Oral digoxin effects on exercise performance, K+ regulation and skeletal muscle Na+ ,K+ -ATPase in healthy humans.

We investigated whether digoxin lowered muscle Na+ ,K+ -ATPase (NKA), impaired muscle performance and exacerbated exercise K+ disturbances. Ten healthy adults ingested digoxin (0.25 mg; DIG) or placebo (CON) for 14 days and performed quadriceps strength and fatiguability, finger flexion (FF, 105%peak-workrate , 3 × 1 min, fourth bout to fatigue) and leg cycling (LC, 10 min at 33% V O 2 peak ${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ and 67% V O 2 peak ${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ , 90% V O 2 peak ${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ to fatigue) trials using a double-blind, crossover, randomised, counter-balanced design. Arterial (a) and antecubital venous (v) blood was sampled (FF, LC) and muscle biopsied (LC, rest, 67% V O 2 peak ${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ , fatigue, 3 h after exercise). In DIG, in resting muscle, [3 H]-ouabain binding site content (OB-Fab ) was unchanged; however, bound-digoxin removal with Digibind revealed total ouabain binding (OB+Fab ) increased (8.2%, P = 0.047), indicating 7.6% NKA-digoxin occupancy. Quadriceps muscle strength declined in DIG (-4.3%, P = 0.010) but fatiguability was unchanged. During LC, in DIG (main effects), time to fatigue and [K+ ]a were unchanged, whilst [K+ ]v was lower (P = 0.042) and [K+ ]a-v greater (P = 0.004) than in CON; with exercise (main effects), muscle OB-Fab was increased at 67% V O 2 peak ${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ (per wet-weight, P = 0.005; per protein P = 0.001) and at fatigue (per protein, P = 0.003), whilst [K+ ]a , [K+ ]v and [K+ ]a-v were each increased at fatigue (P = 0.001). During FF, in DIG (main effects), time to fatigue, [K+ ]a , [K+ ]v and [K+ ]a-v were unchanged; with exercise (main effects), plasma [K+ ]a , [K+ ]v , [K+ ]a-v and muscle K+ efflux were all increased at fatigue (P = 0.001). Thus, muscle strength declined, but functional muscle NKA content was preserved during DIG, despite elevated plasma digoxin and muscle NKA-digoxin occupancy, with K+ disturbances and fatiguability unchanged. KEY POINTS: The Na+ ,K+ -ATPase (NKA) is vital in regulating skeletal muscle extracellular potassium concentration ([K+ ]), excitability and plasma [K+ ] and thereby also in modulating fatigue during intense contractions. NKA is inhibited by digoxin, which in cardiac patients lowers muscle functional NKA content ([3 H]-ouabain binding) and exacerbates K+ disturbances during exercise. In healthy adults, we found that digoxin at clinical levels surprisingly did not reduce functional muscle NKA content, whilst digoxin removal by Digibind antibody revealed an ∼8% increased muscle total NKA content. Accordingly, digoxin did not exacerbate arterial plasma [K+ ] disturbances or worsen fatigue during intense exercise, although quadriceps muscle strength was reduced. Thus, digoxin treatment in healthy participants elevated serum digoxin, but muscle functional NKA content was preserved, whilst K+ disturbances and fatigue with intense exercise were unchanged. This resilience to digoxin NKA inhibition is consistent with the importance of NKA in preserving K+ regulation and muscle function.

Risk factors for asymptomatic echocardiographic abnormalities that predict symptomatic heart failure.

AIMS: Risk factors for asymptomatic echocardiographic abnormalities that predict symptomatic heart failure (HF) may provide insight into early mechanisms of HF pathogenesis. We examined risk factors associated with asymptomatic echocardiographic structural, systolic, and diastolic abnormalities, separately and in combination, and interactions between risk factors, in the prospective community-based SCReening Evaluation of the Evolution of New HF (SCREEN-HF) Study cohort of 3190 participants at increased risk of cardiovascular disease. METHODS AND RESULTS: Inclusion criteria were age ≥ 60 years with one or more of hypertension, diabetes, ischaemic heart disease, valvular heart disease, abnormal heart rhythm, cerebrovascular disease, or renal impairment. Exclusion criteria were known HF, ejection fraction < 50%, or >mild valve abnormality. Structural, systolic, and diastolic echocardiographic abnormalities were defined according to the Atherosclerosis Risk in Communities study criteria, and risk factors for asymptomatic structural, systolic, and diastolic abnormalities were identified using logistic regression analysis. In multivariable analysis, increased body mass index (BMI), non-steroidal anti-inflammatory drug therapy, and alcohol intake were risk factors for isolated structural abnormality, whereas male gender, increased heart rate, atrial fibrillation (AF), angiotensin-converting enzyme inhibitor therapy, and obstructive sleep apnoea were associated with a lower risk. Moreover, male gender, smoking, increased systolic blood pressure, and physical inactivity were risk factors for isolated systolic abnormality, whereas increased pulse pressure and antihypertensive therapy were associated with a lower risk. Furthermore, increased age, blood pressure, amino-terminal pro-B-type natriuretic peptide level, and warfarin therapy (associated with AF) were risk factors for isolated diastolic abnormality, whereas increased heart rate and triglyceride level (associated with BMI) were associated with a lower risk. The association of increased heart rate with lower risk of structural and diastolic abnormalities was independent of ß-blocker therapy. Interactions between risk factors differed for structural, systolic, and diastolic abnormalities. CONCLUSIONS: The different risk factors for asymptomatic structural, systolic, and diastolic abnormalities that predict symptomatic HF, and the interactions between risk factors, illustrate how these structural, systolic, and diastolic abnormalities represent unique trajectories that lead to symptomatic HF. Improved understanding of these trajectories may assist in the design of HF prevention strategies.

Insulin-like growth factor-1 directly affects cardiac cellular remodelling via distinct pathways.

BACKGROUND: Studies of insulin-like growth factor 1 (IGF-1) as a novel therapy for the treatment of cardiovascular diseases have proven promising. However, elevated IGF-1 levels have also been associated with poor patient outcomes in heart failure with reduced ejection fraction. IGF-1 therapy has additionally been shown to not be beneficial in the percutaneous coronary intervention setting. Although IGF-1 activation of the PI3K/Akt and ERK1/2 pathways have been demonstrated as cardioprotective, other cellular mechanisms have not been fully investigated. METHODS: Neonatal rat cardiac myocytes (NCMs) and fibroblasts (NCFs) were isolated from 1 to 2-day old pups using enzymatic digestion. NCMs and NCFs were pre-treated with IGF binding protein 6, inhibitors for the PI3K/Akt Wortmannin, ERK1/2 U0126, Rho Associated Protein Kinase (ROCK) GSK576371, Apoptosis Signal-regulating Kinase-1 (ASK-1) G2261818A, and p38MAPK RWJ67657 pathways before stimulation with IGF-1 for 62 and 50 h, respectively. Cardiac myocyte hypertrophy and fibroblast collagen synthesis were determined by 3H-leucine and 3H-proline incorporation, respectively. RESULTS: IGF-1 dose-dependently stimulated NCM hypertrophy and NCF collagen synthesis.Treatment with IGFBP6 and the kinase inhibitors, Wortmannin, U0126, GSK576371, G2261818A and RWJ67657 significantly inhibited IGF-1 stimulated NCM hypertrophy and NCF collagen synthesis. CONCLUSION: This study is the first to demonstrate that IGF-1 treatment in NCMs and NCFs activates the ROCK, ASK-1 and p38MAPK pathways. Future research may be guided by consideration of the PI3K/Akt and ERK1/2 pathways potentially increasing collagen synthesis, and the utilisation of a biased agonist to reduce activation of the ROCK, ASK-1 and p38MAPK pathways to maximise cardioprotective benefit whilst mitigating risks.

Kidney age - chronological age difference (KCD) score provides an age-adapted measure of kidney function.

BACKGROUND: Given the age-related decline in glomerular filtration rate (GFR) in healthy individuals, we examined the association of all-cause death or cardiovascular event with the Kidney age - Chronological age Difference (KCD) score, whereby an individual's kidney age is estimated from their estimated GFR (eGFR) and the age-dependent eGFR decline reported for healthy living potential kidney donors. METHODS: We examined the association between death or cardiovascular event and KCD score, age-dependent stepped eGFR criteria (eGFRstep), and eGFR < 60 ml/min/1.73 m2 (eGFR60) in a community-based high cardiovascular risk cohort of 3837 individuals aged ≥60 (median 70, interquartile range 65, 75) years, followed for a median of 5.6 years. RESULTS: In proportional hazards analysis, KCD score ≥ 20 years (KCD20) was associated with increased risk of death or cardiovascular event in unadjusted analysis and after adjustment for age, sex and cardiovascular risk factors. Addition of KCD20, eGFRstep or eGFR60 to a cardiovascular risk factor model did not improve area under the curve for identification of individuals who experienced death or cardiovascular event in receiver operating characteristic curve analysis. However, addition of KCD20 or eGFR60, but not eGFRstep, to a cardiovascular risk factor model improved net reclassification and integrated discrimination. KCD20 identified individuals who experienced death or cardiovascular event with greater sensitivity than eGFRstep for all participants, and with greater sensitivity than eGFR60 for participants aged 60-69 years, with similar sensitivities for men and women. CONCLUSIONS: In this high cardiovascular risk cohort aged ≥60 years, the KCD score provided an age-adapted measure of kidney function that may assist patient education, and KCD20 provided an age-adapted criterion of eGFR-related increased risk of death or cardiovascular event. Further studies that include the full age spectrum are required to examine the optimal KCD score cut point that identifies increased risk of death or cardiovascular event, and kidney events, associated with impaired kidney function, and whether the optimal KCD score cut point is similar for men and women. TRIAL REGISTRATION: ClinicalTrials.gov NCT00400257 , NCT00604006 , and NCT01581827 .

Inhibition of apoptosis signal-regulating kinase 1 ameliorates left ventricular dysfunction by reducing hypertrophy and fibrosis in a rat model of cardiorenal syndrome.

BACKGROUND: Cardiorenal syndrome (CRS) is a major health burden worldwide in need of novel therapies, as current treatments remain suboptimal. The present study assessed the therapeutic potential of apoptosis signal-regulating kinase 1 (ASK1) inhibition in a rat model of CRS. METHODS: Adult male Sprague-Dawley rats underwent surgery for myocardial infarction (MI) (week 0) followed by 5/6 subtotal nephrectomy (STNx) at week 4 to induce to induce a combined model of heart and kidney dysfunction. At week 6, MI + STNx animals were randomized to receive either 0.5% carboxymethyl cellulose (Vehicle, n = 15, Sham = 10) or G226 (15 mg/kg daily, n = 11). Cardiac and renal function was assessed by echocardiography and glomerular filtration rate (GFR) respectively, prior to treatment at week 6 and endpoint (week 14). Haemodynamic measurements were determined at endpoint prior to tissue analysis. RESULTS: G226 treatment attenuated the absolute change in left ventricular (LV) fractional shortening and posterior wall thickness compared to Vehicle. G226 also attenuated the reduction in preload recruitable stroke work. Increased myocyte cross sectional area, cardiac interstitial fibrosis, immunoreactivity of cardiac collagen-I and III and cardiac TIMP-2 activation, were significantly reduced following G226 treatment. Although we did not observe improvement in GFR, G226 significantly reduced renal interstitial fibrosis, diminished renal collagen-I and -IV, kidney injury molecule-1 immunoreactivity as well as macrophage infiltration and SMAD2 phosphorylation. CONCLUSION: Inhibition of ASK1 ameliorated LV dysfunction and diminished cardiac hypertrophy and cardiorenal fibrosis in a rat model of CRS. This suggests that ASK1 is a critical pathway with therapeutic potential in the CRS setting.

Age-related longitudinal change in cardiac structure and function in adults at increased cardiovascular risk.

AIM: Heart failure (HF) incidence increases markedly with age. We examined age-associated longitudinal change in cardiac structure and function, and their prediction by age and cardiovascular disease (CVD) risk factors, in a community-based cohort aged ≥60 years at increased CVD risk but without HF. METHODS AND RESULTS: CVD risk factors were recorded in 3065 participants who underwent a baseline echocardiographic examination, of whom 2358 attended a follow-up examination 3.8 [median, inter-quartile range (IQR) 3.5, 4.2] years later. Median age was 71 (IQR 67, 76) years and 55% of participants were male. Age was associated with longitudinal increase in left ventricular (LV) mass index (LVMI); decrease in LV volumes; increase in LV ejection fraction; decrease in mitral annular systolic velocity; decrease in diastolic function (decreased mitral early diastolic annular velocity (e'); and increase in left atrial volume index, mitral peak early diastolic flow velocity (E)/e' ratio, and tricuspid regurgitant velocity (TRVmax ) in men and women, except for TRVmax in men). In multivariable analysis, longitudinal increase in LVMI was explained by CVD risk factors alone, whereas age, together with CVD risk factors, independently predicted longitudinal change in all other echocardiographic parameters. CVD risk factors were differentially associated with longitudinal change in different echocardiographic parameters. CONCLUSIONS: Whereas the increase in LVMI with age was explained by CVD risk factors alone, age, together with risk factors, independently predicted longitudinal change in all other echocardiographic parameters, providing evidence for age-specific mechanisms of change in cardiac structure and function as people age. Age-associated change in LVMI, LV volumes, and diastolic function resembled what might be expected for the evolution of HF with preserved ejection fraction. Given the differential association of different CVD risk factors with longitudinal change in different echocardiographic parameters, therapies aimed at attenuation of age-associated change in cardiac structure and function, and HF evolution, will likely need to address multiple CVD risk factors.

Age-specific diastolic dysfunction improves prediction of symptomatic heart failure by Stage B heart failure.

AIMS: We investigated whether addition of diastolic dysfunction (DD) and longitudinal strain (LS) to Stage B heart failure (SBHF) criteria (structural or systolic abnormality) improves prediction of symptomatic HF in participants of the SCReening Evaluation of the Evolution of New Heart Failure study, a self-selected population at increased cardiovascular disease risk recruited from members of a health insurance fund in Melbourne and Shepparton, Australia. Both American Society of Echocardiography and European Association of Cardiovascular Imaging (ASE/EACVI) criteria and age-specific Atherosclerosis Risk in Communities (ARIC) study criteria, for SBHF and DD, and ARIC criteria for abnormal LS, were examined. METHODS AND RESULTS: Inclusion criteria were age ≥60 years with one or more of self-reported ischaemic or other heart disease, irregular or rapid heart rhythm, cerebrovascular disease, renal impairment, or treatment for hypertension or diabetes for ≥2 years. Exclusion criteria were known HF, or ejection fraction <50% or >mild valve abnormality detected on previous echocardiography or other imaging. Echocardiography was performed in 3190 participants who were followed for a median of 3.9 (interquartile range: 3.4, 4.5) years after echocardiography. Symptomatic HF was diagnosed in 139 participants at a median of 3.1 (interquartile range: 2.1, 3.9) years after echocardiography. ARIC structural, systolic, and diastolic abnormalities predicted HF in univariate and multivariable proportional hazards analyses, whereas ASE/EACVI structural and systolic, but not diastolic, abnormalities predicted HF. ARIC and ASE/EACVI SBHF criteria predicted HF with sensitivities of 81% and 55%, specificities of 39% and 76%, and C statistics of 0.60 (95% confidence interval: 0.57, 0.64) and 0.66 (0.61, 0.71), respectively. Adding ARIC DD to SBHF increased sensitivity to 94% with specificity of 24% and C statistic of 0.59 (0.57, 0.61), whereas addition of ASE/EACVI DD to SBHF increased sensitivity to 97% but reduced specificity to 9% and the C statistic to 0.52 (0.50, 0.54, P < 0.0001). Addition of LS to ARIC or ASE/EACVI SBHF criteria had minimal impact on prediction of HF. CONCLUSIONS: Age-specific ARIC DD criteria, but not ASE/EACVI DD criteria, predicted symptomatic HF, and addition of age-specific ARIC DD criteria to ARIC SBHF criteria improved prediction of symptomatic HF in asymptomatic individuals with cardiovascular disease risk factors. Addition of LS to ASE/EACVI or ARIC SBHF criteria did not improve prediction of symptomatic HF.

Threshold body mass index and sex-specific waist circumference for increased risk of heart failure with preserved ejection fraction.

BACKGROUND: Body mass index †Deceased. (BMI) is a risk factor for heart failure with preserved ejection fraction (HFpEF). DESIGN: We investigated the threshold BMI and sex-specific waist circumference associated with increased HFpEF incidence in the SCReening Evaluation of the Evolution of New Heart Failure (SCREEN-HF) study, a cohort study of a community-based population at increased cardiovascular disease risk. METHODS: Inclusion criteria were age ≥60 years with one or more of self-reported hypertension, diabetes, heart disease, abnormal heart rhythm, cerebrovascular disease or renal impairment. Exclusion criteria were known heart failure, ejection fraction <50% or more than mild valve abnormality. Among 3847 SCREEN-HF participants, 73 were diagnosed with HFpEF at a median of 4.5 (interquartile range: 2.9-5.5) years after enrolment. RESULTS: HFpEF incidence rates were higher for BMI ≥27.5 kg/m2 than for BMI < 25 kg/m2, and for waist circumference >100 cm (men) or > 90 cm (women) than for waist circumference ≤94 cm (men) or ≤ 83 cm (women) in Poisson regression analysis. Semiparametric proportional hazards analyses confirmed these BMI and waist circumference thresholds, and exceeding these thresholds was associated with an attributable risk of HFpEF of 44-49%. CONCLUSIONS: Both central obesity and overweight were associated with increased HFpEF incidence. Although a randomised trial of weight control would be necessary to establish a causal relationship between obesity/overweight and HFpEF incidence, these data suggest that maintenance of BMI and waist circumference below these thresholds in a community similar to that of the SCREEN-HF cohort may reduce the HFpEF incidence rate by as much as 50%.

Prediction of incident heart failure by serum amino-terminal pro-B-type natriuretic peptide level in a community-based cohort.

AIMS: We investigated which serum amino-terminal pro-B-type-natriuretic peptide (NT-proBNP) levels inform heart failure (HF) risk in a community-based population at increased cardiovascular disease (CVD) risk. METHODS AND RESULTS: Inclusion criteria were age ≥ 60 years with one or more of self-reported hypertension, diabetes, heart disease, abnormal heart rhythm, cerebrovascular disease, or renal impairment. Exclusion criteria were known HF, ejection fraction (EF) < 50%, or more than mild valve abnormality. NT-proBNP levels were measured in 3842 participants on enrolment. HF was diagnosed in 162 participants at a median of 4.5 (interquartile range 2.7-5.4) years after enrolment, 73 with HF with preserved EF (HFpEF), 53 with HF with reduced EF (HFrEF), and 36 with valvular HF (VHF). Areas under the receiver operating characteristic curve (AUC) for 5-year prediction of total HF were similar for NT-proBNP alone (0.79, 95% confidence interval 0.74-0.83) and a 7-parameter multivariable model (0.82, 0.77-0.86, P = 0.035). NT-proBNP cut-points of 11, 16, and 25 pmol/L for individuals aged 60-69, 70-79, and ≥ 80 years, respectively, achieved sensitivities > 76% and specificities of 47-69% for 5-year prediction of total HF in men and women in all three age groups. Sensitivities were ≥ 75% in most subgroups according to body mass index, estimated glomerular filtration rate, and the presence or absence of atrial fibrillation, pacemaker, or CVD, and for the prediction of HFpEF, HFrEF and VHF. CONCLUSION: Age-specific serum NT-proBNP levels inform prognosis, and hence therapeutic decisions, regarding HF risk in individuals at increased CVD risk.

Inhibition of Apoptosis Signal-Regulating Kinase 1 Attenuates Myocyte Hypertrophy and Fibroblast Collagen Synthesis.

BACKGROUND: Cardiac remodelling is a dynamic process whereby structural and functional changes occur within the heart in response to injury or inflammation. Recent studies have demonstrated reactive oxygen species sensitive MAPK, apoptosis signal-regulating kinase 1 (ASK1) plays a critical role in cardiac remodelling. This study aims to determine the effectiveness of small molecule ASK1 inhibitors on these processes and their therapeutic potential. METHODS: Neonatal rat cardiac fibroblasts (NCF) were pre-treated with ASK1 inhibitors, G2261818A (G226) and G2358939A (G235), for 2hours before stimulated with 100nM angiotensin II (AngII), 10µM indoxyl sulphate (IS) or 10ng/ml transforming growth factor ß1 (TGFß1) for 48hours. Neonatal rat cardiac myocytes (NCM) were pre-treated with G226 and G235 for 2hours before being stimulated with 100nM AngII for 60hours, 10µM IS, 10ng/ml interleukin 1ß (IL-1ß) or tumour necrosis factor α (TNFα) for 48hours. 3H-proline and 3H-leucine incorporation was used to assess collagen turnover and hypertrophy, respectively. Pro-fibrotic, pro-hypertrophic and THP-1 inflammatory cytokine gene expressions were determined by RT-PCR. RESULTS: Both G226 and G235 dose-dependently attenuated AngII-, IS-, IL-1ß- and TNFα-stimulated NCM hypertrophy and hypertrophic gene expression, IS-, AngII- and TGFß1-stimulated NCF collagen synthesis and AngII- and TGFß1-stimulated pro-fibrotic gene expression. Inhibition of ASK1 by G226 and G235 inhibited lipopolysaccharides-stimulated inflammatory cytokine gene expression in THP-1 cells. CONCLUSIONS: Selective ASK1 inhibition confers anti-hypertrophic and anti-fibrotic effects in cardiac cells, and anti-inflammation in monocytic cells. ASK1 inhibitors may represent novel therapeutic agents to alleviate cardiac remodelling post cardiac injury where hypertrophy, fibrosis and inflammation play critical roles.

Heart Rate as a Predictor of Outcome Following Percutaneous Coronary Intervention.

Data from previous studies of patients with heart failure and coronary artery disease suggest that those with higher resting heart rates (HRs) have worse cardiovascular outcomes. We sought to evaluate whether HR immediately before percutaneous coronary intervention (PCI) is an independent predictor for 30-day outcome. We analyzed the outcome of 3,720 patients who had HR recorded before PCI from the Melbourne Interventional Group registry. HR and outcomes were analyzed by quintiles, and secondarily by dichotomizing into <70 or ≥70 beats/min. Patients with cardiogenic shock, intra-aortic balloon pump or inotropic support, and out-of-hospital arrest were excluded. The mean ± SD HR was 70.9 ± 14.7 beats/min. HR by quintile was 55 ± 5, 64 ± 2, 70 ± 1, 77 ± 3, and 93 ± 13 beats/min, respectively. Patients with higher HR were more likely to be women, current smokers, have higher systolic and diastolic blood pressure, atrial fibrillation, recent heart failure, lower ejection fraction, and ST-elevation myocardial infarction as the indication for the PCI (all p ≤0.002). However, rates of treated hypertension, multivessel disease, previous myocardial infarction, PCI, and coronary bypass surgery were lower (all p ≤0.004). Increased HR was associated with higher 30-day mortality (p for trend = 0.04), target vessel revascularization (p for trend = 0.003), and 30-day major adverse cardiac events (MACE) (p for trend = 0.004). In a multivariable analysis, HR was an independent predictor of 30-day MACE (OR 1.21 per quintile; 95% confidence interval (CI): 1.06 to 1.39, p = 0.004). When dichotomized into <70 or ≥70 beats/min, HR independently predicted both 30-day MACE (OR 1.59, 95% CI 1.08 to 2.36, p = 0.02) and 30-day mortality (OR 2.80, 95% CI 1.10 to 7.08, p = 0.03). In conclusion, HR immediately before PCI is an independent predictor of adverse 30-day cardiovascular outcomes.

Risk factors for incident heart failure with preserved or reduced ejection fraction, and valvular heart failure, in a community-based cohort.

Background: The lack of effective therapies for heart failure with preserved ejection fraction (HFpEF) reflects an incomplete understanding of its pathogenesis. Design: We analysed baseline risk factors for incident HFpEF, heart failure with reduced ejection fraction (HFrEF) and valvular heart failure (VHF) in a community-based cohort. Methods: We recruited 2101 men and 1746 women ≥60 years of age with hypertension, diabetes, ischaemic heart disease (IHD), abnormal heart rhythm, cerebrovascular disease or renal impairment. Exclusion criteria were known heart failure, left ventricular ejection fraction <50% or valve abnormality >mild in severity. Median follow-up was 5.6 (IQR 4.6-6.3) years. Results: Median time to heart failure diagnosis in 162 participants was 4.5 (IQR 2.7-5.4) years, 73 with HFpEF, 53 with HFrEF and 36 with VHF. Baseline age and amino-terminal pro-B-type natriuretic peptide levels were associated with HFpEF, HFrEF and VHF. Pulse pressure, IHD, waist circumference, obstructive sleep apnoea and pacemaker were associated with HFpEF and HFrEF; atrial fibrillation (AF) and warfarin therapy were associated with HFpEF and VHF and peripheral vascular disease and low platelet count were associated with HFrEF and VHF. Additional risk factors for HFpEF were body mass index (BMI), hypertension, diabetes, renal dysfunction, low haemoglobin, white cell count and ß-blocker, statin, loop diuretic, non-steroidal anti-inflammatory and clopidogrel therapies, for HFrEF were male gender and cigarette smoking and for VHF were low diastolic blood pressure and alcohol intake. BMI, diabetes, low haemoglobin, white cell count and warfarin therapy were more strongly associated with HFpEF than HFrEF, whereas male gender and low platelet count were more strongly associated with HFrEF than HFpEF. Conclusions: Our data suggest a major role for BMI, hypertension, diabetes, renal dysfunction, and inflammation in HFpEF pathogenesis; strategies directed to prevention of these risk factors may prevent a sizeable proportion of HFpEF in the community. Trial registration number: NCT00400257, NCT00604006 and NCT01581827.

Angiotensin receptor neprilysin inhibition provides superior cardioprotection compared to angiotensin converting enzyme inhibition after experimental myocardial infarction.

BACKGROUND: Angiotensin receptor neprilysin inhibitor (ARNi) enhances beneficial natriuretic peptides by inhibiting their breakdown through neprilysin. Although the first-in-class ARNi sacubitril/valsartan (LCZ696) reduced mortality and morbidity in heart failure (HF) with reduced ejection fraction (EF) compared to angiotensin converting enzyme inhibitor (ACEi), mechanistic data on ARNi are scarce. ARNi may be superior to ACEi in attenuating adverse cardiac remodeling and dysfunction post-myocardial infarction (MI). METHODS: Rats randomized at 1 week post-MI were administered LCZ696 (60 mg/kg, N = 12), the ACEi perindopril (2 mg/kg, N = 11) or vehicle (corn oil, N = 13), orally for 4 weeks. Sham rats received vehicle (corn oil, N = 9). Echocardiography was assessed before and after treatment, prior to invasive hemodynamics using pressure-volume analysis. Hypertrophy and fibrosis was evaluated by histochemical staining, and analysis of myocardial gene and protein expression using real-time quantitative PCR and Western blot. RESULTS: Compared to Sham, MI groups had large infarcts (>40%) and reduced left ventricular (LV) EF. LCZ696 improved LVEF and end systolic pressure-volume relationship compared to perindopril (P < 0.05). LCZ696 but not perindopril reduced lung weight and LV filling pressures post-MI. Reductions in cardiac hypertrophy and fibrosis were similar, however gene expression of hypertrophic markers, ANP and ßMHC were reduced with LCZ696 versus perindopril. LCZ696 versus perindopril reduced myocardial TIMP2 gene expression with a trend (P = 0.067) to lowering collagen I. CONCLUSION: LCZ696 attenuated adverse cardiac remodeling and dysfunction and reduced pulmonary congestion and hypertrophic markers after MI compared to perindopril. This study supports clinical evaluation of ARNi versus ACEi in targeting post-MI cardiac dysfunction and remodeling.

Cardiac Resynchronization Therapy in Patients With Heart Failure and Narrow QRS Complexes.

BACKGROUND: Cross correlation analysis (CCA) using tissue Doppler imaging has been shown to be associated with outcome after cardiac resynchronization therapy (CRT) in patients with heart failure (HF) with wide QRS. However, its significance in patients with narrow QRS treated with CRT is unknown. OBJECTIVES: The aim of the current study was to investigate the association of mechanical activation delay by CCA with study outcome in patients with HF enrolled in the EchoCRT trial. METHODS: Baseline CCA could be performed from tissue Doppler imaging in the apical views in 807 of 809 (99.7%) enrolled patients, and 6-month follow-up could be performed in 610 of 635 (96%) patients with available echocardiograms. Patients with a pre-specified maximal activation delay ≥35 ms were considered to have significant delay. The study outcome was HF hospitalization or death. RESULTS: Of 807 patients, 375 (46%) did not have delayed mechanical activation at baseline by CCA. Patients without delayed mechanical activation who were randomized to CRT-On compared with CRT-Off had an increased risk of poor outcome (hazard ratio: 1.70; 95% confidence interval: 1.13 to 2.55; p = 0.01) with a significant interaction term (p = 0.04) between delayed mechanical activation and device randomization for the endpoint. Among patients with paired baseline and follow-up data with no events before 6-month follow-up (n = 541), new-onset delayed mechanical activation in the CRT-On group showed a significant increase in unfavorable events (hazard ratio: 3.73; 95% confidence interval: 1.15 to 12.14; p = 0.03). CONCLUSIONS: In the EchoCRT population, absence of delayed mechanical activation by CCA was significantly associated with poor outcomes, possibly due to the onset of new delayed mechanical activation with CRT pacing. (Echocardiography Guided Cardiac Resynchronization Therapy [EchoCRT] Trial; NCT00683696).

Daily home BNP monitoring in heart failure for prediction of impending clinical deterioration: results from the HOME HF study.

BACKGROUND: Serial measurement of natriuretic peptides may guide management in heart failure (HF) patients. In previous trials, natriuretic peptides were infrequently monitored, which may undervalue the benefit of this approach. METHODS AND RESULTS: HOME was an adaptive three-arm randomized clinical study to test whether home monitoring of BNP could reduce HF-related death, hospitalization due to acute decompensated HF (ADHF), and ADHF treated with intravenous diuretics in the emergency department or outpatient setting. Enrolment was terminated early because of slow enrolment, low event rates, and the belief that an algorithm for assessing BNP trends was needed. Justification for pooling data from all study arms was made and analysis as a single observational study was performed. The analysis resulted in 107 patients who were monitored for a median of 172 days with BNP measures on a median of 74% of days. BNP values were highly variable within a patient. Dispersion between serial BNPs was calculated to be 39.3%, 57.7%, and 73.6% for 1, 60, and 120 days between measures, respectively. A moving average filter (fBNP) was calculated to reduce day-to-day fluctuations and track changes from week to week. There were 27 primary events in 17 362 patient days of monitoring; the hazard ratio for time-varying fBNP was 2.22 (95% confidence interval 1.48-3.34) per unit natural log (corresponding to a 2.72-fold change in fBNP level). CONCLUSION: The HOME HF study demonstrates the feasibility of home BNP measurement and shows the potential value of fBNP as an index of emerging clinical deterioration. Assessment of the clinical value of this is required.

Chronic kidney disease with comorbid cardiac dysfunction exacerbates cardiac and renal damage.

To address the pathophysiological mechanisms underlying chronic kidney disease with comorbid cardiac dysfunction, we investigated renal and cardiac, functional and structural damage when myocardial infarction (MI) was applied in the setting of kidney injury (induced by 5/6 nephrectomy-STNx). STNx or Sham surgery was induced in male Sprague-Dawley rats with MI or Sham surgery performed 4 weeks later. Rats were maintained for a further 8 weeks. Rats (n = 36) were randomized into four groups: Sham+Sham, Sham+MI, STNx+Sham and STNx+MI. Increased renal tubulointerstitial fibrosis (P < 0.01) and kidney injury molecule-1 expression (P < 0.01) was observed in STNx+MI compared to STNx+Sham animals, while there were no further reductions in renal function. Heart weight was increased in STNx+MI compared to STNx+Sham or Sham+MI animals (P < 0.05), despite no difference in blood pressure. STNx+MI rats demonstrated greater cardiomyocyte cross-sectional area and increased cardiac interstitial fibrosis compared to either STNx+Sham (P < 0.01) or Sham+MI (P < 0.01) animals which was accompanied by an increase in diastolic dysfunction. These changes were associated with increases in ANP, cTGF and collagen I gene expression and phospho-p38 MAPK and phospho-p44/42 MAPK protein expression in the left ventricle. Addition of MI accelerated STNx-induced structural damage but failed to significantly exacerbate renal dysfunction. These findings highlight the bidirectional response in this model known to occur in cardiorenal syndrome (CRS) and provide a useful model for examining potential therapies for CRS.

Risk factor management in a contemporary Australian population at increased cardiovascular disease risk.

BACKGROUND: Effective management of cardiovascular and chronic kidney disease risk factors offers longer, healthier lives and savings in healthcare. AIM: To examine risk factor management in participants of the SCReening Evaluation of the Evolution of New Heart Failure study, a self-selected population at increased cardiovascular disease risk recruited from members of a health insurance fund in Melbourne and Shepparton, Australia. METHODS: Inclusion criteria were age ≥ 60 years with one or more self-reported ischaemic or other heart diseases, irregular or rapid heart rhythm, cerebrovascular disease, renal impairment or treatment for hypertension or diabetes for ≥2 years. Exclusion criteria were known heart failure or cardiac abnormality on echocardiography or other imaging. Medical history, clinical examination, full blood examination and biochemistry (without lipids and glycated haemoglobin (HbA1c)) were performed for 3847 participants on enrolment, and blood pressure, lipids and HbA1c were measured 1-2 years after enrolment for 3203 participants. RESULTS: Despite 99% of 3294 participants with hypertension receiving antihypertensive medication, half had blood pressures >140/90 mmHg. Approximately 77% of participants were overweight or obese, with one third being obese. Additionally, 74% of participants at high cardiovascular disease risk had low-density lipoprotein cholesterol levels ≥2 mmol/L, one third of diabetic participants had HbA1c >7%, 22% had an estimated glomerular filtration rate < 60 mL/min/1.73m2 , and substantial proportions had under-utilisation of antiplatelet therapy and anticoagulation for atrial fibrillation and were physically inactive. CONCLUSIONS: This population demonstrated substantial potential to reduce cardiovascular and renal morbidity and mortality and healthcare costs through more effective management of modifiable risk factors.

Effects of Vildagliptin on Ventricular Function in Patients With Type 2 Diabetes Mellitus and Heart Failure: A Randomized Placebo-Controlled Trial.

OBJECTIVES: This study sought to examine the safety of the dipeptidyl peptidase-4 inhibitor, vildagliptin, in patients with heart failure and reduced ejection fraction. BACKGROUND: Many patients with type 2 diabetes mellitus have heart failure and it is important to know about the safety of new treatments for diabetes in these individuals. METHODS: Patients 18 to 85 years of age with type 2 diabetes and heart failure (New York Heart Association functional class I to III and left ventricular ejection fraction [LVEF] <0.40) were randomized to 52 weeks treatment with vildagliptin 50 mg twice daily (50 mg once daily if treated with a sulfonylurea) or matching placebo. The primary endpoint was between-treatment change from baseline in echocardiographic LVEF using a noninferiority margin of -3.5%. RESULTS: A total of 254 patients were randomly assigned to vildagliptin (n = 128) or placebo (n = 126). Baseline LVEF was 30.6 ± 6.8% in the vildagliptin group and 29.6 ± 7.7% in the placebo group. The adjusted mean change in LVEF was 4.95 ± 1.25% in vildagliptin treated patients and 4.33 ± 1.23% in placebo treated patients, a difference of 0.62 (95% confidence interval [CI]: -2.21 to 3.44; p = 0.667). This difference met the predefined noninferiority margin of -3.5%. Left ventricular end-diastolic and end-systolic volumes increased more in the vildagliptin group by 17.1 ml (95% CI: 4.6 to 29.5 ml; p = 0.007) and 9.4 ml (95% CI: -0.49 to 19.4 ml; p = 0.062), respectively. Decrease in hemoglobin A1c from baseline to 16 weeks, the main secondary endpoint, was greater in the vildagliptin group: -0.62% (95% CI: -0.93 to -0.30%; p < 0.001; -6.8 mmol/mol; 95% CI: -10.2 to -3.3 mmol/mol). CONCLUSIONS: Compared with placebo, vildagliptin had no major effect on LVEF but did lead to an increase in left ventricular volumes, the cause and clinical significance of which is unknown. More evidence is needed regarding the safety of dipeptidyl peptidase-4 inhibitors in patients with heart failure and left ventricular systolic dysfunction. (Effect of Vildagliptin on Left Ventricular Function in Patients With Type 2 Diabetes and Congestive Heart Failure; NCT00894868).

Apoptosis signal-regulating kinase 1 inhibition attenuates cardiac hypertrophy and cardiorenal fibrosis induced by uremic toxins: Implications for cardiorenal syndrome.

Intracellular accumulation of protein-bound uremic toxins in the setting of cardiorenal syndrome leads to adverse effects on cardiorenal cellular functions, where cardiac hypertrophy and cardiorenal fibrosis are the hallmarks. In this study, we sought to determine if Apoptosis Signal-Regulated Kinase 1 (ASK1), an upstream regulator of cellular stress response, mediates cardiac hypertrophy and cardiorenal fibrosis induced by indoxyl sulfate (IS) and p-cresol sulfate (PCS) in vitro, and whether ASK1 inhibition is beneficial to ameliorate these cellular effects. PCS augmented cardiac myocyte hypertrophy and fibroblast collagen synthesis (as determined by 3H-leucine and 3H-proline incorporation, respectively), similar to our previous finding with IS. IS and PCS also increased collagen synthesis of proximal tubular cells and renal mesangial cells. Pro-hypertrophic (α-skeletal muscle actin and ß-MHC) and pro-fibrotic genes (TGF-ß1 and ctgf) were induced by both IS and PCS. Western blot analyses revealed the activation of ASK1 and downstream mitogen activated protein kinases (MAPKs) (p38MAPK and ERK1/2) as well as nuclear factor-kappa B (NF-κB) by IS and PCS. ASK1, OAT1/3, ERK1/2 and p38MAPK inhibitors suppressed all these effects. In summary, IS and PCS exhibit pro-hypertrophic and pro-fibrotic properties, at least in part, via the activation of ASK1 and its downstream pathways. ASK1 inhibitor is an effective therapeutic agent to alleviate protein-bound uremic toxin-induced cardiac hypertrophy and cardiorenal fibrosis in vitro, and may be translated further for cardiorenal syndrome therapy.