The emerging role of the gut microbiome in cardiovascular diseases is posited to be mediated by the microbial metabolites, some of which yield beneficial effects while others may accelerate the heart ...diseases. The beneficial metabolites like short‐chain fatty acids, particularly butyrate, exhibit several beneficial effects on metabolic diseases including cardiovascular functions. We have previously demonstrated that butyrate promotes the production of glucagon‐like protein‐1 (GLP‐1). GLP‐1 and its therapeutic agonists are known to promote cardiovascular functions. Herein, we investigated the role of systemic deletion of GLP‐1 receptor (using GLP1R KO) on cardiac functions in 16 weeks high‐fat diet (HFD)‐fed obese mice and assessed the impact of feeding a butyrate‐producing probiotic cocktail (consisting 5 Lactobacillus and 5 Enterococcus strains isolated from infant's gut) on cardiac functions, using the non‐invasive high‐frequency ultrasound echocardiography system (VEVO, VisualSonics, Toronto, Ontario, Canada). GLP1R‐KO mice show reduced cardiac output and stroke volume, and higher ejection fraction and fractional shortening of the left ventricle compared GLP1R‐WT mice. In addition, the GLP1R‐KO mice also exhibited significantly reduced systolic and diastolic diameter and volume, along with higher ratio of aortic acceleration and ejection time. Interestingly, feeding of probiotic cocktail protected from such dysfunctions in GLP‐KO mice, and also all these measures remain unchanged in GLP‐WT mice with and without probiotics treatments. No significant differences in body weight and diet intake was observed, however, glucose and insulin tolerance tests were improved in both probiotic‐fed groups. Results indicate that GLP1‐receptor depletion causes cardiovascular dysfunctions and feeding of the human‐origin probiotic cocktail ameliorates such dysfunctions, and probiotics effects are independent of GLP‐1 receptor signaling. Further analyses to better understand the mechanisms of actions of probiotics cocktail contributing these effects, are directed to establish a new cardioprotective probiotic biotherapy in obesity and type 2 diabetes.
Support or Funding Information
We thank the support provide by Center of Cardiovascular Sciences Center, Wake Forest School of Medicine, and the Department of Defense funding PR170446, as well funds and services provided from Center for Diabetes, Obesity and Metabolism, Wake Forest Baptist Medical Center and National Center for Advancing Translational Sciences (NCATS), National Institutes of Health funded Wake Forest Clinical and Translational Science Institute (WF CTSI) through Grant Award Number UL1TR001420.
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Abstract only Background: Sex-specific modulation of β-adrenergic receptor (AR) stimulation plays a pivotal role in cardiac function and in the manifestation of heart disease, including aging. ...However, the sex and age influences on 3 cardiac β-AR subtypes have not been systematically evaluated. Their effects on β 1 -AR have yielded mixed results. Virtually no previous studies have examined sex and age-related changes on the functional cardiac β 3 -AR. We hypothesized that sex differences exist in aging-induced changes in myocyte β 1 - and β 3 -AR. Aged males may exhibit a greater selective β 1 -AR downregulation with a more pronounced decline of β-AR reserve. Methods: LV myocytes were obtained from young (Y) (6 mo) and aged (A) (24 mo) (6/group) male (M) and female (F) wild-type mice. We simultaneously compared LV myocyte protein levels of β 1 -, β 2 -, and β 3 -AR, and the responses of cell contractile function (dL/dt max ) to β-AR subtype stimulation by random exposure of myocytes to isoproterenol (ISO) (10 -8 M) or a selective β 1 -, β 2 -, or β 3 -agonist, Norepinephrine (NE, 10 -7 M), Zinterol (ZIN,10 -5 M) and BRL-37,344 (BRL,10 -8 M), respectively. Results: In Y mice, no sex differences were found in myocyte protein levels of β 1 - (YM: 0.73 vs YF: 0.74), β 2 - (0.28 vs 0.29) and β 3 -AR (0.19 vs 0.17). Consistently, there were similarly significant increases in dL/dt max in responses to ISO (YM: 73%, 209.5 vs121.1; YF: 72%, 210.7 vs122.5 μm/s), NE (48% vs 45%), ZIN (18% vs 20%) and decrease after BRL (8.1% vs 7.9%). Compared with sex-matched Y, in both AM and AF, aging caused a ~58% significant increase in β 3 (AM: 0.30 vs AF: 0.27) and slightly reduced β 2 (11% vs 6%) (P=NS). Aging caused ~30% decline in basal cell contractility. No sex differences in dL/dt max of aging myocyte response to ZIN (increased AM: 17% vs AF: 20%), and BRL (decreased 19% vs 21%). However, in AM, β 1 decreased 33% (0.48) which was significantly greater than that in AF (26%, 0.55). Versus AF, in AM, ISO caused significantly less increase in dL/dt max (34% vs 48%) accompanied by attenuated NE-mediated increase in dL/dt max (17% vs 26%). Conclusions: Aging is associated with LV myocyte β 1 -AR downregulation and β 3 -AR upregulation. Sex affects age-related β 1 -AR downregulation, with males exhibiting a more profound decrease with increasing age.
Abstract only Background: Recent evidence showed that CaMKII inhibition with KN93 protects against diabetic cardiomyopathy (DCM). However, the off-target effects have limited its use. There are no ...CaMKII inhibitors available clinically. It may be best to use some complementary approaches for CaMKII inhibition. Previously we showed that diabetes produced upregulation of cardiac β 3 -AR-mediated inhibitory pathway promoting DCM progression. There is a significant crosstalk between β-AR signaling and CaMKII activation presenting CaMKII as a possible downstream mediator of detrimental β 3 -AR signaling in DCM. It is possible that the benefit of β 3 -AR antagonists (β 3 ANT) might involve modulation of CaMKII. We tested the hypothesis that chronic L-748-337, a selective β 3 ANT may inhibit CaMKII activity and limit DCM. Methods: LV myocyte CaMKIIδ expression and activity and myocyte function were determined in 3 groups (7/group) wild-type female mice over 14 weeks (W): Type 2 DM ( T2 ), 14 W fed high-fat diet (HFD), but after HFD for 4 W receiving streptozotocin (STZ, 40 mg/kg/day, i.p. 5 days); T2β 3 ANT , T2 mice at 10 W received L-748,337 (10 -7 M/kg/day, mini-pump) for 4 W; and Vehicle controls (C). Results: Versus C, T2 diabetes was induced in mice received HFD and low dose STZ with significantly elevated blood glucose. But only T2 myocytes had significantly increased protein levels of CaMKIIδ (T2: 29%, 0.53 vs C: 0.41) and CaMKIIδ phosphorylation (at Thr287) (PCaMKIIδ) (79%, 0.52 vs 0.29) followed by significantly reduced cell contraction (dL/dt max , 75 vs 134 μm/s), relaxation (dR/dt max , 60 vs 114 μ m/s) and Ca 2+ iT (0.16 vs 0.21). The isoproterenol (ISO, 10 -8 M)-stimulated increases in dL/dt max (38% vs 58%), dR/dt max and Ca 2+ iT (19% vs 30%) were also significantly reduced. By contrary, versus C, T2β 3 ANT myocytes had similar levels of CaMKIIδ (0.37) and PCaMKIIδ (0.31) with preserved cell contractility (131 μm/s), relaxation (109 μm/s) and Ca 2+ iT (0.21). ISO caused increases in dL/dt max (57%), dR/dt max (52%) and Ca 2+ iT (30%) were also closed to control values. Conclusions: Chronic β 3 ANT prevents Type II diabetes-caused upregulation of cardiac CaMKIIδ, thereby leading to the preservation of normal myocyte function, Ca 2+ iT , and β-adrenergic reserve in a DCM murine model.
Abstract only Background: Fibroblast growth factor-23 (FGF-23), a protein regulating phosphorus levels, is associated with the risk of heart failure, particularly in patients with chronic kidney ...disease (CKD), and with left ventricular (LV) hypertrophy in CKD. However, few studies have explored this association in the general population, and it is unknown whether FGF23 is associated with other parameters of cardiac structure and function. Methods: Among 5,533 Black or White participants attending Visit 5 (2011-2013) of the community-based ARIC study, we quantified the cross-sectional association of serum FGF-23 levels with echocardiographic measures of cardiac structure and function after accounting for potential confounders including kidney function. Results: Mean age was 76 SD 5 years, 58 % were women, and 21 % were Black. Among the echocardiographic parameters tested ( Table ), higher FGF-23 levels were robustly associated with LV hypertrophy (adjusted odds ratio aOR 1.35 95%CI 1.02-1.79 in top vs. bottom quartile), abnormal peak longitudinal strain (aOR 1.88 1.32-2.69), and left atrial enlargement based on left atrium volume index (aOR 1.34 1.05-1.70). No association was observed with E/e’ ratio. Higher FGF-23 was also associated with end-diastolic right ventricular (RV) enlargement (aOR 1.36 1.04-1.78). Similar results were observed when echocardiographic measures were modeled as continuous variables and when we stratified participants by demographics (age, sex, and race) or a history of cardiovascular disease. Conclusions: In community-dwelling older adults, in addition to LV hypertrophy, FGF-23 was associated with LV systolic and diastolic function as well as RV size, independent of kidney function and other potential confounders. These findings further support the involvement of FGF-23 in the pathophysiology of cardiac remodeling.
Abstract only Background: Emergent evidence indicates that CaMKII overactivity in diabetes (DM) plays a crucial role in the pathophysiology of diabetic cardiomyopathy (DCM) by targeting a diverse ...array of proteins involved in cardiac electrical, structural and functional remodeling. CaMKII has been proposed to be a therapeutic target for DCM. However, although chronic inhibition of CaMKII has been associated with cardioprotection in several cardiovascular diseases, the direct cardiac effects of CaMKII activation in type 2 (T2) DM are unclear. Moreover, whether and how DCM alters cardiac responses to CaMKII are undefined. We tested the hypothesis that in DCM, CaMKII is upregulated, which alters cardiac contractile behavior. Endogenous CaMKII activation may produce direct depressions in LV myocyte basal function and β-adrenergic reserve. Acute inactivation of CaMKII with KN93 would have a beneficial impact in DCM. Methods: LV myocyte CaMKIIδ expression and activity and myocyte functional responses were compared in 2 groups (n=9/group) of wild-type female mice: Vehicle Control (C) , animals fed chow for 14 weeks (W); T2DM, i nduced with a high-fat diet (HFD) intake for 14 W, but after fed HFD for 4 W receiving streptozotocin (STZ, 40 mg/kg/day, i.p. for 5 days). In T2DM, we further assessed myocyte contractile and Ca 2+ i transient (Ca 2+ iT ) responses with and without acute treatment of myocytes with KN93 (10 -6 M, 30 min). Results: Versus C, in T2DM myocytes, the CaMKIIδ protein levels (28%, 0.51 vs 0.40) and CaMKIIδ phosphorylation (79%, 0.52 vs 0.29) were significantly increased. These changes were followed by significantly reduced cell contraction (dL/dt max , 76.0 vs 137.3 μm/s), relaxation (dR/dt max , 61.7 vs 116.0 μm/s) and Ca 2+ iT (0.16 vs 0.21). ISO-stimulated increases dL/dt max (39% vs 58%), dR/dt max (35% vs 54%) and Ca 2+ iT (20% vs 30%) were also significantly reduced. Moreover, in T2DM myocytes, superfusion with KN93 significantly improved myocyte basal contraction (104.2 μm/s), relaxation (79.3 μm/s) and Ca 2+ iT (0.21). Conclusions: In T2 diabetes-induced DCM, upregulation of CaMKIIδ has adverse functional effects. Acute endogenous CaMKII activation exacerbates LV myocyte dysfunction. The inhibition of CaMKII has a significant beneficial impact.
Abstract only Background: Physical frailty is common among older patients with acute decompensated HF (ADHF) and is associated with worse quality of life (QOL) and a higher risk of adverse CV events. ...In the REHAB-HF trial, a 12-week, multidomain physical function intervention improved functional status and QOL in older ADHF patients. Whether baseline frailty status modifies the benefits of the intervention remains unclear. Objective: Evaluate the interaction between baseline frailty and treatment effects of the physical function intervention in the REHAB-HF trial. Methods: Frailty status was assessed by the modified Fried criteria. Outcomes were change in physical function (Short Physical Performance Battery SPPB score and 6-minute walk distance 6-MWD), QOL (Overall KCCQ score), and Geriatric Depression Scale (GDS) score at the end of the 12-week intervention. Association between changes in frailty score and rates all-cause hospitalization were assessed using adjusted linear regression models. Results: At baseline, among 337 participants (age: 72 y, 54% women) 57% were frail, and 43% were prefrail. At 12-week f/u, both prefrail and frail groups improved with the intervention; however, the frail group had significantly greater improvements over the prefrail group in SPPB score, 6MWD, and KCCQ (Table). A significant improvement was also noted in the GDS score with the intervention among frail but not prefrail participants (Table). In adjusted analysis, an improvement in frailty score at 12-weeks was significantly associated with lower rates of all-cause hospitalization in the 3 months following the intervention period (rate ratio 95%CI = 0.650.55-0.76, p<0.001). Conclusion: ADHF patients with worse frailty status at baseline had greater improvement in functional status and QOL than those who were prefrail. Furthermore, improvement in frailty burden with the rehabilitation intervention was significantly associated with a lower risk of rehospitalization.
Abstract only
Introduction:
Older patients with acute decompensated heart failure (ADHF) have severely impaired QOL. We recently reported that a novel physical rehab intervention improves QOL. Here ...we report trajectories of improvement and relationship to participation in a rehab intervention.
Methods:
Patients with ADHF, regardless of EF and ≥ 60 years old were randomized to either attention control (AC) or rehab intervention (RI). Participants completed the KCCQ, a disease-specific QOL instrument, and 12-Item Short-Form Health Survey (SF-12), a general QOL instrument composed of a mental and physical composite score, at baseline (inpatient), 1 month and 3 months. Effects of the intervention were assessed using linear mixed effects models including the main effect of intervention, follow-up visit, and interaction term with adjustment for EF category, age, and sex.
Results:
The REHAB-HF trial enrolled 349 patients with a mean age of 72.7±8.1 years, 52% women and 49% non-white. Baseline KCCQ scores were low for both arms (Figure 1). There was a substantial increase in KCCQ score at 1 month in both arms. However, in contrast to the AC participants who showed no further improvement, RI participants continued to experience an increase in QOL at 3 months creating a significant difference between arms (p< 0.01). Both SF-12 composite scores also increased in both arms at 1 month with continued improvement only in the RI arm; reaching significance for the mental composite at 1 month (50.8±1.1 vs. 46.9±1.1, p < 0.01) and at 3 months (52.7±1.1 vs. 48.2±1.1, p< 0.01).
Conclusions:
Older patients hospitalized with ADHF have severely impaired disease-specific and general QOL that improves soon after discharge. Patients receiving a novel physical rehabilitation intervention experienced an early benefit in terms of QOL that continued to improve throughout the 3 months trial period. Future studies will help determine if these benefits are sustained with longer term follow-up.
Abstract only Background: We have shown previously that aging-induced cardiomyocyte dysfunction and impaired β-adrenergic regulation were prevented in β 3 -adrenergic receptor (AR) knockout (β 3 KO) ...aged mice. However, the molecular mechanism is unclear. We hypothesize that reversal of aging-induced down-regulation of SR Ca 2+ -ATPase (SERCA 2a) and β 1 -ARs by β 3 -AR deficiency may play a key role for the protective effect. Methods: We compared cardiac SERCA 2a, phospholamban (PLB), β 1 - and β 3 -AR protein expression and myocyte contractile and Ca 2+ i transient (Ca 2+ iT ) responses to isoproterenol (ISO, 10 -8 M) in left ventriclar (LV) myocytes obtained from 2 young (Y)(~4-6 mo) and 2 aged (A) (~18-24 mo) groups (7/group) of wild-type (WT) and β 3 KO mice, respectively. Results: Compared with YWT, AWT myocytes had significantly decreased SERCA 2a (66%, AWT: 0.21 vs YWT: 0.61), SERCA 2a/PLB ratio (0.76 vs 1.77) and β 1 -AR (33%, 0.39 vs 0.58), but increased β 3 -AR (93%, 0.27 vs 0.14). These changes were associated with reduced basal cell contraction (dL/dt max ) (AWT: 84.3 vs YWT: 124.8 μm/s), relaxation (dR/dt max ) (60.1 vs 89.8 μm/s) and Ca 2+ iT (0.17 vs 0.22). This was accompanied by diminished ISO-stimulated positive inotropic effect; in AWT myocytes, ISO (10 -8 M) caused significantly less increases in dL/dt max (AWT: 33% vs YWT: 81%), dR/dt max (24% vs 58%), and Ca 2+ iT (14% vs 34%). Compared with YWT, Yβ 3 KO did not alter basal contraction and ISO response of myocytes, but SERCA 2a (Yβ 3 KO: 1.2 vs YWT: 0.61) and SERCA 2a/PLB ratio were doubled with relatively unchanged β 1 -AR (0.62 vs 0.58); Aβ 3 KO mice had similar alterations. Importantly, in contrast to AWT, in Aβ 3 KO myocytes, the increased SERCA 2a (1.1) and β 1 -AR (0.61) correlated with normal basal cell contraction and relaxation with preserved ISO-stimulated positive inotropic response. ISO caused similar increases in dL/dt max (84% vs 82%) and Ca 2+ iT (32% vs 34%) compared to Yβ 3 KO mice. Conclusions: Chronic β 3 -AR deficiency upregulates cardiac SERCA 2a, prevents aging-induced downregulation of β 1 -ARs, and leads to the preservation of myocyte function, Ca 2+ iT , and β-adrenergic responsiveness in aged hearts. Thus, antagonizing β 3 -AR could be a new therapeutic strategy for age-related decline in myocardial function.
Abstract only Introduction: Heart failure with preserved ejection fraction (HFpEF) is the most rapidly increasing type of heart failure. Markedly reduced exercise capacity (peak VO 2 ) is the primary ...manifestation of chronic HFpEF and impacts quality of life (QOL); however, its relationship to objectively measured physical activity (PA) levels is unknown. Accordingly, we prospectively measured PA, exercise performance, and QOL in older patients with chronic obese HFpEF. Hypothesis: PA levels would be low in obese HFpEF patients and would be strongly correlated with reduced exercise performance and QOL. Methods: Obese HFpEF patients ≥60 years old (N=58) wore Kenz Lifecorder EX accelerometers to obtain light PA (LPA), moderate-vigorous PA (MVPA), PA energy expenditure (PAEE), and steps. Peak VO 2 and ventilatory anaerobic threshold (VAT) were assessed by cardiopulmonary exercise testing, and six-minute walk distance (6MWD) was assessed using the Guyatt method. QOL was assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ), Minnesota Living with Heart Failure Questionnaire (MLHF), and Short Form 36 (SF-36). Pearson correlations were performed to examine relationships between PA, exercise performance, and QOL. Results: Patients were 68.0±5.7 years old, 78% (45 of 58) female, 59% (34 of 58) white, obese (BMI 39.1±6.1 kg/m 2 ), and had predominantly NYHA class II symptoms (62%, 36 of 58). Patients had low PA levels with 33.4±12.6 min/day of LPA, 10.4±6.7 min/day of MVPA, 3785±1436 steps/day, and a PAEE of 147±57 kcal/day. Patients also had low exercise performance with peak VO 2 of 14.4±2.7 ml/kg/min, VAT of 9.7±1.9 ml/kg/min, and 6MWD of 410±75 meters. LPA (r=0.32, p=0.014) and steps/day (r =0.30, p=0.022) were modestly correlated with peak VO 2 , but MVPA and PAEE were not. All PA measures were moderately correlated with 6MWD (r=0.41-0.49, all p<0.002). None of the PA measures were correlated with any of the QOL assessments (KCCQ r=0.00-0.15, p=0.25-0.99; MLHF r=-0.13-0.00, p=0.33-0.99; SF-36 r=0.05-0.11, p=0.41-0.70). Conclusion: Obese HFpEF patients had low levels of objectively measured daily PA and low exercise performance. Contrary to our hypothesis, PA levels were only modestly correlated with exercise performance including peak VO 2 and 6MWD. PA was not correlated with any assessment of QOL. This indicates that measures of PA, exercise capacity, and QOL assess different aspects of the patient experience in obese HFpEF and are largely independent of each other. While each remains a valid potential target for intervention, they should not be considered interchangeable.
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