Left ventricular (LV) flow state is associated with unfavorable outcome in patient with severe aortic stenosis. However, there is little information on its impact on long-term prognosis in a population without valvular disease. To examine the impact of low-flow state (LFS) on all-cause mortality in multiethnic population, we analyzed 4,398 asymptomatic participants without clinical cardiovascular disease undergoing cardiac magnetic resonance (CMR) in the multiethnic study of atherosclerosis. LV stroke volume index (SVi), LV ejection fraction (LVEF), and myocardial contraction fraction (MCF) were measured. LV flow states were classified as normal flow state (NFS: SVi > 35 mL/m2), low-flow state (LFS, 30-34 mL/m2), and very low-flow state (VLFS: SVi < 30 mL/m2). Clinical data were collected at enrollment. Participants were followed up for a median of 14.2 yr. All-cause and cardiovascular disease mortalities were used as primary endpoints. All-cause mortality was 16.2%, and cardiovascular disease mortality was 3.5%. VLFS and LFS groups had more cardiovascular risk factors and lower cardiac performance than NFS. The relationship between all-cause mortality and SVi was "L-shape" with the "breakpoint" at 33.5 mL/m2 for a statistical significance (P = 0.009). All-cause mortality was significantly associated with LFS after adjusted for age, sex, LVEF, and LV mass index with hazard ratio (HR) 1.81, 95% confidence interval (CI): 1.31-2.49 for VLF and HR: 1.21, 95% CI: 0.95-1.54 for LFS with overall P value 0.001. The highest cardiovascular disease mortality was seen in VLFS. LFS was significantly associated with increased all-cause mortality despite normal LVEF and no valvular disease.NEW & NOTEWORTHY This is the first study demonstrating that low-flow state (LFS) has a significant impact on mortality in multiethnic study of atherosclerosis (MESA) participants with no valvular disease. The study may have a clinical implication since LFS is commonly present in multiethnic population. The current study provides new information on clinical characteristics and myocardial performance of LFS suggesting that further prospective studies to determine whether targeting modifiable risk factors for cardiovascular disease and metabolic syndrome would have any favorable impact on LFS.

Background: Permanent pacemaker (PPM) implantation remains a common complication after transcatheter aortic valve replacement (TAVR). Existing clinical and imaging-based risk prediction models showing limited and inconsistent performance. We evaluated whether a pre-procedural ECG-based artificial intelligence (ECG-AI) model predicts 30-day PPM post-TAVR. Methods: In this retrospective multicenter study, a 1-dimensional convolutional neural network was trained on 34,745 ECGs from 5,932 patients with moderate-to-severe aortic stenosis (proxy cohort) to enable prediction of 30-day PPM implantation after TAVR using preprocedural ECGs. Zero-shot external validation was performed in two independent TAVR cohorts (Atrium Health Wake Forest Baptist [AHWFB] and Sanger Heart and Vascular Institute [SHVI]) without recalibration or fine-tuning. Model performance was assessed using discrimination and calibration metrics, with subgroup analyses by valve platform, clinical factors, and ECG-to-TAVR timing. Incremental and independent prognostic value was evaluated using multivariable logistic regression incorporating clinical and imaging covariates. Findings: The model was evaluated in two heterogeneous TAVR cohorts (AHWFB, n=823; SHVI, n=162) with differences in baseline characteristics and valve use, demonstrating moderate but consistent discrimination across cohorts (AHWFB: AUROC 0·67 [0·61–0·73], Brier 0·11 [0·09–0·13]; SHVI: AUROC 0·78 [0·67–0·88], Brier 0·07 [0·04–0·11]) with high negative predictive value (0·92–0·99). Performance remained stable for ECGs obtained within 0–2 days pre-TAVR (AUROC ~0·75–0·78) and in Sapien-only analyses (AHWFB: 0·77 [0·70–0·84]; SHVI: 0·79 [0·68–0·89]). In multivariable models, baseline covariates modestly improved discrimination (ΔAUC ≤0·06 in SHVI), while ECG-AI remained the only independent and consistent predictor (OR 1·36–2·18). Interpretation: An ECG-AI model trained in a large cohort demonstrated robust, transferable prediction of 30-day PPM post-TAVR using pre-procedural ECGs across multiple TAVR cohorts without recalibration. It captured prognostic information beyond traditional baseline risk factors and showed consistent independent and incremental predictive value.

Objective:To assess prevalence, clinical characteristics, and risk factors associated with low flow state (LFS) in a multiethnic population with normal left ventricular ejection fraction (LVEF). Patients and Methods:The study included 4398 asymptomatic participants undergoing cardiac magnetic resonance from July 17, 2000, to August 29, 2002. Left ventricular (LV) mass, volume, and myocardial contraction fraction were assessed. Low flow state was defined as stroke volume index (SVi of <35 mL/m2). Clinical characteristics, cardiac risk factors, and cardiac magnetic resonance findings were compared between LFS and normal flow state (NFS) groups (NFS: SVi of ≥35 mL/m2). Results:There were significant differences in the prevalence of LFS in different ethnic groups. Individuals with LFS were older (66±9.6 vs 61±10 years; P<.0001). The prevalence of LFS was 19% in the group aged older than 70 years. The logistic multivariable regression analysis found that age was independently associated with LFS. The LFS group had significantly higher prevalence of diabetes (30% vs 24%; P=.001), LV mass-volume ratio (1.13±0.22 vs 0.91±0.15; P<.0001), inflammatory markers, a lower LV mass index (59±10 vs 65±11 kg/m2; P<.001), lower myocardial contraction fraction (58.1±10.6% vs 75.7±13%; P<.001), and a lower left atrial size index (32.2±4.6 vs 36.7±5.9 mm/m2; P<.0001) than NFS. Conclusion:Low flow state may be considered an under-recognized clinical entity associated with increasing age, multiple risk factors, increased inflammatory markers, a lower LV mass index, and suboptimal myocardial performance despite the presence of normal LVEF and absence of valvular disease.

Abstract Rationale, Aims and Objectives Type 2 diabetes (T2D) is an archetypical chronic condition of significant prevalence. Yet the concept of cure in the context of T2D reveals an interplay between the medical imagination and clinical realities that can shift the course of a patient's care. There are two domains in which cure is sociologically constructed: the professional domain occupied by clinicians treating people with T2D, and the lay domain occupied by T2D patients. Lay epistemologies of cure tend to be focused on modifying the experience of having T2D, while professional epistemologies tend to focus on modifying the disease through medical treatment. The objective of this study is to explore the role of the concept of cure in the context of type 2 diabetes, a model for chronic disease. Methods Through surveys and interviews of T2D patients, providers and researchers at an urban academic medical centre, I explore the perspectives and attitudes each group have towards the concept of cure in T2D. Semi‐structured interviews of T2D professionals and patient surveys consisting of free response questions and Likert scale items were thematically analysed for perspectives on cure in T2D. Results Sixteen T2D patients met inclusion criteria and consented to the survey and ten T2D professionals were interviewed. Cure is conceived of heterogeneously both within and between epistemologies. Patients carry hopes of cure predicated on eliminating the unpleasant experiences of T2D and its treatments, while T2D professionals tend to avoid invoking the concept of cure, at least to patients, on grounds of clinical uncertainty. However, the concept of cure is a significant motivator of treatment in both lay and professional epistemologies. Conclusion Different viewpoints on cure in T2D present an opportunity for shared meaning and decision making between patients and their providers that can frame the best possible outcome for patient care.

Background: Catheter ablation for atrial fibrillation (CAAF) can result in stiff left atrial syndrome (SLAS) in up to 8% of patients. SLAS can be challenging to diagnose and difficult to distinguish from heart failure with preserved ejection fraction (HFpEF), presenting with similar signs and symptoms. Case presentation: We report the first case of using an interatrial stent to maintain therapeutic benefit of atrial septostomy in a patient with symptomatic SLAS. While interatrial shunt devices have preliminarily been shown to be safe and efficacious for the treatment of HFpEF, their utilization in those with SLAS has not previously been described [1]. Conclusions: In patients with prior CAAF, SLAS should be considered to explain dyspnea when alternative processes have been excluded. Treatment of SLAS can be challenging with medical therapy alone, and septostomy may provide significant symptomatic benefit in these patients. Interatrial stenting can improve the patency of such interventions. (c) 2022 Elsevier Inc. All rights reserved.

Objectives: This study describes a real-world experience of implanting a novel balloon expandable transcatheteraortic valve replacement (TAVR) compared to devices commonly used in clinical practice. As a secondary objective,the effect of balloon angioplasty (BAV) before TAVR on the transvalvular gradient 1 and 30 days after implantationwas evaluated.Background: For most commercial TAVR valves, the 30-day average mean aortic valve gradients have been reported.Our experience with the Lotus Valve System had indicated higher immediate post-implant gradients than those in the literature. We sought to evaluate both these valves, comparing them to other valves.Methods: We analyzed discharge and 30-day echocardiograms of Lotus valves from 7/5/2019 to 8/27/2020. In responseto higher-than-expected post-implant gradients, patients from 11/4/19 to 8/27/20 underwent BAV before the valve implantation, whereas patients from 7/5/19 to 10/18/19 did not (no-BAV). We compared these samples to each other and to a random sampling of TAVR valves implanted by the same interventionalist.Results: At discharge, 27 patients received Lotus valves. The average mean aortic valve gradient was 16.7 mmHg(SD = 5.5 mmHg) for the no-BAV and 14.7 mmHg (SD = 3.7 mmHg) for the BAV (P = 0.177) cohorts. No-BAV Lotus valve mean gradients were significantly higher (P < 0.001) than those of the Sapien valve (M = 12 mmHg, SD = 4.3)and CoreValve (M = 9.18 mmHg, SD = 3.96). At the 30-day assessment, the mean gradients in the no-BAV and BAV groups were similar to those in the literature (M = 11 mmHg SD 3.5; M = 12 mmHg, SD 4.1 (P = 0.287)) and those ofother valves.Conclusions: The Lotus valve demonstrated higher post-implantation gradients than other valves. This effect wasnot attenuated by BAV. These elevated gradients were not significant at the 30-day follow-up.

Background: Cocaine, one of the most commonly used illegal drugs, exaggerates sympathetic nervous activity and has profound effects on the cardiovascular system. It is well known that acute doses of cocaine raise the heart rate, and cause acute hypertension, arrhythmia, and reduce coronary blood flow. However, its role and mechanism on the arterial-left ventricular (LV) coupling (ALVC) and LV mechanical efficiency remain to be critically examined. We hypothesized cocaine may impair ALVC and produce myocardial contractile and metabolic abnormalities, and thus impair LV ability to convert metabolic energy to external work. Methods: We examined the effect of cocaine (4 mg/kg/iv) on ALVC and the conversion of metabolic energy [measured as myocardial oxygen consumption (MVO 2 )] to mechanical work [measured as pressure (P)-volume (V) area (PVA)], and PVA to external work (SW) in 6 conscious chronically instrumented dogs. The control MVO 2 -PVA relation was generated by altering loading conditions using three graded doses of Phenylephrine after autonomic blockade with hexamethonium and atropine. Results: Ten minutes after cocaine administration, blood cocaine level was 7.3±2.4 mg/L. There were significant decreases in the slope (E ES ) of LV end-systolic P-V relation (5.0±0.09 vs 6.7±1.4 mmHg/ml, p<0.05), SW (1379±284 vs 1739±204 mmHg•ml, p<0.05) and increases in arterial elastance (E A ) (13.6±2.6 vs 7.6±1.8 mmHg•ml, p<0.05). Despite the decrease in E ES , energy utilization as calculated from LV MVO 2 was increased (0.13±0.01 vs 0.10±0.02 ml O 2 /beat/100g LV, p<0.01) and the MVO 2 -PVA point was shifted above the control MVO 2 -PVA relation by 0.010±0.002 ml O 2 /beat/100g LV, (p<0.05). The SW/PVA ratio decreased (56±8% vs 75±12%, p<0.05) as impaired arterial-LV coupling indicated by a significantly increased the ratio of E A to E ES (from 1.2±0.4 of baseline to 2.8±0.05 after cocaine (p<0.05). Thus, SW/MVO 2 , representing LV mechanical efficiency, decreased from 11.0±1.9 to 8.8±1.2% (p<0.05) with cocaine. Conclusions: Acute doses of cocaine impair arterial LV coupling and decrease LV mechanical efficiency due to the decreased conversion of mechanical energy (PVA) to external work (SW) which mainly resulted from the deterioration of arteria-LV coupling.

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 a...

Abstract Frail older adults are at high risk of negative consequences from hospitalization and are discharged without completely returning to their pre-existing health status. Transitional care is needed to maintain care continuity from hospital to home. This systematic review aimed to examine transitional care for frail older adults and its effectiveness. The Cochrane guidelines were followed, and search terms were determined by PICO: (P) frail older adults, not disease-specified; (I) transitional care initiated before discharge; (C) usual care; and (O) all health outcomes. Four databases were searched for English-written randomized controlled trials (inception to 2020), and eight trials were ultimately included. Frail older adults in eight trials (1996–2019) totaled 2,785, with a mean sample size of 310. The intervention components varied from hospital care (e.g., geriatric assessment, discharge planning, rehabilitation) to follow-up care after discharge (e.g., home visit, phone follow-up, community service). Most measured outcomes were readmission (n = 7), function (n = 4), quality of life (n = 4), self-rated health (n = 3), and mortality (n = 3). Statistical significance was reported in the following number of trials: readmission (n = 2), function (n = 2), quality of life (n = 1), self-rated health (n = 3), and mortality (n = 0). The effectiveness of the intervention on each outcome was inconsistent across the trials. Varied transitional care between hospital and home was implemented to improve health status; however, its effectiveness was controversial. A novel, yet evidence-based approach is needed to develop transitional care interventions for these vulnerable populations.

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.

Background: Diabetic cardiomyopathy (DCM) is a serious complication of diabetes (DM). As yet, no effective therapeutic strategies exist. Recently, we found that DM-induced LV dysfunction was prevented by chronic treatment with a β 3 -adrenergic receptor (AR) antagonist (β 3 ANT). However, the molecular mechanism is unclear. We hypothesized that reversal of DM-induced detrimental alterations on the expressions of cardiac SR Ca 2+ -ATPase (SERCA2a), β-ARs, nitric oxide synthase (NOS) by β 3 ANT may play a key role for its salutary role in DCM. Methods: The protein levels of myocyte β 1 - and β 3 - AR, SERCA2a, NOS and myocyte functional responses were determined in 3 groups (7/group) wild-type female mice over 14 weeks (W): Type 2 DM ( T2 ), 14 W fed a 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, a selective β 3 ANT (10 -7 M/kg/day, mini-pump) for 4 W; and Vehicle controls (C). Results: Versus C, T2DM was induced in mice received HFD and low dose STZ with significantly elevated blood glucose (~340 to 380 mg/dl). Only T2 mice had significantly decreased protein levels of LV myocyte β 1 -AR (T2: 0.35 vs C: 0.49) and SERCA2a (0.19 vs 0.29), but increased β 3 -AR (0.25 vs 0.14) and iNOS (0.25 vs 0.15) without significant changes in eNOS (0.14 vs 0.13) and nNOS. These changes were followed by significantly reduced basal cell contraction (dL/dt max , 75.4 vs 133.7 μm/s), relaxation (dR/dt max , 59.6 vs 113.8 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 (34% vs 55%) and [Ca 2+ ] iT (19% vs 30%) were also significantly reduced. By contrary, versus C, T2β 3 ANT myocytes had similar protein levels of β 1 -AR (0.52), SERCA2a (0.75) and iNOS (0.36) with preserved normal basal cell contractility (127.8 μm/s), relaxation (109.4 μm/s) and [Ca 2+ ] iT (0.21). ISO caused increases in dL/dt max (57%), dL/dt max (52%), and [Ca 2+ ] iT (30%) were also closed to control values. Conclusions: Chronic β 3 ANT prevents DCM-caused downregulations of cardiac β 1 -ARs and SERCA2a, and normalized upregulations of iNOS and β 3 -AR, thus leading to the preservation of normal myocyte contractile function, [Ca 2+ ] iT , and β-adrenergic reserve in a mouse model of T2DM.

The purpose of this study was to explore the utility of echocardiography and the EuroSCORE II in stratifying patients with low-gradient severe aortic stenosis (LG SAS) and preserved left ventricular ejection fraction (LVEF ≥ 50%) with or without aortic valve intervention (AVI). The study included 323 patients with LG SAS (aortic valve area ≤ 1.0 cm2 and mean pressure gradient < 40 mmHg). Patients were divided into two groups: a high-risk group (EuroSCORE II ≥ 4%, n = 115) and a low-risk group (EuroSCORE II < 4%, n = 208). Echocardiographic and clinical characteristics were analyzed. All-cause mortality was used as a clinical outcome during mean follow-up of 2 ± 1.3 years. Two-year cumulative survival was significantly lower in the high-risk group than the low-risk patients (62.3% vs. 81.7%, p = 0.001). AVI tended to reduce mortality in the high-risk patients (70% vs. 59%; p = 0.065). It did not significantly reduce mortality in the low-risk patients (82.8% with AVI vs. 81.2%, p = 0.68). Multivariable analysis identified heart failure, renal dysfunction and stroke volume index (SVi) as independent predictors for mortality. The study suggested that individualization of AVI based on risk stratification could be considered in a patient with LG SAS and preserved LVEF.

Background: We have shown that L-748,337 (L-7), a selective β 3 -adrenergic receptor (AR) antagonist reversed LV dysfunction and β-AR desensitization in diabetes (DM) caused diabetic cardiomyopathy (DCM). The mechanism is unclear. Recent evidence suggests that normal myocardial performance depends on the balance in myocyte β 3 -, β 1 -, and β 2 -AR. Pivotal restructuring of β-AR system resulting in the decline of β-AR reserve plays a crucial role in DCM. We assessed the hypothesis that chronic L-7 would prevent DCM-induced abnormalities of β-AR subtype-stimulated regulation on intrinsic LV myocyte function and [Ca 2+ ] i regulation, thus restoring cardiac function. Methods: Studies were conducted in 3 groups of female mice: Type 2 DM (T2) (n=9), induced with high-fat diet (HFD) intake for 14 weeks (W), but after fed HFD for 4 W receiving streptozotocin (STZ, 40 mg/kg/day, i.p. for 5 days); T2/L-7 (n=7), T2 mice at 10 W received L-7 (10 -7 M/kg/day, mini-pump) for 4 W; and Controls (C)(n=9). We compared LV myocyte contractile and [Ca 2+ ] iT responses 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, during drug perfusion. Results: T2 and T2/L-7 mice had mean blood glucose levels of 388 mg/dl and 369 mg/dl, respectively. Versus C, only in T2, basal LV myocyte contractility (dL/dt max , 76 vs 133 μm/s), relaxation and [Ca 2+ ] iT (0.16 vs 0.21) were significantly decreased. ISO-stimulated dL/dt max (40% vs 58%) was attenuated accompanied by a diminished NE-mediated increase in dL/dt max (28% vs 44%), but enhanced BRL-induced decreases in dL/dt max (29% vs 12%).The response of dL/dt max (24% vs 15%) to ZIN was increased. Importantly, in T2/L-7 myocytes, the basal dL/dt max (128 μm/s) and [Ca 2+ ] iT (0.21) remained close to control values with preserved β-stimulated positive modulation on cell contraction. The increases in dL/dt max in response to ISO (57%), NE (40%) or ZIN (15%) were similar to that in control myocytes, respectively. Conclusions: Chronic β 3 -AR antagonist reverses β-AR signaling defects, resensitizing the β-AR subtype system modulation on LV myocytes function, thus playing a salutary role in DCM.

Background: Heart failure (CHF) causes cardiac β 3 -adrenergic receptor (AR) upregulation with resultant enhanced β 3 -AR-stimulated-G i -coupled negative modulation on cardiac function. This suggests a direct and contributing role of β 3 -AR activation on CHF progression. However, its precise role is unclear. We hypothesize that up-regulation of cardiac β 3 -AR promotes CHF progression. Chronic β 3 -AR antagonist (ANT) may improve Left ventricular (LV) myocyte function, and β-adrenergic reserve, thus preventing the progression of CHF. Methods: LV and myocyte functional response and β 1 - and β 3 -AR expression were compared in 3 groups of SD male rats (8 each) during 3 months: 1) CHF, 3 months after receiving Isoproterenol (ISO, 170 mg/kg, sq, for 2 days); 2) CHF/β 3 -ANT, 2 months after receiving ISO, L-748,337, a selective β 3 -AR antagonist (β 3 -ANT) (10 -7 M/kg/day, mini pump) was initiated and was given for 1 month; and 3) sham controls. Results: Versus controls, ISO-treated rats had CHF onset at 1 month after ISO and progressed to severe CHF at 3 months. Plasma norepinephrine (NE, 1298 vs 261 pg/ml) increased 4-fold; whereas, stroke volume (SV) and ejection fraction (EF, 34 vs 62%) decreased more than 45%. These changes were parallel with significant reductions in cell contraction (dL/dt max , 95 vs 189 μm/s), relaxation (dR/dt max ,75 vs 158 μm/s) and [Ca 2+ ] i transient ([Ca 2+ ] iT ) (0.17 vs 0.26). Acute superfusion of ISO (10 -8 M) caused much less increases in dL/dt max (34 vs 74%), dR/dt max and [Ca 2+ ] IT (14 vs 28%). These changes were associated with significantly decreased β 1 -AR mRNA (52%, 0.30 vs 0.62), but increased β 3 -AR mRNA (119%, 1.25 vs 0.57) expression. CHF with β 3 -ANT treatment, significantly decreased plasma NE (197 pg/ml). EF (59%) and SV returned to normal control values. The signal ratios of β 1 -AR mRNA (0.59) and β 3 -AR mRNA (0.66) recovered to control levels. ISO-induced increases in dL/dt max (75%), dR/dt max and [Ca 2+ ] iT were also significantly augmented. Conclusion: Chronic β 3 -ANT leads to normalization of LV myocyte β 1 - and β 3 -AR gene expression, restores normal LV myocyte β-AR reserve, and leads to regression of LV and myocyte dysfunction in a rat model of progressive CHF. Thus, β 3 -AR blocker may provide a new therapeutic strategy for the treatment of CHF.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is upregulated in congestive heart failure (CHF), contributing to electrical, structural, and functional remodeling. CaMKII inhibition is known to improve CHF, but its direct cardiac effects in CHF remain unclear. We hypothesized that CaMKII inhibition improves cardiomyocyte function, [Ca2+]i regulation, and β-adrenergic reserve, thus improving advanced CHF. In a 16-week study, we compared plasma neurohormonal levels and left ventricular (LV)- and myocyte-functional and calcium transient ([Ca2+]iT) responses in male Sprague-Dawley rats (10/group) with CHF induced by isoproterenol (170 mg/kg sq for 2 days). In rats with CHF, we studied the effects of the CaMKII inhibitor KN-93 or its inactive analog KN-92 (n = 4) (70 µg/kg per day, mini-pump) for 4 weeks. Compared with controls, isoproterenol-treated rats had severe CHF with 5-fold–increased plasma norepinephrine and about 50% decreases in ejection fraction (EF) and LV contractility [slope of LV end-systolic pressure–LV end-systolic volume relation (EES)] but increased time constant of LV relaxation (τ). They also showed significantly reduced myocyte contraction [maximum rate of myocyte shortening (dL/dtmax)], relaxation (dL/dtmax), and [Ca2+]iT. Isoproterenol superfusion caused significantly fewer increases in dL/dtmax and [Ca2+]iT. KN-93 treatment prevented plasma norepinephrine elevation, with increased basal and acute isoproterenol-stimulated increases in EF and EES and decreased τ in CHF. KN-93 treatment preserved normal myocyte contraction, relaxation, [Ca2+]iT, and β-adrenergic reserve, whereas KN-92 treatment failed to improve LV and myocyte function, and plasma norepinephrine remained high in CHF. Thus, chronic CaMKII inhibition prevented CHF-induced activation of the sympathetic nervous system, restoring normal LV and cardiomyocyte basal and β-adrenergic–stimulated contraction, relaxation, and [Ca2+]iT, thereby playing a rescue role in advanced CHF. SIGNIFICANCE STATEMENT We investigated the therapeutic efficacy of late initiation of chronic Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibition on progression of advanced congestive heart failure (CHF). Chronic CaMKII inhibition prevented CHF-induced activation of the sympathetic nervous system and restored normal intrinsic cardiomyocyte basal and β-adrenergic receptor–stimulated relaxation, contraction, and [Ca2+]i regulation, leading to reversal of CHF progression. These data provide new evidence that CaMKII inhibition is able and sufficient to rescue a failing heart, and thus cardiac CaMKII inhibition is a promising target for improving CHF treatment.

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.

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.

BACKGROUND:Accurate calculation of stroke volume (SV) by Doppler echocardiography is important for the assessment of aortic stenosis (AS), which may be impacted by anatomical variations of left ventricular outflow tract (LVOT). METHODS:Patients with AS (n = 64) were studied using computed tomography (CT) and transthoracic echocardiography (TTE). Anatomical variations of LVOT areas were measured at (a) the aortic annulus (Aa ); (b) 5 mm (A5 ); and (c) 10 mm below the annulus (A10 ) by CT. LVOT diameters were also measured by 2D TTE at these three levels for calculation of LVOT areas. Stroke volumes (SV) were calculated using continuity equation. The impacts of anatomical variations of LVOT on SV calculation were evaluated. RESULTS:Anatomical LVOT area increased from Aa to A10 (5.0 ± 0.9 cm2 vs 5.8 ± 1.9 cm2 , P < .01). Differences between TTE-calculated LVOT areas and anatomical areas were most significant at A10 due to elongation of mediolateral diameters with variable changes in anteroposterior diameters (5.8 ± 1.9 cm2 vs 3.4 ± 1.1 cm2 , P < .001). Although mean calculated SV by TTE was not significant at different LVOT levels (Aa 69 ± 22 mL, vs A5 66 ± 21 mL, vs A10 66 ± 28 ± 22 mL, P > .05), the most significant variations in individuals were at A10 levels (ΔSV: 8.2 ± 6.4 mL, 12 ± 9%). CONCLUSION:Variations of LVOT anatomy in individuals with AS significantly impact the SV calculated by Doppler echocardiography. These features should be taken into account for AS diagnosis and a clinical decision-making for intervention.

Background: Cardiac aging (CA) leads to the progressive decline in cardiac function- increasing risk for heart failure (HF) and cardiac mortality. Both down-regulation of β 1 -adrenergic receptors (AR) and up-regulation of a newly-described inhibitory pathway mediated by β 3 -AR may play a crucial role in the development of CA. β-AR blockers are a mainstay in the therapy of several cardiovascular diseases, including HF. However the therapeutic effects of different β blockers in CA are unknown. We tested the hypothesis that up-regulation of cardiac β 3 -AR with enhanced negative inotropic actions, rather than the desensitization of β 1 -AR, is the critical determinant of the dysfunctional β-AR regulation that occurs in CA. Thus, β 3 -AR antagonists (β 3 ANT), but not β 1 Blockade, may reverse the progression of age-associated deficits in LV myocyte functional performance. Methods: LV myocyte basal and isoproterenol (ISO)-stimulated functional and [Ca 2+ ] i transient ([Ca 2+ ] iT ) responses were compared in 4 groups (7/group) of wild-type (WT) mice: 1) YWT , young (Y, 6 mo); 2) Aβ 3 ANT , aged (A, 26 mo) treated with β 3 ANT (L-748,337, 10 -7 M/kg/day, mini-pump) for 12 weeks (W);3) Aβ 1 Blockade , metoprolol XL (1.5 mg/kg/day, po), a selective β 1 blocker was given for 12 W and 4) AWT , aged sham control. Results: Compared with YWT, AWT myocytes had about 30% decreases in basal cell contraction (dL/dt max , 85.9 vs 122.3 μm/s) and relaxation (dR/dt max , 69.4 vs 99.2 μm/s) with reduced the peak [Ca 2+ ] iT (0.17 vs 0.21). ISO (10 -8 M)-stimulated increases in dL/dt max (33% vs 69%), dR/dt max (31% vs 62%) and [Ca 2+ ] iT (15% vs 34%) also significantly reduced. In Aβ 1 Blockade group, metoprolol therapy failed to improve basal dL/dt max (86.3 μm/s), dR/dt max (68.9 μm/s) and [Ca 2+ ] iT (0.18). ISO-stimulated increases in dL/dt max (34%), dR/dt max (35%) and [Ca 2+ ] iT (17%) remained attenuated. By contrary, Aβ 3 ANT myocytes showed normal basal cell contraction (131.0 μm/s), relaxation (101.9 μm/s) and [Ca 2+ ] iT (0.21) with preserved ISO-stimulated increases in dL/dt max (68%), dR/dt max (59%) and [Ca 2+ ] iT (32%). Conclusions: Chronic β 3 -AR antagonist, but not β 1 -AR blocker leads to the preservation of myocyte function, [Ca 2+ ] iT , and β-adrenergic responsiveness in a murine model of cardiac aging.