Diminished Global Arginine Bioavailability as a Metabolic Defect in Chronic Systolic Heart Failure

BackgroundSystemic alterations in arginine bioavailability occur in heart failure (HF) patients with more advanced myocardial dysfunction and poorer clinical outcomes, and they improve with beta-blocker therapy.Methods and ResultsWe measured fasting plasma levels of L-arginine and related biogenic amine metabolites in 138 stable symptomatic HF patients with left ventricular ejection fraction ≤35% and comprehensive echocardiographic evaluation. Long-term adverse clinical outcomes (death and cardiac transplantation) were followed for 5 years. Lower global arginine bioavailability ratio (GABR; ratio of L-arginine to L-ornithine + L-citrulline) was associated with higher plasma natriuretic peptide levels, more advanced left ventricular diastolic dysfunction, and more severe right ventricular systolic dysfunction (all P < .001). Patients taking beta-blockers had significantly higher GABR than those not taking beta-blockers (0.86 [interquartile range (IQR) 0.68–1.17] vs 0.61 [0.44–0.89]; P < .001). Subjects with higher GABR experienced fewer long-term adverse clinical events (hazard ratio 0.61 [95% confidence interval 0.43–0.84]; P = .002). In an independent beta-blocker naïve patient cohort, GABR increased following long-term (6 month) beta-blocker therapy (0.89 [IQR 0.52–1.07] to 0.97 [0.81–1.20]; P = .019).ConclusionsIn patients with chronic systolic heart failure, diminished global L-arginine bioavailability is associated with more advanced myocardial dysfunction and poorer long-term adverse clinical outcomes. GABR levels improved with beta-blocker therapy.     

Plasma Corin Levels Provide Minimal Prognostic Utility Incremental to Natriuretic Peptides in Chronic Systolic Heart Failure

BackgroundCorin is a serine protease that cleaves pro-atrial and pro-B-type natriuretic peptides into biologically active hormones. The relationship between soluble plasma corin levels, plasma natriuretic peptide levels, myocardial structure and performance, and long-term clinical outcomes in the setting of chronic systolic heart failure has not been described.Methods and ResultsIn 126 patients with chronic systolic heart failure (left ventricular ejection fraction ≤35%, New York Heart Association functional Class I-IV), we measured plasma corin and natriuretic peptide levels and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse clinical events (all-cause mortality, cardiac transplantation, or heart failure hospitalization) were prospectively tracked for a median of 38 months. Plasma corin levels modestly correlated with echocardiographic indices of cardiac structure, including left ventricular mass index (r = 0.30, P = .003) and interventricular septum width (r = 0.22, P = .013). However, plasma corin levels did not correlate with age, arterial pressures, estimated glomerular filtration rate, echocardiographic indices of systolic or diastolic function, or plasma natriuretic peptide levels. In Cox proportional hazards analysis, higher plasma corin levels did not predict reduced risk of adverse clinical events (hazard ratio 0.91; 95% confidence interval 0.67-1.24, P = .52), and did not provide incremental prognostic value to natriuretic peptide levels.ConclusionIn our cohort of ambulatory patients with chronic systolic heart failure, soluble plasma corin levels did not provide prognostic utility incremental to that of natriuretic peptides.     

Protein Carbamylation in Chronic Systolic Heart Failure: Relationship With Renal Impairment and Adverse Long-Term Outcomes

BackgroundProtein carbamylation, a posttranslational modification promoted during uremia and catalyzed by myeloperoxidase (MPO) at sites of inflammation, is linked to altered protein structure, vascular dysfunction, and poor prognosis. We examine the relationship between plasma protein-bound homocitrulline (PBHCit) levels, a marker of protein lysine residue carbamylation, with cardiorenal function and long-term outcomes in chronic systolic heart failure (HF).Methods and ResultsIn 115 patients with chronic systolic HF (left ventricular ejection fraction ≤35%), we measured plasma PBHCit by quantitative mass spectrometry and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse long-term events (death, cardiac transplantation) were tracked for 5 years. In our study cohort, the median PBHCit level was 87 (interquartile range 59–128) μmol/mol lysine. Higher plasma PBHcit levels were associated with poorer renal function (estimated glomerular filtration rate [eGFR]: Spearman r = ?0.37; P < .001), cystatin C (r = 0.31; P = .001), and elevated plasma amino-terminal pro–B-type natriuretic peptide (NT-proBNP) levels (r = 0.26; P = .006), but not with markers of systemic inflammation or oxidant stress (high-sensitivity C-reactive protein and myeloperoxidase [MPO]: P > .10 for each). Furthermore, elevated plasma PBHCit levels were not related to indices of cardiac structure or function (P > .10 for all examined) except modestly with increased right atrial volume index (r = 0.31; P = .002). PBHCit levels predicted adverse long-term events (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.3–2.6; P < .001), including after adjustment for age, eGFR, MPO, and NT-proBNP (HR 1.9, 95% CI 1.2–3.1; P = .006).ConclusionsIn chronic systolic HF, protein carbamylation is associated with poorer renal but not cardiac function, and portends poorer long-term adverse clinical outcomes even when adjusted for cardiorenal indices of adverse prognosis.     

Prognostic value and echocardiographic determinants of plasma myeloperoxidase levels in chronic heart failure.

OBJECTIVES: The purpose of this study was to explore the relationship between myeloperoxidase (MPO) and cardiac structure, performance, and prognosis. BACKGROUND: Myeloperoxidase is an inflammatory marker that is elevated in patients with heart failure (HF) and cardiac dysfunction, with mechanistic links to plaque vulnerability and left ventricular (LV) remodeling. METHODS: We evaluated plasma MPO levels (CardioMPO, PrognostiX, Inc., Cleveland, Ohio) in 140 patients with chronic systolic HF (LV ejection fraction <35%) and examined the plasma MPO levels' relationships with echocardiographic indexes of systolic and diastolic performance, as well as long-term clinical outcomes (death, cardiac transplantation, or HF hospitalization). RESULTS: Within the overall cohort, increasing plasma MPO levels were associated with increasing likelihood of more advanced HF (restrictive diastolic stage, right ventricular systolic dysfunction > or =3+, and tricuspid regurgitation area > or =1.8 cm2). Plasma MPO levels were predictive of long-term clinical outcomes (risk ratio [95% confidence interval] = 3.35 [1.52 to 8.86]), even after adjustment for age, LV ejection fraction, plasma B-type natriuretic peptide (BNP), creatinine clearance, or diastolic stage. In receiver-operator characteristic curve analyses, addition of MPO to BNP testing augmented the predictive accuracy of future adverse clinical events (area under the curve 0.66 for BNP only [chi-square test = 12.9, p = 0.0003], and 0.70 for BNP plus MPO [chi-square test = 15.87, p = 0.0004]). CONCLUSIONS: In chronic systolic HF, elevated plasma MPO levels are associated with an increased likelihood of more advanced HF. Moreover, elevated plasma MPO levels within a HF subject seem to be predictive of increased adverse clinical outcomes.     

Plasma matrix metalloproteinase-9 level is correlated with left ventricular volumes and ejection fraction in patients with heart failure

BackgroundMatrix metalloproteinases (MMPs) can alter myocardial extracellular matrix and thereby contribute to adverse ventricular remodeling in progressive heart failure (HF). We hypothesized that increased plasma MMP levels correlate with increased left ventricular (LV) volumes and reduced LV ejection fraction (LVEF) in patients with HF.Methods and ResultsIn the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, patients with symptomatic HF and LVEF <0.40 were randomized to receive various combinations of therapies with candesartan, enalapril, and metoprolol CR. Left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), and LVEF were determined by radionuclide angiography at baseline and at Week 43. Baseline and Week 43 plasma MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured by enzyme-linked immunosorbent assay in 184 patients in this substudy. At baseline, plasma MMP-9 correlated positively with ESV (Spearman's rank correlation coefficient ρ = 0.17, P = .02) and negatively with LVEF (ρ = –0.18, P = .01). After 43 weeks, LVEF, EDV, and ESV increased significantly (all P < .01); MMP-2 level increased (P = .01), but MMP-9 and TIMP-1 levels did not change significantly overall in the study population. Temporal changes in MMP-9 level were inversely correlated with changes in LVEF (ρ = –0.16, P = .04). In multivariable analysis adjusting for clinical characteristics and treatment, a smaller proportional change in MMP-9 level after 43 weeks (below versus above median) predicted a concurrent improvement in LVEF (odds ratio = 2.35, 95% CI 1.24–4.46; P < .01). Similar relationships for MMP-2 and TIMP-1 were not observed.ConclusionsElevated plasma MMP-9 levels correlated with lower LVEF and higher ESV, whereas increasing MMP-9 levels are associated with a concurrent deterioration of LV function. These findings suggest that monitoring of plasma markers of myocardial matrix remodeling may provide important prognostic information with respect to ongoing adverse LV remodeling in HF patients.     

Effects of Acute Intravenous Infusion of Apelin on Left Ventricular Function in Dogs With Advanced Heart Failure

BackgroundApelin-13 (APLN) through apelin receptor (APJ) exerts peripheral vasodilatory and potent positive inotropic effects. We examined the effects of exogenous intravenous infusion of APLN on left ventricular (LV) systolic function in dogs with heart failure (HF, LV ejection fraction, EF～30%).Methods and ResultsStudies were performed in 7 dogs with microembolization-induced HF. Each dog received an intravenous infusion of low dose and high dose APLN followed by washout period. LV end-diastolic volume (EDV), end-systolic volume (ESV) and LV EF were measured at specified time points. APLN protein level was determined in plasma at all time points. mRNA and protein levels of APLN and APJ in LV tissue were also measured in 7 normal (NL) and 7 heart failure (HF) dogs. APLN reduced EDV only at the high dose, significantly reduced ESV and increased EF with both doses. In plasma of HF dogs, APLN levels were reduced significantly compared to NL dogs. APLN treatment in HF dogs significantly increased the plasma APLN levels at both low and high doses. Expression of APLN, but not of APJ, was reduced in LV tissue of HF dogs compared to NL.ConclusionsExogenous administration of APLN improved LV systolic function in dogs with advanced HF.     

Integrating plasma high-sensitivity C-reactive protein and myeloperoxidase for risk prediction in chronic systolic heart failure

Various inflammatory biomarkers predict long-term outcomes in patients with acute and chronic heart failure (HF). Their relative contributions when measured in combination have not been evaluated. The authors measured both plasma levels of high-sensitivity C-reactive protein (hsCRP) and myeloperoxidase (MPO) in 136 patients with chronic systolic HF (left ventricular ejection fraction ≤ 40%), and performed echocardiography with prospective follow-up of adverse clinical events (death, cardiac transplant, and HF hospitalizations) over 34 ± 17 months. A lack of significant correlation between log-transformed hsCRP and MPO (Spearman's r = 0.11, P = .185) was observed. Within the lower two hsCRP tertiles (<5.34 mg/L), patients with plasma MPO above median levels demonstrated a 2.9-fold increased risk in adverse clinical events (95% confidence interval [CI], 1.2-8.1; P < .05), whereas within lower plasma MPO levels (<303 pM), increase in hsCRP demonstrated a 1.9-fold increased risk (95% CI, 0.56-6.2; P = not significant). Combined analysis of hsCRP and MPO levels demonstrated a 6-fold increased risk (95% CI, 2.4-16.8; P < .01) when both markers were elevated. Stratifying patients according to hsCRP, MPO, and amino-terminal pro-B-type natriuretic peptide cutoff values provided a stepwise increment of risk prediction of adverse clinical events. Combining hsCRP and MPO measurements provided distinct and complementary prognostic value in a patient cohort of chronic systolic HF.     

Soluble Angiotensin-Converting Enzyme 2 in Human Heart Failure: Relation With Myocardial Function and Clinical Outcomes

BackgroundAngiotensin-converting enzyme 2 (ACE2) is an endogenous counterregulator of the renin-angiotensin system. The relationship between soluble ACE2 (sACE2), myocardial function, and clinical outcomes in patients with chronic systolic heart failure is not well established.Methods and ResultsWe measured sACE2 activity in 113 patients with chronic systolic heart failure (left ventricular ejection fraction [LVEF] ≤35%, New York Heart Association Class II-IV). Comprehensive echocardiography was performed at the time of blood sampling. We prospectively examined adverse clinical events (death, cardiac transplant, and heart failure hospitalizations) over 34 ± 17 months. Patients who had higher sACE2 plasma activity were more likely to have a lower LVEF (Spearman's r = –0.36, P < .001), greater right ventricular systolic dysfunction (r = 0.33, P < .001), higher estimated pulmonary artery systolic pressure (r = 0.35, P = .002), larger left ventricular end-diastolic diameter (r = 0.23, P = .02), and higher plasma NT-proBNP levels (r = 0.35, P < .001). sACE2 was less associated with diastolic dysfunction (r = 0.19, P = .05), and was similar between patients with ischemic and nonischemic cardiomyopathies. There was no relationship between sACE2 activity and markers of systemic inflammation. After adjusting for NT-proBNP and LVEF, sACE2 activity remained an independent predictor of adverse clinical events (HR = 1.7 [95% CI: 1.1–2.6], P = .018).ConclusionsElevated plasma sACE2 activity was associated with greater severity of myocardial dysfunction and was an independent predictor of adverse clinical events.     

Aldosterone antagonism improves endothelial-dependent vasorelaxation in heart failure via upregulation of endothelial nitric oxide synthase production

BackgroundAltering the renin-angiotensin aldosterone system improve mortality in heart failure (HF) in part through an improvement in nitric oxide (NO)-mediated endothelial function. This study examined if spironolactone affects endothelial nitric oxide synthase (eNOS) and NO-mediated vasorelaxation in HF.Methods and ResultsRats with HF after coronary artery ligation were treated with spironolactone for 4 weeks. Rats with HF had a decrease (P < .05) in left ventricular (LV) systolic pressure (130 ± 7 versus 118 ± 6 mm Hg) and LV pressure with respect to time (9122 ± 876 versus 4500 ± 1971 mm Hg/second) with an increase in LV end-diastolic pressure (4 ± 2 versus 23 ± 8 mm Hg). Spironolactone did not affect hemodynamics but it improved (P < .05) endothelial-dependent vasorelaxation at more than 10⁻⁸ M acetylcholine that was abolished with N^G-monomethyl-L-arginine. The eNOS levels were decreased (P < .05) in the LV and the aorta; spironolactone restored LV and aortic eNOs levels to normal.ConclusionSpironolactone prevents the decrease in eNOS in the LV and aorta and improves NO-dependent vasorelaxation, suggesting that one potential mechanism of spironolactone is an improvement in vasoreactivity mediated though an increase in NO.     

Usefulness of C-reactive protein and left ventricular diastolic performance for prognosis in patients with left ventricular systolic heart failure

High-sensitivity C-reactive protein (hs-CRP) is a hepatocyte-derived inflammatory cytokine shown to be increased in the setting of acute heart failure (HF), particularly with increased intracardiac filling pressures. In the chronic HF setting, the relation between hs-CRP and echocardiographic indexes of left ventricular (LV) diastolic performance has not been examined. We measured plasma hs-CRP levels using a particle-enhanced immunonephelometry assay (Dade Behring, Inc., Deerfield, Illinois) in 136 subjects with chronic HF (LV ejection fraction [EF]相似文献   

Intravenous Infusion of the β3-Adrenergic Receptor Antagonist APD418 Improves Left Ventricular Systolic Function in Dogs With Systolic Heart Failure

BackgroundUnlike β₁- and β₂-adrenergic receptors (ARs), β₃-AR stimulation inhibits cardiac contractility and relaxation. In the failing left ventricular (LV) myocardium, β₃-ARs are upregulated, and can be maladaptive in the setting of decompensation by contributing to LV dysfunction. This study examined the effects of intravenous infusions of the β₃-AR antagonist APD418 on cardiovascular function and safety in dogs with systolic heart failure (HF).Methods and ResultsThree separate studies were performed in 21 dogs with coronary microembolization-induced HF (LV ejection fraction [LVEF] of approximately 35%). Studies 1 and 2 (n = 7 dogs each) were APD418 dose escalation studies (dosing range, 0.35–15.00 mg/kg/h) designed to identify an effective dose of APD418 to be used in study 3. Study 3, the sustained efficacy study, (n = 7 dogs) was a 6-hour constant intravenous infusion of APD418 at a dose of 4.224 mg/kg (0.70 mg/kg/h) measuring key hemodynamic endpoints (e.g., EF, cardiac output, the time velocity integral of the mitral inflow velocity waveform representing early filling to time-velocity integral representing left atrial contraction [Ei/Ai]). Studies 1 and 2 showed a dose-dependent increase of LVEF and Ei/Ai, the latter being an index of LV diastolic function. In study 3, infusion of APD418 over 6 hours increased LVEF from 31 ± 1% to 38 ± 1% (P < .05) and increased Ei/Ai from 3.4 ± 0.4 to 4.9 ± 0.5 (P < .05). Vehicle had no effect on the LVEF or Ei/Ai. In study 3, APD418 had no significant effects on the HR or the systemic blood pressure.ConclusionsIntravenous infusions of APD418 in dogs with systolic HF elicit significant positive inotropic and lusitropic effects. These findings support the development of APD418 for the in-hospital treatment of patients with an acute exacerbation of chronic HF.     

Plasma myeloperoxidase levels in patients with chronic heart failure

Increased oxidative stress and endothelial dysfunction are commonly observed in patients with chronic heart failure (HF). The relation between myeloperoxidase (MPO), an inflammatory marker with mechanistic links to plaque vulnerability and abnormal ventricular remodeling, and degrees of severity in chronic HF has not been reported. Plasma MPO levels were measured in 105 normal controls (no history of HF or left ventricular dysfunction) and 102 patients with chronic systolic HF (left ventricular ejection fraction <50%), and the relations among plasma MPO levels, plasma B-type natriuretic peptide levels, and the left ventricular ejection fraction were examined. Plasma MPO levels in patients with chronic systolic HF were significantly elevated compared with those of healthy controls (1,158 +/- 2,965 vs 204 +/- 139 pM, p <0.0001). Plasma MPO levels increased in parallel with increasing New York Heart Association class (p <0.0001) and were correlated with plasma B-type natriuretic peptide levels (Spearman's r = 0.39, p <0.0001). Levels of MPO were strongly associated with the prevalence of HF (unadjusted odds ratio 30.3, 95% confidence interval 11.1 to 94.5) and remained significant when adjusted for age and B-type natriuretic peptide (odds ratio 27.7, 95% confidence interval 3.6 to 371.1). In conclusion, in a cohort of patients with chronic HF, plasma MPO levels were elevated compared with those of normal controls and were associated with worsening functional class.     

Effects of Angiotensin-Neprilysin Inhibition in Canines with Experimentally Induced Cardiorenal Syndrome

BackgroundSacubitril/valsartan (Sac/Val), a combined angiotensin-II receptor blocker (Val) and neprilysin inhibitor (Sac) in a 1:1 molar ratio, was shown to decrease the risk of cardiovascular death or heart failure (HF) hospitalization in patients with HF and reduced left ventricular (LV) ejection fraction. This study examined the effects of Sac/Val on LV structure, function, and bioenergetics, and on biomarkers of kidney injury and kidney function in dogs with experimental cardiorenal syndrome.Methods and ResultsFourteen dogs with cardiorenal syndrome (coronary microembolization-induced HF and renal dysfunction) were randomized to 3 months Sac/Val therapy (100 mg once daily, n = 7) or no therapy (control, n = 7). LV ejection fraction and troponin-I, as well as biomarkers of kidney injury/function including serum creatinine and urinary kidney injury molecule-1 were measured before and at end of therapy and the change (treatment effect change) calculated. Mitochondrial function measures, including the maximum rate of adenosine triphosphate synthesis, were measured in isolated cardiomyocytes at end of therapy. In Sac/Val dogs, the change in ejection fraction increased compared with controls, 6.9 ± 1.4 vs 0.7 ± 0.6%, P < .002, whereas change in troponin I decreased, –0.16 ± 0.03 vs –0.03 ± 0.02 ng/mL, P < .001. Urinary change in kidney injury molecule 1 decreased in Sac/Val–treated dogs compared with controls, –17.2 ± 7.9 vs 7.7 ± 3.0 mg/mL, P < .007, whereas the change in serum creatinine was not significantly different. Treatment with Sac/Val increased adenosine triphosphate synthesis compared with controls, 3240 ± 121 vs 986 ± 84 RLU/µg protein, P < .05.ConclusionsIn dogs with cardiorenal syndrome, Sac/Val improves LV systolic function, improves mitochondrial function and decreases biomarkers of heart and kidney injury. The results offer mechanistic insights into the benefits of Sac/Val in HF with compromised renal function.     

Heart Failure Due to High-Degree Atrioventricular Block: How Frequent Is It and What Is the Cause?

BackgroundThe causes of heart failure (HF) during high-grade atrioventricular block (AVB) are poorly understood. This study assessed the mechanisms of HF in patients with AVB.MethodsWe studied patients presenting (between 2012 and 2016) with high-grade AVB not related to acute myocardial infarction. Patients with preexisting significant valvular heart disease were excluded. All patients underwent comprehensive echocardiographic evaluation during AVB, before pacemaker implantation. The diagnosis of HF was based on the Framingham criteria.ResultsA total of 122 patients were included in the study, 50% male, average age 76 ± 13 years. Twenty-eight patients (23%) with AVB presented with HF. Univariate correlates associated with HF were decrease in cardiac output (CO) (odds ratio [OR] 0.68 [95% confidence interval 0.49-0.9] per L/min; P = 0.007), measures of impaired left ventricular (LV) compliance, and increase in diastolic mitral regurgitation (MR) volume (OR 1.04 [1.01-1.07] per cc; P = 0.0016). Ventricular rate during AVB and LV ejection fraction were not significantly associated with the presence of HF. By multivariate nominal logistic analysis, the best model associated with HF included diastolic MR volume (OR 1.04 [1.001-1.09]; P = 0.02), A-wave deceleration time (OR 0.96 [0.94-0.9]; P = 0.001), and CO (OR 0.92 [0.4-1.00]; P = 0.005) (χ² = 30.6; area under the receiver operating characteristic curve = 0.84; P < 0.0001 for the entire model).ConclusionsIn the setting of high-degree AVB, clinical HF occurrence correlates with impaired LV compliance and diastolic MR volume, but not with heart rate or LV ejection fraction. The cardiac performance of patients with poor LV compliance and high-volume diastolic MR may show maladjustment to slow heart rates, manifesting as low CO and HF.     

Osteoprotegerin Is Associated With Subclinical Left Ventricular Systolic Dysfunction in Diabetic Hypertensive Patients: A Speckle Tracking Study

BackgroundRecently, the role of osteoprotegerin (OPG) in the pathogenesis of heart failure through different mechanisms has received much attention. Subclinical changes in left ventricular (LV) function can be identified using quantification of myocardial strain, and global longitudinal strain (GLS) is a superior predictor of outcomes than ejection fraction. We hypothesized that increased OPG levels could predict subclinical LV systolic dysfunction in treated diabetic hypertensive patients with preserved LV ejection fraction.MethodsThe study was composed of 86 diabetic hypertensive and 30 nondiabetic hypertensive patients. All patients underwent echocardiography and venous blood samples were taken for determination of OPG. The relation between OPG levels and LV GLS was investigated using 2-dimensional speckle tracking echocardiography.ResultsDiabetic hypertensive patients had higher diastolic peak early/early diastolic tissue velocity and lower systolic tissue velocity, GLS, GLS rate systolic, and GLS rate early diastolic than nondiabetic hypertensive patients (P = 0.009, P = 0.049, P < 0.001, P = 0.004, and P < 0.001, respectively). Diabetic hypertensive patients were divided into 2 groups according to median GLS value (> 18.5 and ≤ 18.5). The patients with GLS ≤ 18.5 had higher diastolic blood pressure (mm Hg; P = 0.048), OPG (pmol/L; P < 0.001), and hemoglobin A1c (%; P = 0.042) values than those with GLS > 18.5. In multivariate logistic regression analysis, OPG was found to be an independent predictor of impaired GLS (P = 0.001). Receiver operating characteristic curve analysis revealed that OPG values of > 6.45 (pmol/L) identified the patients with GLS ≤ 18.5.ConclusionsPlasma OPG values could predict subclinical LV systolic dysfunction in diabetic hypertensive patients.     

Concordant Versus Discordant Left Bundle Branch Block in Heart Failure Patients: Novel Clinical Value of an Old Electrocardiographic Diagnosis

BackgroundOver the last 50 years left bundle branch block (LBBB) has been defined as homophasic (concordant: cLBBB) or heterophasic (discordant: dLBBB) when associated with a positive or negative T wave in leads I and V5-V6, respectively. LBBB is recognized as an adverse prognostic factor in heart failure (HF). The prevalence and clinical significance of cLBBB and dLBBB in HF patients are unknown.Methods and ResultsA total of 897 consecutive systolic HF patients (age 65 ± 13 years, left ventricular ejection fraction [LVEF], 34 ± 10%) underwent clinical characterization, electrocardiographic evaluation for LBBB diagnosis and classification, and follow-up for cardiac events (median 37 months, range 1-84). LBBB was diagnosed in 232 patients (26%), cLBBB in 71 (31%), and dLBBB in 161 (69%). The dLBBB patients were older than those with cLBBB, and presented with lower LVEF, greater left ventricular telediastolic diameter and left ventricular mass index, higher level of brain natriuretic peptide, N-terminal pro-brain natriuretic peptide, renin activity, and norepinephrine (all P < .05). At Kaplan-Meier analysis, LBBB (P = .003) and dLBBB (P = .036) were associated with a worse prognosis when the composite end point of sudden death and implantable cardioverter defibrillator shock was considered.ConclusionsIn systolic HF, dLBBB is associated with a worse clinical, neurohormonal, and prognostic profile. LBBB classification could represent a useful tool in routine clinical evaluation.     

Associations of right ventricular pulsatile load and cardiac power output to clinical outcomes in heart failure: Difference from systemic circulation

BackgroundAlthough left ventricular (LV) cardiac power output (CPO) is a powerful prognostic indicator in heart failure (HF), the significance of right ventricular (RV) CPO is unknown. In contrast, RV pulsatile load is a key prognostic marker in HF. We investigated the impact of RV-CPO and pulsatile load on cardiac outcome and the prognostic performance of the combined systemic and pulmonary circulation parameters in HF.MethodsRight heart catheterization and echocardiography were performed in 231 HF patients (62 ± 16 years, LV ejection fraction 42 ± 18 %). Invasive and noninvasive CPOs were calculated from mean systemic or pulmonary arterial pressure and cardiac output. LV-CPO was then normalized to LV mass (LV-P/M). Pulmonary arterial capacitance and the ratio of acceleration time to ejection time (AcT/ET) of RV outflow were used as parameters of RV pulsatile load. The primary endpoints, defined as a composite of cardiac death, HF hospitalization, ventricular arrythmia, and LVAD implantation after the examination, were recorded.ResultsNoninvasive CPOs were moderately correlated with invasive ones (LV: ρ = 0.787, RV: ρ = 0.568, and p < 0.001 for both). During a median follow-up period of 441 days, 57 cardiovascular events occurred. Lower LV-P/M and higher RV pulsatile load were associated with cardiovascular events; however, RV-CPO was not associated with the outcome. Echocardiographic LV-P/M and AcT/ET showed significant incremental prognostic value over the clinical parameters.ConclusionsRV pulsatile load assessed by AcT/ET may be a predictor of clinical events in HF patients. The combination of echocardiographic LV-P/M and AcT/ET could be a novel noninvasive prognostic indicator in HF patients.     

Classification of Heart Failure Events by Severity: Insights From the VICTORIA Trial

BackgroundHospitalization due to heart failure (HFH) is a major source of morbidity, consumes significant economic resources and is a key endpoint in HF clinical trials. HFH events vary in severity and implications, but they are typically considered equivalent when analyzing clinical trial outcomes.ObjectivesWe aimed to evaluate the frequency and severity of HF events, assess treatment effects and describe differences in outcomes by type of HF event in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction).MethodsVICTORIA compared vericiguat with placebo in patients with HF with reduced ejection fraction (< 45%) and a recent worsening HF event. All HFHs were prospectively adjudicated by an independent clinical events committee (CEC) whose members were blinded to treatment assignment. We evaluated the frequency and clinical impact of HF events by severity, categorized by highest intensity of HF treatment (urgent outpatient visit or hospitalization treated with oral diuretics, intravenous diuretics, intravenous vasodilators, intravenous inotropes, or mechanical support) and treatment effect by event categories.ResultsIn VICTORIA, 2948 HF events occurred in 5050 enrolled patients. Overall total CEC HF events for vericiguat vs placebo were 43.9 vs 49.1 events/100 patient-years (P = 0.01). Hospitalization for intravenous diuretics was the most common type of HFH event (54%). HF event types differed markedly in their clinical implications for both in-hospital and post-discharge events. We observed no difference in the distribution of HF events between randomized treatment groups (P = 0.78).ConclusionHF events in large global trials vary significantly in severity and clinical implications, which may have implications for more nuanced trial design and interpretation.Clinical trial registrationClinicalTrials.gov (NCT02861534)     

Persistent Myocardial Production of Follistatin-like 1 Is Associated With Left Ventricular Adverse Remodeling in Patients With Myocardial Infarction: Myocardial production of FSTL1 in AMI patients

BackgroundAlthough animal studies showed that Follistatin-like 1 (FSTL1) exerts cardioprotective effects against ischemic injury, little is known in humans. We examined whether FSTL1 is secreted in an infarcted myocardium and whether its production is associated with left ventricular (LV) remodeling in survivors of acute myocardial infarction.Methods and ResultsFSTL1 levels were measured by enzyme-linked immunosorbent assay in plasma collected from the aortic root and the anterior interventricular vein in 93 patients with anterior acute myocardial infarction. Measurement of FSTL1 levels and left ventriculography were repeated during the early phase (2 weeks) and the chronic phase (6 months) after MI. A persistent increment in FSTL1 levels from the aortic root to the anterior interventricular vein, reflecting FSTL1 production in the infarcted myocardium at both the early and chronic phases, was seen in 22 patients (24%). A linear regression analysis revealed that a persistent transmyocardial increment in FSTL1 levels was significantly associated with percent changes in LV end-diastolic volume index, LV end-systolic volume index, and LV ejection fraction from the early to the chronic phase (r = 0.44, 0.51, and −0.43, respectively, all P < .001).ConclusionsThe persistent production of FSTL1 in the infarcted myocardium was associated with adverse LV remodeling in survivors of acute myocardial infarction.     

The relationship between aldosterone, oxidative stress, and inflammation in chronic, stable human heart failure

BackgroundAldosterone antagonists reduce morbidity and mortality in patients with severe heart failure, but the mechanisms responsible are not fully understood. Observations in animal models suggest that elevated levels of aldosterone promote oxidative stress and inflammation in the myocardium. It is unknown if these findings are relevant to heart failure patients who may have much lower aldosterone levels.Methods and ResultsWe therefore examined the relationship of plasma aldosterone levels to markers of oxidative stress, inflammation and matrix turnover in 58 patients with chronic, stable heart failure from systolic dysfunction (LV ejection fraction <0.40) who were not receiving aldosterone antagonists. Chronic, stable heart failure patients had modestly elevated levels of aldosterone. Additionally, these patients had elevated levels of 8-isoprostaglandin F_2α, C-reactive protein, soluble intercellular adhesion molecule-1, osteopontin, brain natriuretic peptide, procollagen type III aminoterminal peptide, and tissue inhibitor of metalloproteinase-1. Among these patients with heart failure, aldosterone levels correlated with 8-iso-PGF_2α (P = .003), ICAM-1 (P = .008), and TIMP-1 (P = .006) after adjustment for age, gender, race, diabetes, smoking, heart rate, left ventricular mass, and body mass index.ConclusionIn chronic, stable heart failure patients on standard therapy, higher aldosterone levels are associated with systemic evidence of oxidative stress, inflammation, and matrix turnover.