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Abstract Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbidity and mortality. Here, we report genetic evidence that relaxin family peptide receptor 2 (RXFP2) is associated with rHTN in men, but not in women. This study shows that adrenal gland gene expression of RXFP2 is increased in men with hypertension and the RXFP2 natural ligand, INSL3, increases adrenal steroidogenesis and corticosteroid secretion in human adrenal cells. To address the hypothesis that RXFP2 activation is an important mechanism in rHTN, we discovered and characterized small molecule and monoclonal antibody (mAb) blockers of RXFP2. The novel chemical entities and mAbs show potent, selective inhibition of RXFP2 and reduce aldosterone and cortisol synthesis and release. The RXFP2 mAbs have suitable rat pharmacokinetic profiles to evaluate the role of RXFP2 in the development and maintenance of rHTN. Overall, we identified RXFP2 activity as a potential new mechanism in rHTN and discovered RXFP2 antagonists for the future interrogation of RXFP2 in cardiovascular and renal diseases.

The expanding field of precision gene editing using CRISPR/Cas9 has demonstrated its potential as a transformative technology in the treatment of various diseases. However, whether this genome-editing tool could be used to modify neural circuits in the central nervous system (CNS), which are implicated in complex behavioral traits, remains uncertain. In this study, we demonstrate the feasibility of noninvasive, intranasal delivery of adeno-associated virus serotype 9 (AAV9) vectors containing CRISPR/Cas9 cargo within the CNS resulting in modification of the HTR2A receptor gene. In vitro, exposure to primary mouse cortical neurons to AAV9 vectors targeting the HT2RA gene led to a concentration-dependent decrease in spontaneous electrical activity following multielectrode array (MEA) analysis. In vivo, at 5 weeks postintranasal delivery in mice, analysis of brain samples revealed single base pair deletions and nonsense mutations, leading to an 8.46-fold reduction in mRNA expression and a corresponding 68% decrease in the 5HT-2A receptor staining. Our findings also demonstrate a significant decrease in anxiety-like behavior in treated mice. This study constitutes the first successful demonstration of a noninvasive CRISPR/Cas9 delivery platform, capable of bypassing the blood-brain barrier and enabling modulation of neuronal 5HT-2A receptor pathways. The results of this study targeting the HTR2A gene provide a foundation for the development of innovative therapeutic strategies for a broad range of neurological disorders, including anxiety, depression, attentional deficits, and cognitive dysfunction.

This article reports on the understanding of the function concept by pre-service mathematics teachers from two countries (Germany and Croatia). We focused on investigating students' concept definition and concept image of the function in relation to their curriculum experiences. Data were collected using a questionnaire in the form of open-ended questions followed by interviews. The results indicate that the curriculum has a great influence on the development of the concept definition and concept image. The curriculum strongly influenced the theoretical background of the function concept and thus the gap between the formal and the personal definition of function. Later and more intensive work with the formal definition of function led to a better development of the function concept in general. The curriculum also had an influence on the range of the concept image developed by the pre-service mathematics teachers, with no proportional dependence in relation to the better developed understanding of the concept of function.

IntroductionFrailty is common among patients entering cardiac rehabilitation (CR). Frailty is associated with poor health outcomes; however, it is unclear if frailty influences achieving goals in CR.MethodsWe report a secondary analysis of participants who were referred to an exercise and education-based CR program from 2005 to 2015. Frailty was measured by a 25-item accumulation of deficits frailty index (FI) ranging from 0 to 1; higher scores indicate higher frailty. Participants were categorized by admission frailty levels (FI scores: 0.40). CR goals were determined with shared decision-making between CR staff and the patients. We conducted logistic regression analyses to examine the odds of goal attainment by CR completion, adjusting for age, sex, education, marital status, and referring diagnosis. Analyses were performed using baseline frailty as a categorical and continuous outcome, and frailty change as a continuous outcome in separate models.ResultsOf 759 eligible participants (age: 59.5 ± 9.8, 24% female), 607 (80%) participants achieved a CR goal at graduation. CR goals were categorized into similar themes: control or lose weight (n = 381, 50%), improve physical activity behaviour and fitness (n = 228, 30%), and improve cardiovascular profile (n = 150, 20%). Compared to the most severe frailty group (FI >0.40), lower levels of frailty at baseline were associated with achieving a goal at CR completion [FI

Introduction: Spondyloarthropathy is a group of different chronic rheumatic diseases. There are a number of physiotherapy interventions that all aim to support the trunk flexors and extensors, relieve pain, and mobilize the joints. The aim of this study is to compare isokinetic exercises (IE) with a standard exercise protocol in patients with spondyloarthropathies. Methods: A total of 16 subjects participated in the study and were randomly divided into two groups: The group with the standard protocol (SP) and the other in the isokinetic protocol (IP). Both groups underwent the same follow-up testing: Muscle strength, pain, and functional status. Both groups underwent a total of 15 physiotherapy interventions over a 3-week period. Results: The mean age in the standard group was 36 ± 7.93 and in the isokinetic group 46.13 ± 13.88. In the isokinetic group, there was a difference in pain intensity between the second and third measurements (p = 0.016). There was an improvement in muscle strength in the isokinetic group (Cohen’s d = 0.33). At an angular velocity (AV) of 60°/s, this group is better than the delayed SP, while it is directly better at an AV of 90°/s (d = 0.30). The delayed measurement of the groups (IP) showed a lower functional deficit than the SP group (p = 0.012). Conclusion: Based on the results of this study and a search of the scientific literature, we can conclude that IE has been shown to be beneficial rather than harmful. Further longitudinal studies with a larger number of subjects are needed to investigate the effects of isokinetics on functional outcomes in rheumatology patients.

This study investigates the immobilization of cyanobacterial photosystem I (PSI) from Synechocystis sp. PCC 6803 onto fluorine-doped tin oxide (FTO) conducting glass plates to create photoelectrodes for biohybrid solar cells. The fabrication of these PSI–FTO photoelectrodes is based on two immobilization processes: rapid electrodeposition driven by an external electric field and slower adsorption during solvent evaporation, both influenced by gravitational sedimentation. Deposition and performance of photoelectrodes was investigated by UV–Vis absorption spectroscopy and photocurrent measurements. We investigated the efficiency of PSI immobilization under varying conditions, including solution pH, applied electric field intensity and duration, and electrode polarization, with the goals to control (1) the direction of migration and (2) the orientation of the PSI particles on the substrate surface. Variation in the pH value of the PSI solution alters the surface charge distribution, affecting the net charge and the electric dipole moment of these proteins. Results showed PSI migration to the positively charged electrode at pH 6, 7, and 8, and to the negatively charged electrode at pH 4.4 and 5, suggesting an isoelectric point of PSI between 5 and 6. At acidic pH, the electrophoretic migration was largely hindered by protein aggregation. Notably, photocurrent generation was consistently cathodic and correlated with PSI layer thickness, and no conclusions can be drawn on the orientation of the immobilized proteins. Overall, these findings suggest mediated electron transfer from FTO to PSI by the used electrolyte containing 10 mM sodium ascorbate and 200 μM dichlorophenolindophenol.

Abstract Background Resistance and balance training are important exercise interventions for older populations living with chronic diseases. Accurately measuring if an individual is adhering to exercises as prescribed is important to determine if lack of improvement in health outcomes is because of issues with adherence. Measuring adherence to resistance and balance exercises is limited by current methods that depend heavily on self-report and are often better at and tailored towards capturing aerobic training parameters (e.g., step count, minutes of moderate to vigorous physical activity). Adherence measures must meet users’ needs to be useful. Methods Using a Dillman tailored study design, we surveyed researchers who conduct exercise trials, clinicians who prescribe exercise for older adults, and older adults to determine: (1) how they are currently measuring adherence; (2) barriers and facilitators they have experienced to measurement; and (3) the information they would like collected about adherence (e.g., repetitions, sets, intensity, duration, frequency, quality). Surveys were disseminated internationally through professional networks, professional organizations, and social media. Participants completed an online survey between August 2021 and April 2022. Results Eighty-eight older adults, 149 clinicians, and 41 researchers responded to the surveys. Most clinicians and researchers were between the ages of 30 and 39 years, and 70.0% were female. Most older adults were aged 70–79 years, and 46.6% were female. Diaries and calendars (either analog or digital) were the most common current methods of collecting adherence data. Users would like information about the intensity and quality of exercises completed that are presented in clear, easy to use formats that are meaningful for older adults where all data can be tracked in one place. Most older adults did not measure adherence because they did not want to, while clinicians most frequently reported not having measurement tools for adherence. Time, resources, motivation, and health were also identified as barriers to recording adherence. Conclusions Our work provides information about current methods of measuring exercise adherence and suggestions to inform the design of future adherence measures. Future measures should comprehensively track adherence data in one place, including the intensity and quality of exercises.

Abstract Background Hospitalized older patients spend most of the waking hours in bed, even if they can walk independently. Excessive bedrest contributes to the development of frailty and worse hospital outcomes. We describe the study protocol for the Breaking Bad Rest Study, a randomized clinical trial aimed to promoting more movement in acute care using a novel device-based approach that could mitigate the impact of too much bedrest on frailty. Methods Fifty patients in a geriatric unit will be randomized into an intervention or usual care control group. Both groups will be equipped with an activPAL (a measure of posture) and StepWatch (a measure of step counts) to wear throughout their entire hospital stay to capture their physical activity levels and posture. Frailty will be assessed via a multi-item questionnaire assessing health deficits at admission, weekly for the first month, then monthly thereafter, and at 1-month post-discharge. Secondary measures including geriatric assessments, cognitive function, falls, and hospital re-admissions will be assessed. Mixed models for repeated measures will determine whether daily activity differed between groups, changed over the course of their hospital stay, and impacted frailty levels. Discussion This randomized clinical trial will add to the evidence base on addressing frailty in older adults in acute care settings through a devices-based movement intervention. The findings of this trial may inform guidelines for limiting time spent sedentary or in bed during a patient’s stay in geriatric units, with the intention of scaling up this study model to other acute care sites if successful. Trial Registration The protocol has been registered at clinicaltrials.gov (identifier: NCT03682523).

Introduction: One of the most drastic changes in cancer is the altered glycosylation of proteins and lipids, giving rise to truncated O-glycans like the Thomsen Friedenreich (TF) or Thomsen nouvelle (Tn) antigen, which are almost absent on normal cells. Combined protein-carbohydrate epitopes comprising these specific glycans are ideal candidates for potent targeted therapies given their excellent tumor specificity and broad cancer expression.Methods and results: We have generated GT-002, a monoclonal antibody specifically targeting the epithelial glycoprotein LYPD3 only in the presence of a TF glycosylation. It does not cross-react with non-glycosylated LYPD3 or TF on other glycoproteins in ELISA and flow cytometry. GT-002 binds to various tumor cell lines and stains tumor tissues of different cancer indications including squamous cell carcinoma of the head and neck. The remarkable tumor specificity was confirmed in an immunohistochemistry study on a normal human tissue panel including several LYPD3-positive organs, where GT-002 elicited almost completely abolished normal tissue binding. Consequently, we observed markedly reduced binding of GT-002 to normal human tissues compared to Lupartumab, a conventional anti-LYPD3 antibody previously in clinical development as antibody-drug conjugate (BAY1129980). Neuraminidase treatment of healthy tissues, resulting in cleavage of sialic acid residues, re-established binding of GT-002 comparable to Lupartumab, showing that the GT-002 epitope is masked by sialic acid in normal cells.Discussion: We believe that GT-002 is a promising candidate for development of antibody-drug- and radio-conjugates as well as bispecific molecules and chimeric antigen receptor therapeutics and highlights the powerful potential of antibodies against combined protein-carbohydrate epitopes to reduce on-target/off-tumor cytotoxicity.

The sentence 'The boss fired the employee who is always late' invites the defeasible inference that the speaker is attempting to convey that the lateness caused the firing (cf. 'The boss fired the employee who is from Philadelphia', which does not invite an analogous inference). We argue that such inferences cannot be understood in terms of familiar approaches to extrasemantic enrichment such as implicature, impliciture, explicature, or species of local enrichment already in the literature. Rather, we propose that they arise from more basic cognitive strategies, grounded in processes of coherence establishment, that thinkers use to make sense of the world. Attention to such cases provides a richer and more varied landscape of extrasemantic enrichment than has been appreciated to date.

BackgroundRemoval of cytokines, chemokines, and microvesicles from the supernatant of allogeneic erythrocytes may help mitigate adverse transfusion reactions. Blood bank-based washing procedures present logistical difficulties; therefore, we tested the hypothesis that on-demand bedside washing of allogeneic erythrocyte units is capable of removing soluble factors and is feasible in a clinical setting.MethodsThere were in vitro and prospective, observation cohort components to this a priori planned substudy evaluating bedside allogeneic erythrocyte washing, with a cell saver, during cardiac surgery. Laboratory data were collected from the first 75 washed units given to a subset of patients nested in the intervention arm of a parent clinical trial. Paired pre- and postwash samples from the blood unit bags were centrifuged. The supernatant was aspirated and frozen at -70°C, then batch-tested for cell-derived microvesicles, soluble CD40 ligand, chemokine ligand 5, and neutral lipids (all previously associated with transfusion reactions) and cell-free hemoglobin (possibly increased by washing). From the entire cohort randomized to the intervention arm of the trial, bedside washing was defined as feasible if at least 75% of prescribed units were washed per protocol.ResultsPaired data were available for 74 units. Washing reduced soluble CD40 ligand (median [interquartile range]; from 143 [1 to 338] ng/ml to zero), chemokine ligand 5 (from 1,314 [715 to 2,551] to 305 [179 to 488] ng/ml), and microvesicle numbers (from 6.90 [4.10 to 20.0] to 0.83 [0.33 to 2.80] × 106), while cell-free hemoglobin concentration increased from 72.6 (53.6 to 171.6) mg/dl to 210.5 (126.6 to 479.6) mg/dl (P < 0.0001 for each). There was no effect on neutral lipids. Bedside washing was determined as feasible for 80 of 81 patients (99%); overall, 293 of 314 (93%) units were washed per protocol.ConclusionsBedside erythrocyte washing was clinically feasible and greatly reduced concentrations of soluble factors thought to be associated with transfusion-related adverse reactions, increasing concentrations of cell-free hemoglobin while maintaining acceptable (less than 0.8%) hemolysis.Editor’s perspective

Impacts from a changing climate, in particular sea-level rise, will be most acutely felt on small oceanic islands. A common configuration of mid-latitude islands is the sandy barrier island. Sable Island, Nova Scotia, Canada is a vegetated sand island near the shelf edge, 160 km from the nearest point of land, that is morphologically similar to a barrier island. This study uses 60 years of airphoto records to analyse changes in coastline position through digitized shore and vegetation (foredune proxy) lines. Rates of coastal movement are analysed to model the future (2039) coastal configuration. The analyses suggest that the majority of the coastline on Sable Island is in retreat, with net retreat on the south side of the island only partially offset by modest net advance on the north side. The different morphologies of the beach-dune systems of South Beach and North Beach, driven by incident wind and waves, yield these different coastline responses. Projected loss of 10 ha by 2039 of the climax heath vegetative community to shoreline retreat suggests a trend toward island instability due to coastline migration. Island-wide data set trends show support for two different but complementary hypotheses about whole-island evolution: (1) the island is mobile via bank migration driving southern coastline changes and experiencing sediment transport toward the east, or (2) the island is generally immobile and losing subaerial sediments (and thus shrinking) likely due to ongoing (and accelerating) sea-level rise. Key words: coastal change, coastal erosion, small island geomorphology, Sable Island, sea-level rise. C'est dans les petites îles océaniques que les impacts d'un climat changeant, en particulier la hausse du niveau de la mer, se feront le plus fortement sentir. Les îles de moyennes latitudes se présentent souvent sous forme d'îles-barrières constituées de sable. L'île de Sable (Nouvelle-Ecosse, Canada) est une île de sable végétalisée située près de la marge du plateau continental, à 160 km de la terre la plus proche et s'apparente, du point de vue morphologique, à une île-barrière. Nous utilisons 60 années de photographies aériennes pour analyser les changements de l'emplacement du trait de côte reflété par les lignes numérisées du rivage et de la végétation (variable substitutive de l'avant-dune). Les vitesses de déplacement du trait de côte sont analysées afin de modéliser la configuration future (2039) de la côte. Les analyses portent à croire que la majeure partie de la ligne de côte de l'île de Sable est en recul, un recul net étant observé du côté sud de l'île qui n'est que partiellement compensé par une modeste avancée nette du côté nord. Les différentes formes adoptées par les systèmes plage-dune des plages Sud et Nord, modelées par le vent et les vagues incidents, produisent différentes réactions de la ligne de côte. La disparition projetée, d'ici 2039, de 10 ha de la communauté végétale climacique d'éricacées en raison du recul du rivage laisse présager une tendance à l'instabilité de l'île causée par la migration de la ligne de côte. Les tendances émanant des ensembles de données pour l'ensemble de l'île appuient deux hypothèses différentes, mais complémentaires concernant l'évolution globale de l'île, à savoir : (1) l'île est mobile, la migration des rives entraînant des modifications de la ligne de côte sud et le transport de sédiments vers l'est ou (2) l'île est généralement immobile et perd des sédiments subaériens (de sorte qu'elle rapetisse), probablement en raison de la hausse en cours (et s'accélérant) du niveau de la mer. [Traduit par la Rédaction] Mots-clés : changement des côtes, érosion côtière, géomorphologie des petites îles, île de Sable, hausse du niveau de la mer., Introduction Small oceanic islands are important scaled-down indicators of coastal change driven by changing ocean dynamics. In particular, sea-level rise (SLR), projected globally to be between 0.26 and 0.77 m [...]

High-grade gliomas (HGGs) and glioblastoma multiforme (GBM) are characterized by a heterogeneous and aggressive population of tissue-infiltrating cells that promote both destructive tissue remodeling and aberrant vascularization of the brain. The formation of defective and permeable blood vessels and microchannels and destructive tissue remodeling prevent efficient vascular delivery of pharmacological agents to tumor cells and are the significant reason why therapeutic chemotherapy and immunotherapy intervention are primarily ineffective. Vessel-forming endothelial cells and microchannel-forming glial cells that recapitulate vascular mimicry have both infiltration and destructive remodeling tissue capacities. The transmembrane protein TMEM230 (C20orf30) is a master regulator of infiltration, sprouting of endothelial cells, and microchannel formation of glial and phagocytic cells. A high level of TMEM230 expression was identified in patients with HGG, GBM, and U87-MG cells. In this study, we identified candidate genes and molecular pathways that support that aberrantly elevated levels of TMEM230 play an important role in regulating genes associated with the initial stages of cell infiltration and blood vessel and microchannel (also referred to as tumor microtubule) formation in the progression from low-grade to high-grade gliomas. As TMEM230 regulates infiltration, vascularization, and tissue destruction capacities of diverse cell types in the brain, TMEM230 is a promising cancer target for heterogeneous HGG tumors.

IntroductionChimeric antigen receptor-engineered T cells (CAR-Ts) are investigated in various clinical trials for the treatment of cancer entities beyond hematologic malignancies. A major hurdle is the identification of a target antigen with high expression on the tumor but no expression on healthy cells, since “on-target/off-tumor” cytotoxicity is usually intolerable. Approximately 90% of carcinomas and leukemias are positive for the Thomsen-Friedenreich carbohydrate antigen CD176, which is associated with tumor progression, metastasis and therapy resistance. In contrast, CD176 is not accessible for ligand binding on healthy cells due to prolongation by carbohydrate chains or sialylation. Thus, no “on-target/off-tumor” cytotoxicity and low probability of antigen escape is expected for corresponding CD176-CAR-Ts.MethodsUsing the anti-CD176 monoclonal antibody (mAb) Nemod-TF2, the presence of CD176 was evaluated on multiple healthy or cancerous tissues and cells. To target CD176, we generated two different 2nd generation CD176-CAR constructs differing in spacer length. Their specificity for CD176 was tested in reporter cells as well as primary CD8+ T cells upon co-cultivation with CD176+ tumor cell lines as models for CD176+ blood and solid cancer entities, as well as after unmasking CD176 on healthy cells by vibrio cholerae neuraminidase (VCN) treatment. Following that, both CD176-CARs were thoroughly examined for their ability to initiate target-specific T-cell signaling and activation, cytokine release, as well as cytotoxicity.ResultsSpecific expression of CD176 was detected on primary tumor tissues as well as on cell lines from corresponding blood and solid cancer entities. CD176-CARs mediated T-cell signaling (NF-κB activation) and T-cell activation (CD69, CD137 expression) upon recognition of CD176+ cancer cell lines and unmasked CD176, whereby a short spacer enabled superior target recognition. Importantly, they also released effector molecules (e.g. interferon-γ, granzyme B and perforin), mediated cytotoxicity against CD176+ cancer cells, and maintained functionality upon repetitive antigen stimulation. Here, CD176L-CAR-Ts exhibited slightly higher proliferation and mediator-release capacities. Since both CD176-CAR-Ts did not react towards CD176- control cells, their response proved to be target-specific.DiscussionGenetically engineered CD176-CAR-Ts specifically recognize CD176 which is widely expressed on cancer cells. Since CD176 is masked on most healthy cells, this antigen and the corresponding CAR-Ts represent a promising approach for the treatment of various blood and solid cancers while avoiding “on-target/off-tumor” cytotoxicity.

Abstract Background Despite the high burden of frailty among cardiac rehabilitation (CR) participants, it is unclear which frailty-related deficits are related to program completion. Methods Data from a single-centre exercise- and education-based CR program were included. A frailty index (FI) based on 25 health deficits was constructed. Logistic regression was used to estimate the odds of CR completion based on the presence of individual FI items. The odds of completion for cumulative deficits related to biomarkers, body composition, quality of life, as well as a composite of traditional and non-traditional cardiovascular risk factor domains were examined. Results A total of 3,756 individuals were included in analyses. Eight of 25 FI variables were positively associated with program completion while 8 others were negatively associated with completion. The variable with the strongest positive association was the food frequency questionnaire score (OR 1.27 (95% CI 1.14, 1.41), whereas the deficit with strongest negative association was a decline in health over the last year (OR 0.74 (95% CI 0.58, 0.93). An increased number of cardiovascular deficits were associated with an increased odds of CR completion (OR per 1 deficit increase 1.16 (95% CI 1.11, 1.22)). A higher number of traditional CR deficits were predictive of CR completion (OR 1.22 (95% CI 1.16, 1.29)), but non-traditional measures predicted non-completion (OR 0.95 (95% CI 0.92, 0.97)). Conclusion A greater number of non-traditional cardiovascular deficits was associated with non-completion. These data should be used to implement intervention to patients who are most vulnerable to drop out to maximize retention.

Abstract This paper will update care providers on the clinical and scientific aspects of frailty which affects an increasing proportion of older people living with HIV (PLWH). The successful use of combination antiretroviral therapy has improved long-term survival in PLWH. This has increased the proportion of PLWH older than 50 to more than 50% of the HIV population. Concurrently, there has been an increase in the premature development of age-related comorbidities as well as geriatric syndromes, especially frailty, which affects an important minority of older PLWH. As the number of frail older PLWH increases, this will have an important impact on their health care delivery. Frailty negatively affects a PLWH’s clinical status, and increases their risk of adverse outcomes, impacting quality of life and health-span. The biologic constructs underlying the development of frailty integrate interrelated pathways which are affected by the process of aging and those factors which accelerate aging. The negative impact of sarcopenia in maintaining musculoskeletal integrity and thereby functional status may represent a bidirectional interaction with frailty in PLWH. Furthermore, there is a growing body of literature that frailty states may be transitional. The recognition and management of related risk factors will help to mitigate the development of frailty. The application of interdisciplinary geriatric management principles to the care of older PLWH allows reliable screening and care practices for frailty. Insight into frailty, increasingly recognized as an important marker of biologic age, will help to understand the diversity of clinical status occurring in PLWH, which therefore represents a fundamentally new and important aspect to be evaluated in their health care.

Abstract Background The effect of frailty and poor cardiovascular health on mortality for males and females is not fully elucidated. We investigated whether the combined burden of frailty and poor cardiovascular health is associated with all-cause and cardiovascular disease (CVD) mortality by sex and age. Methods We analyzed data of 35,207 non-institutionalized US residents aged 20–85 years old (mean age [standard deviation]: 46.6 [16.7 years], 51.4% female, 70.8% White, 10.3% Black, 13.2% Hispanic) from the National Health and Nutrition Examination Survey (1999–2015). Cardiovascular health was measured with the American Heart Association’s Life’s Simple 7 score (LS7). A 33-item frailty index (FI) was constructed to exclude cardiovascular health deficits. We grouped the FI into 0.1 increments (non-frail: FI < 0.10, very mildly frail: 0.1 ≤ FI < 0.20, mildly frail: 0.20 ≤ FI < 0.30, and moderately/severely frail: FI ≥ 0.30) and LS7 into tertiles (T1[poor] = 0–7, T2[intermediate] = 8-9, T3[ideal] = 10–14). All-cause and CVD mortality data were analyzed up to 16 years. All regression models were stratified by sex. Results The average FI was 0.09 (SD 0.10); 29.6% were at least very mildly frail, and the average LS7 was 7.9 (2.3). Mortality from all-causes and CVD were 8.5% (4228/35,207) and 6.1% (2917/35,207), respectively. The median length of follow-up was 8.1 years. The combined burden of frailty and poor cardiovascular health on mortality risk varied according to age in males (FI*age interaction p = 0.01; LS7*age interaction p < 0.001) but not in females. In females, poor FI and LS7 combined to predict all-cause and CVD mortality in a dose-response manner. All-cause and CVD mortality risk was greater for older males (60 and 70 years old) who were at least mildly frail and had intermediate cardiovascular health or worse (hazard ratio [lower/higher confidence interval ranges] range: all-cause mortality = 2.02–5.30 [1.20–4.04, 3.15–6.94]; CVD-related mortality = 2.22–7.16 [1.03–4.46, 4.49–11.50]) but not for younger males (30, 40, and 50 years old). Conclusions The combined burden of frailty and LS7 on mortality is similar across all ages in females. In males, this burden is greater among older people. Adding frailty to assessments of overall cardiovascular health may identify more individuals at risk for mortality and better inform decisions to implement preventative or treatment approaches.