Circulation: Heart Failure最新文献

Background: Iron deficiency (ID) is currently defined as a serum ferritin level <100 or 100 to 299 ng/mL with transferrin saturation (TSAT) <20%. Serum ferritin and TSAT are currently used to define absolute and functional ID. However, individual markers of iron metabolism may be more informative than current arbitrary definitions of ID.

Methods: We assessed prognostic associations of ferritin, serum iron, and TSAT among 2050 participants with heart failure (HF) with reduced/mid-range (n=1821) or preserved (n=229) left ventricular ejection fraction enrolled in the PHFS (Penn HF Study), a prospective cohort study. We measured 4928 plasma proteins using an aptamer-based assay (SOMAScanv4) and assessed prognostic and proteomic associations of markers of iron metabolism.

Results: Ferritin concentrations were not associated with outcomes, whereas low TSAT and serum iron were associated with the risk of all-cause death (TSAT: standardized hazard ratio, 0.84 [95% CI, 0.76-0.93]; P=0.001; serum iron: standardized hazard ratio, 0.87 [95% CI, 0.79-0.96]; P=0.007). Similarly, TSAT was associated with the risk of death or HF-related admission (standardized hazard ratio, 0.89 [95% CI, 0.83-0.95]; P=0.0006). Significant interactions between TSAT and HF with preserved ejection fraction status were found such that TSAT was more strongly associated with the risk of death and death or HF-related admission in HF with preserved ejection fraction. We identified 359 proteins associated with TSAT, including TFRC (transferrin receptor protein; β, -0.455; P<0.0001) and CRP (C-reactive protein; β, -0.355; P<0.0001). Pathway analyses demonstrated associations with lipid metabolism, complement activation, and inflammation. In contrast to the robust associations between TSAT and outcomes, ID and absolute ID defined by current criteria were not associated with death or death or HF-related admission. TSAT was associated with outcomes regardless of the presence of functional versus absolute ID.

Conclusions: Low TSAT, but not ferritin concentrations, is significantly associated with adverse outcomes in HF. Low TSAT is more strongly associated with outcomes in HF with preserved ejection fraction. Pathways related to inflammation and lipid metabolism are associated with low TSAT in HF.

Background: Hypertrophic cardiomyopathy is the most common genetic cardiomyopathy and causes major adverse cardiovascular events (MACE). SVEP1 (Sushi, von Willebrand factor type A, epidermal growth factor, and pentraxin domain containing 1) is a large extracellular matrix protein that is detectable in the plasma. However, it is unknown whether adding plasma SVEP1 levels to clinical predictors including NT-proBNP (N-terminal pro-B-type natriuretic peptide) improves the prognostication in patients with hypertrophic cardiomyopathy.

Methods: We performed a multicenter prospective cohort study of 610 patients with hypertrophic cardiomyopathy. The outcome was MACE defined as heart failure hospitalization or cardiac death. In 4 groups stratified by the median levels of SVEP1 and NT-proBNP, we compared the risk of MACE using the Cox proportional hazards model adjusting for 15 clinical predictors. We also developed a Lasso-regularized Cox proportional hazards model to predict time to first MACE by adding SVEP1 to the 15 clinical predictors with or without NT-proBNP and compared the predictive performance based on C statistics using 10-fold cross-validation.

Results: Even in the low NT-proBNP groups, the high SVEP1 group had higher risks of MACE compared with the low SVEP1 group (adjusted hazard ratio, 4.52 [95% CI, 1.05-19.4]; P=0.042). In predicting time to first MACE, the addition of SVEP1 improved the C statistics of the clinical plus NT-proBNP model (0.87 [0.83-0.91] versus 0.82 [0.78-0.86]; P=0.01). The clinical plus SVEP1 model also outperformed the clinical plus NT-proBNP model (0.86 [0.82-0.91] versus 0.82 [0.78-0.86]; P=0.04).

Conclusions: SVEP1 improved the predictive performance of conventional models, including known clinical parameters with or without NT-proBNP, to predict future MACE in patients with hypertrophic cardiomyopathy.

The integrative physiology of the left ventricle and systemic circulation is fundamental to our understanding of advanced heart failure and cardiogenic shock. In simplest terms, any increase in aortic stiffness increases the vascular afterload presented to the failing left ventricle. The net effect is increased myocardial oxygen demand and reduced coronary perfusion pressure, thereby further deteriorating contractile function. Although mechanical circulatory support devices should theoretically work in concert with guideline-directed medical therapy, cardiac resynchronization and inotropic and vasopressor agents designed to support myocardial performance and enhance left ventricle recovery, this does not always occur. Each therapy and intervention may result in vastly different and sometimes deleterious effects on vascular afterload. Although best described by a combination of both steady-state and pulsatile components, the latter is frequently overlooked when mean arterial pressure or systemic vascular resistance alone is used to quantify vascular afterload in advanced heart failure and cardiogenic shock. In this state-of-the-art review, we examine what is known about vascular afterload in advanced heart failure and cardiogenic shock, including the use of temporary and permanent mechanical circulatory support systems. Importantly, we outline 4 key components for a more complete assessment of vascular afterload. Unlike previous discussions on this topic, we set aside considerations of venous return and ventricular preload, as important as they are, to focus exclusively on the hydraulic load within the systemic circulation against which the impaired left ventricle must contract.

Background: Right ventricular dysfunction (RVD) is common in patients with heart failure with reduced ejection fraction, and it is associated with poor prognosis. However, no biomarker reflecting RVD is available for routine clinical use.

Methods: Proteomic analysis of myocardium from the left ventricle and right ventricle (RV) of patients with heart failure with reduced ejection fraction with (n=10) and without RVD (n=10) who underwent heart transplantation was performed. Concentrations of 2 ECM (extracellular matrix) proteins with the highest myocardial upregulation in RVD, FMOD (fibromodulin) and FBLN5 (fibulin-5), were assayed in the blood and tested in a separate cohort of patients with heart failure with reduced ejection fraction (n=232) to test for the association of the 2 proteins with RV function and long-term outcomes.

Results: Multivariable linear regression revealed that plasma concentrations of both FMOD and FBLN5 were significantly associated with RV function regardless of the RV function assessment method. No association of FMOD or FBLN5 with left ventricular dysfunction, cardiac index, body mass index, diabetes status, or kidney function was found. Plasma levels of FMOD and FBLN5 were significantly associated with patient outcomes (P=0.005; P=0.004). Area under the curve analysis showed that the addition of FBLN5 or FMOD to RV function assessment had a significantly higher area under the curve after 4 years of follow-up (0.653 and 0.631, respectively) compared with RV function alone (0.570; P<0.05 for both). Similarly, the combination of MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) score, FBLN5, and FMOD had a significantly larger area under the curve (0.669) than the combination of MAGGIC score+RVD grade (0.572; P=0.02). The Kaplan-Meier analysis demonstrated that patients with the elevation of both FMOD and FBLN5 (ie, FMOD >64 ng/mL and FMOD >27 ng/mL) had a worse prognosis than those with the elevation of either FBLN5 or FMOD (P=0.03) demonstrating the additive prognostic value of both proteins.

Conclusions: Our study proposes that circulating levels of FMOD and FBLN5 may serve as new biomarkers of RVD in patients with heart failure with reduced ejection fraction.

Background: Patients with end-stage heart failure and low pulmonary capillary wedge pressure are referred to as cold and dry and represent an understudied minority in whom the benefit of left ventricular assist device (LVAD) therapy is unclear.

Methods: Adults receiving LVADs between 2006 and 2017 in the Interagency Registry for Mechanically Assisted Circulatory Support database were classified as cold and wet (pulmonary capillary wedge pressure >15 mm Hg) and cold and dry (pulmonary capillary wedge pressure ≤15 mm Hg) based on pre-LVAD hemodynamics obtained via right heart catheterization. The primary outcome was 1-year survival. Secondary outcomes were rehospitalizations, change in 6-minute walk test distance, change in Kansas City Cardiomyopathy Questionnaire, and change in EuroQol questionnaire scores 1 year after LVAD.

Results: Our study included 10 310 patients with complete clinical, echocardiographic, and functional capacity profiles. The median follow-up was 364 days (interquartile range, 326-381 days). Overall, the mean pulmonary capillary wedge pressure before LVAD implantation was 25±9 mm Hg. Cold and dry patients comprised 15% of the cohort and were more frequently female, had smaller mean body size, smaller mean left ventricular size, and better mean baseline renal function. Compared with cold and wet patients, cold and dry patients also had better baseline functional capacity and quality of life and experienced milder improvements after LVAD: EuroQol (+0.11 versus +0.17; P=0.001), Kansas City Cardiomyopathy Questionnaire (+26 versus +31; P=0.031), and 6-minute walk test distance (+194 feet versus +340 feet; P=0.026). There was no statistically significant difference between the rate of hospitalizations (P=0.76), adverse events, and mortality (log-rank P=0.81) at 1 year between the 2 groups.

Conclusions: In cold and dry patients with end-stage heart failure, LVADs are associated with milder but significant improvements in functional capacity and quality of life with a similar incidence of adverse events and survival at 1 year.

Background: In heart failure, sympathetic excess and exercise intolerance impair quality of life. In heart failure with reduced ejection fraction, exercise stimulates a reflex increase in muscle sympathetic nerve activity (MSNA) that relates inversely to peak oxygen uptake (V̇O_2peak). Whether similar sympathoexcitatory responses are present in heart failure with preserved EF (HFpEF) and relate to V̇O_2peak are unknown.

Methods: In 13 patients with HFpEF (70±6 years), 17 comorbidity-matched controls (CMC; 67±8 years), and 18 healthy controls (65±8 years), we measured heart rate, blood pressure, and MSNA (microneurography) during (1) 7-minute baseline; (2) 2-minute isometric handgrip (40% maximal voluntary contraction) or rhythmic handgrip (50% and 30% maximal voluntary contraction) exercise, followed by 2-minute postexercise circulatory occlusion; and (3) 4-minute 1-leg cycling (2 minutes each at mild and moderate intensity). V̇O_2peak was obtained by open-circuit spirometry.

Results: Resting MSNA was higher and V̇O_2peak was lower in HFpEF versus CMCs and healthy controls (all P<0.05). During handgrip, MSNA increased in all groups (all P<0.05); in HFpEF, MSNA was greater than CMCs and healthy controls during HG and postexercise circulatory occlusion at 40% isometric handgrip (all P<0.05) and HG only at 50% and 30% rhythmic handgrip (all P<0.05). During cycling, MSNA (bursts·min^-1) decreased during mild (-4±4; P=0.01) and moderate (-8±6; P<0.001) cycling in healthy controls, was unchanged during mild (+1±7; P=0.42) and moderate (+2±8; P=0.28) cycling in CMCs, yet increased in HFpEF during mild (+8±8; P<0.001) and moderate (+9±10; P<0.001) cycling. In HFpEF, the change in MSNA during moderate cycling related inversely to relative (r=-0.72; R ²=0.51; P<0.01) and percent-predicted (r=-0.63; R ²=0.39; P=0.03) V̇O_2peak. No statistically significant relationships were detected in controls (P>0.05).

Conclusions: In contrast to CMCs, patients with HFpEF exhibit augmented MSNA at rest and during exercise. The magnitude of such paradoxical sympathoexcitation during dynamic cycling relates inversely to V̇O_2peak, consistent with a neurogenic, vasoconstrictor limit on exercise capacity in HFpEF.