role in kidney repair.

The Importance of Cardiovascular Risk Assessment and Pregnancy Heart Team in the Management of Cardiovascular Disease in Pregnancy.

Pregnancy-related maternal morbidity and mortality is increasing because of complications from cardiovascular disease. Pregnancy results in physiologic changes that can adversely impact the cardiovascular system and lead to adverse pregnancy outcomes. A multidisciplinary pregnancy heart team is essential to safely navigate women with heart disease through pregnancy. This role of the pregnancy heart team is to offer preconception counseling, determine pregnancy risks and educate women about those risks, develop a comprehensive antenatal and delivery plan, and ensure appropriate postpartum follow-up. These steps are important to improve cardiovascular outcomes in pregnancy.

Prevention Starts in the Womb: Opportunities for Addressing Cardiovascular Risk Factors During Pregnancy and Beyond.

Early identification and mitigation of sex-specific cardiovascular disease risk factors is a potential trajectory-changing strategy to improve lifelong cardiovascular health in women. These sex-specific risk factors include adverse pregnancy outcomes, polycystic ovarian syndrome, and premature menopause. We start by discussing the impact and management of risk factors for adverse pregnancy outcomes as an upstream intervention for cardiovascular disease risk reduction and then address the long-term effect and mitigation of sex-specific risk factors for cardiovascular disease.

Visceral adiposity, muscle composition, and exercise tolerance in heart failure with preserved ejection fraction.

AIMS: Visceral adipose tissue (AT) promotes inflammation and may be associated with disease progression in heart failure with preserved ejection fraction (HFpEF). We characterized regional AT distribution in HFpEF patients and controls and analysed associations with co-morbidities and exercise tolerance. METHODS AND RESULTS: Magnetic resonance imaging was performed to quantify epicardial, liver, abdominal, and thigh skeletal muscle AT. We assessed New York Heart Association (NYHA) class, 6 min walk distance, and global well-being score. Multivariable linear regression models adjusting for body surface area were used. We studied 55 HFpEF patients (41 women, mean age 67 ± 11 years) and 33 controls (21 women, mean age 57 ± 10 years). Epicardial AT (median [interquartile range] 4.6 [2.0] vs. 3.2 [1.4] mm, P < 0.001), thigh intermuscular fat (11.0 [11.5] vs. 5.0 [2.7] cm2 , P < 0.001) and liver fat fraction (6.4% [6.1] vs. 4.1% [5.5], P = 0.001) were higher in HFpEF patients than controls. Women with HFpEF had higher abdominal and thigh subcutaneous AT than men. Greater thigh intermuscular fat was associated with higher blood pressure (ß [SE] 0.73 [0.17], P < 0.001) and diabetes (odds ratio [95% confidence interval] 1.2 [1.0-1.5], P = 0.03). Greater thigh intramuscular fat was associated with both worse NYHA class (ß [SE] 2.7 [1.0], P = 0.01) and shorter 6 min walk distance (ß [SE] -4.1 [1.9], P = 0.03), and greater epicardial AT (ß [SE] -0.2 [0.1], P < 0.001) and liver fat fraction (ß [SE] -0.4 [0.2], P = 0.04) were associated with lower global well-being score. CONCLUSIONS: Heart failure with preserved ejection fraction patients have increased epicardial, liver, and skeletal muscle fat compared with controls out of proportion to their increased body size, and adiposity was associated with worse NYHA class and exercise tolerance in HFpEF. These results provide the basis for further investigation into the effect of interventions to reduce regional AT distribution in relation to HFpEF symptoms and pathophysiology.

Associations between menopause, cardiac remodeling, and diastolic function: the CARDIA study.

OBJECTIVES: Heart failure with preserved ejection fraction (HFpEF) affects more women than men. Menopause may influence HFpEF development in women. We assessed cross-sectional and longitudinal associations between menopause and echocardiographic measures of left ventricular (LV) function and cardiac remodeling. METHODS: We studied 1,723 women with available echo data from at least two of: year 5 (Y5) (1990-1991), Y25 (2010-2011), or Y30 (2015-2016) in the Coronary Artery Risk Development in Young Adults study. Cardiac structure and function were measured using 2D and Doppler echocardiography. Cross-sectional associations between menopausal status and repeated echo measures at Y25 and Y30 were analyzed using linear mixed models. Two-segmented models were used to compare longitudinal changes in echocardiographic measures in the premenopausal period to changes in the postmenopausal period. RESULTS: Mean ±â€ŠSD age (years) at enrollment was 27 ±â€Š3 in those with menopause by Y25, 25 ±â€Š3 in those with menopause between Y25 and Y30, and 21 ±â€Š3 in those premenopausal at Y30. There were no significant differences in race, body mass index, systolic blood pressure, or diabetes between the groups. Postmenopausal women had higher early diastolic mitral inflow (E) to annular (e') velocity ratio than premenopausal after adjusting for demographics and risk factors (P < 0.05). Menopause was associated with relative increases in the rates of change in LV mass and left atrial volume, even after adjustment. Change in E/e' ratio was similar before and after menopause. CONCLUSIONS: Menopause is associated cross-sectionally with worse diastolic function and longitudinally with adverse LV and left atrial remodeling. This may contribute to the increased HFpEF risk in postmenopausal women.

Video Summary:http://links.lww.com/MENO/A787 .

Acute myopericarditis as a cause of isolated right ventricular failure.

Myopericarditis is characterized by pericardial and myocardial inflammation and is a known cause of chest pain and heart failure. It is primarily associated with biventricular or left ventricular dysfunction. We describe an unusual case of a 57-year-old woman with myopericarditis causing isolated right ventricular (RV) failure. She initially presented with chest pain and cardiogenic shock and was found to have acute RV dysfunction with a normally functioning left ventricle. After excluding more common causes of RV failure, she was diagnosed with acute myopericarditis. In this report, we discuss the differential diagnoses and work-up of acute RV failure, as well as review prior cases of RV-predominant myocarditis/myopericarditis. We highlight the importance of recognizing isolated RV failure as a possible, but rare, presentation of myopericarditis.

Sex Hormones and Incident Heart Failure in Men and Postmenopausal Women: The Atherosclerosis Risk in Communities Study.

CONTEXT: Sex differences exist in heart failure (HF) phenotypes, but there is limited research on the role of sex hormones in HF and its subtypes. OBJECTIVE: To examine the associations of total testosterone, dehydroepiandrosterone sulfate (DHEA-S), and sex hormone-binding globulin (SHBG) with incident HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF). DESIGN: Atherosclerosis Risk in Communities (ARIC) study (prospective cohort study). Median follow-up is 19.2 years. SETTING: General community. PARTICIPANTS: 4107 men and 4839 postmenopausal women, with mean age of 63.2 (standard deviation [SD] 5.7) and 62.8 (5.5) years, respectively. EXPOSURE: Plasma sex hormone levels were measured at visit 4 (1996-1998). MAIN OUTCOME MEASURES: Incident HF events were identified through hospital discharge codes and death certificates. RESULTS: The Hazard Ratios for HF associated with 1 SD decrease in log-transformed total testosterone, DHEA-S, and SHBG were 1.10 (95% confidence interval 1.03, 1.17), 1.07 (1.00, 1.15), and 1.04 (0.96, 1.11) in men, and 1.05 (0.99, 1.13), 1.17 (1.09, 1.24), and 0.93 (0.85, 1.01) in women, respectively. The associations between sex hormones with subtypes of HF had similar patterns but were attenuated and became statistically insignificant. CONCLUSION: In this prospective cohort, lower levels of endogenous testosterone and DHEA-S in men and DHEA-S in postmenopausal women were associated with the development of HF. Similar directions of association in both sexes and both HF subtypes suggest that sex hormones play a role in the development of HF through common pathways regardless of sex.

The Association of Adverse Pregnancy Outcomes and Cardiovascular Disease: Current Knowledge and Future Directions.

Purpose of review: Adverse pregnancy outcomes are associated with increased risk for future cardiovascular disease. The goal of this review is to share what is currently known about the increased risk and to identify areas for future research. Recent findings: Severe studies have identified a strong association between adverse pregnancy outcomes and cardiovascular disease such as heart failure, valvular disease, ischemic heart disease, stroke, hypertension, and metabolic syndrome. The recognition of this increased risk is reflected in recent changes in prevention guidelines. The guidelines now recognize sex-specific risks such as preeclampsia and preterm delivery and recommend incorporating a pregnancy history to identify them earlier. However, no robust risk prediction tools incorporating these pregnancy risk factors have been developed and validated. While smaller clinical trials have been performed in reducing cardiovascular risk factors in the postpartum timeframe, there remains a paucity of large-scale randomized clinical trials that continue to show a risk reduction in these women. Summary: While there is increasing recognition of the long-term cardiovascular risks associated with adverse pregnancy outcomes, there remains a need for interventional studies aimed at reducing this risk and for incorporation of pregnancy risk factors into traditional cardiovascular risk prediction tools.

Cyclic Guanosine Monophosphate and Risk of Incident Heart Failure and Other Cardiovascular Events: the ARIC Study.

Background Cyclic guanosine monophosphate (cGMP) is a second messenger regulated through natriuretic peptide and nitric oxide pathways. Stimulation of cGMP signaling is a potential therapeutic strategy for heart failure with preserved ejection fraction (HFpEF) and atherosclerotic cardiovascular disease (ASCVD). We hypothesized that plasma cGMP levels would be associated with lower risk for incident HFpEF, any HF, ASCVD, and coronary heart disease (CHD). Methods and Results We conducted a case-cohort analysis nested in the ARIC (Atherosclerosis Risk in Communities) study. Plasma cGMP was measured in 875 participants at visit 4 (1996-1998), with oversampling of incident HFpEF cases. We used Cox proportional hazard models to assess associations of cGMP with incident HFpEF, HF, ASCVD (CHD+stroke), and CHD. The mean (SD) age was 62.4 (5.6) years and median (interquartile interval) cGMP was 3.4 pmol/mL (2.4-4.6). During a median follow-up of 9.9 years, there were 283 incident cases of HFpEF, 329 any HF, 151 ASCVD, and 125 CHD. In models adjusted for CVD risk factors, the hazard ratios (95% CI) associated with the highest cGMP tertile compared with lowest for HFpEF, HF, ASCVD, and CHD were 1.88 (1.17-3.02), 2.18 (1.18-4.06), 2.84 (1.44-5.60), and 2.43 (1.19-5.00), respectively. In models further adjusted for N-terminal-proB-type natriuretic peptide, associations were attenuated for HFpEF and HF but remained statistically significant for ASCVD (2.56 [1.26-5.20]) and CHD (2.25 [1.07-4.71]). Conclusions Contrary to our hypothesis, higher cGMP levels were associated with incident CVD in a community-based cohort. The associations of cGMP with HF or HFpEF may be explained by N-terminal-proB-type natriuretic peptide, but not for ASCVD and CHD.

Endomyocardial Biopsy Characterization of Heart Failure With Preserved Ejection Fraction and Prevalence of Cardiac Amyloidosis.

OBJECTIVES: This study prospectively evaluated endomyocardial biopsies in patients with heart failure with preserved ejection fraction (HFpEF) to identify histopathologic phenotypes and their association with clinical characteristics. BACKGROUND: Myocardial tissue analysis from a prospectively defined HFpEF cohort reflecting contemporary comorbidities is lacking. METHODS: Patients with HFpEF (EF ≥50%) referred to the Johns Hopkins HFpEF Clinic between August 2014 and September 2018 were enrolled for right heart catheterization and endomyocardial biopsy. Clinical features, echocardiography, hemodynamics, and tissue histology were determined and compared with controls (unused donor hearts) and HF with reduced EF (HFrEF). RESULTS: Of the 108 patients enrolled, median age was 66 years (25th to 75th percentile: 57 to 74 years), 61% were women, 57% were African American, 62% had a previous HF hospitalization, median systolic blood pressure was 141 mm Hg (25th to 75th percentile: 125 to 162 mm Hg), body mass index (BMI) was 37 kg/m2 (25th to 75th percentile: 32 to 45 kg/m2), and 97% were on a loop diuretic. Myocardial fibrosis and myocyte hypertrophy were often present (93% and 88%, respectively); however, mild in 71% with fibrosis and in 52% with hypertrophy. Monocyte infiltration (CD68+ cells/mm2) was greater in patients with HFpEF versus controls (60.4 cells/mm2 [25th to 75th percentile: 36.8 to 97.8] vs. 32.1 cells/mm2 [25th to 75th percentile: 22.3 to 59.2]; p = 0.02) and correlated with age and renal disease. Cardiac amyloidosis (CA) was diagnosed in 15 (14%) patients (HFpEF-CA: 7 patients with wild-type transthyretin amyloidosis [ATTR], 4 patients with hereditary ATTR, 3 patients with light-chain amyloidosis, and 1 patient with AA (secondary) amyloidosis), of which 7 cases were unsuspected. Patients with HFpEF-CA were older, with lower BMI, higher left ventricular mass index, and higher N-terminal pro-B-type natriuretic peptide and troponin I levels. CONCLUSIONS: In this large, prospective myocardial tissue analysis of HFpEF, myocardial fibrosis and hypertrophy were common, CD68+ inflammation was increased, and CA prevalence was 14%. Tissue analysis in HFpEF might improve precision therapies by identifying relevant myocardial mechanisms.