Reddy, Yogesh N.V.

Abstract Aims Pulmonary hypertension (PH) represents an important phenotype among the broader spectrum of patients with heart failure with preserved ejection fraction (HFpEF), but its mechanistic basis remains unclear. We hypothesized that activation of endothelin and adrenomedullin, two counterregulatory pathways important in the pathophysiology of PH, would be greater in HFpEF patients with worsening PH, and would correlate with the severity of haemodynamic derangements and limitations in aerobic capacity and cardiopulmonary reserve. Methods and results Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM), central haemodynamics, echocardiography, and oxygen consumption (VO2) were measured at rest and during exercise in subjects with invasively-verified HFpEF (n = 38) and controls free of HF (n = 20) as part of a prospective study. Plasma levels of CT-proET-1 and MR-proADM were highly correlated with one another (r = 0.89, P < 0.0001), and compared to controls, subjects with HFpEF displayed higher levels of each neurohormone at rest and during exercise. C-terminal pro-endothelin-1 and MR-proADM levels were strongly correlated with mean pulmonary artery (PA) pressure (r = 0.73 and 0.65, both P < 0.0001) and pulmonary capillary wedge pressure (r = 0.67 and r = 0.62, both P < 0.0001) and inversely correlated with PA compliance (r = −0.52 and −0.43, both P < 0.001). As compared to controls, subjects with HFpEF displayed right ventricular (RV) reserve limitation, evidenced by less increases in RV s′ and e′ tissue velocities, during exercise. Baseline CT-proET-1 and MR-proADM levels were correlated with worse RV diastolic reserve (ΔRV e′, r = −0.59 and −0.67, both P < 0.001), reduced cardiac output responses to exercise (r = −0.59 and −0.61, both P < 0.0001), and more severely impaired peak VO2 (r = −0.60 and −0.67, both P < 0.0001). Conclusion Subjects with HFpEF display activation of the endothelin and adrenomedullin neurohormonal pathways, the magnitude of which is associated with pulmonary haemodynamic derangements, limitations in RV functional reserve, reduced cardiac output, and more profoundly impaired exercise capacity in HFpEF. Further study is required to evaluate for causal relationships and determine if therapies targeting these counterregulatory pathways can improve outcomes in patients with the HFpEF-PH phenotype. Clinical trial registration NCT01418248; https://clinicaltrials.gov/ct2/results? term=NCT01418248&Search=Search

Background Neprilysin is a metalloprotease involved in proteolysis of numerous peptides, including natriuretic peptides, and is of prognostic and therapeutic importance in heart failure with reduced ejection fraction. No studies have investigated circulating neprilysin in the community, its clinical correlates, or its relationship to cardiovascular disease in the general population. Methods and Results Plasma neprilysin was measured in 1536 participants from Olmsted County, Minnesota, using a commercially available sandwich ELISA assay. Clinical and echocardiographic correlates and subsequent outcomes were determined. Soluble neprilysin is non‐normally distributed in the community (median: 3.9 ng/mL; interquartile range: 1.0–43.0 ng/mL). There was no relationship between plasma neprilysin and age (Spearman correlation: −0.04, P =0.16); body mass index (Spearman correlation: −0.04, P =0.16); glomerular filtration rate (Spearman correlation: −0.007, P =0.8); or A‐, B‐, or C‐type natriuretic peptides (Spearman correlation: 0.03, P =0.22; −0.001, P =0.96; 0.01, P =0.67, respectively). Among tertiles of neprilysin, the lowest tertile group had the highest prevalence of smokers ( P <0.001), hypertension ( P =0.04), dyslipidemia ( P =0.03), and diastolic dysfunction ( P =0.02). Soluble neprilysin was not prospectively associated with death or heart failure over a median of 10.7 years. Conclusions In a large community‐based cohort, for the first time, we described the distribution of circulating neprilysin in the general community. We observed that neprilysin does not correlate with natriuretic peptide levels and is not independently associated with adverse outcomes. The novel associations observed between low soluble neprilysin levels and an adverse cardiometabolic and smoking profile requires further investigation.

Abstract Despite improvements in outcomes in the last few decades for heart failure (HF) with reduced ejection fraction (HFrEF), there still remains a need for novel therapies as many patients incompletely recover with existing therapies and progress to advanced HF. In this review, we will discuss recent advances in the management of HFrEF with a focus on upcoming therapies that hold the greatest promise for clinical use. We will discuss novel pharmacological therapies and areas of uncertainty with existing therapies. We will also discuss the potential utility and controversy surrounding novel interventions for HF such as percutaneous mitral valve repair, atrial fibrillation ablation, and other emerging interventions with positive signals for benefit in HFrEF. Finally, we will summarize the current state of stem cell and gene therapy for HFrEF and future directions.

Purpose of review Despite human leukocyte antigen (HLA) matching and monitoring for donor-specific HLA antibodies, antibody-mediated rejection and chronic rejection in the form of allograft vasculopathy and chronic graft dysfunction continue to occur. There has been increasing interest in non-HLA antibodies as mediators of these changes. Recent findings In this review, we discuss the recent literature describing the importance of non-HLA antibodies in organ transplantation and summarize the literature evaluating such antibodies in heart transplantation. Summary Monitoring of non-HLA antibodies requires additional measurement standardization and correlation of specific antibodies with outcomes. However, there is promise that identification with newer immunoproteomic techniques and therapy toward such antibodies may improve long-term graft outcomes and decrease acute rejection and allograft vasculopathy.

Abstract Aims Left atrial (LA) function is impaired in heart failure with preserved ejection fraction (HFpEF) and predicts disease severity and risk of adverse outcome. We sought to evaluate whether LA strain could enhance diagnosis of HFpEF. Methods and results Consecutive patients with unexplained exertional dyspnoea and image quality suitable for measuring LA strain underwent invasive cardiopulmonary exercise testing to ascertain the presence of HFpEF or non-cardiac causes of dyspnoea (NCD). LA reservoir strain was measured in all patients, while LA conduit and booster strain were measured in patients with sinus rhythm. LA strain was measurable in 363 of 378 examinations (96.5%; HFpEF: 238, NCD: 125). LA reservoir strain (29 ± 16% vs. 40 ± 13%, P &lt; 0.0001) and conduit strain (18 ± 10% vs. 22 ± 10%, P = 0.0001) were significantly impaired in HFpEF compared to NCD. Of all echocardiographic indices, LA reservoir strain best discriminated HFpEF from NCD [area under the curve (AUC) 0.719, P &lt; 0.0001], outperforming E/e' (AUC difference +0.117, P &lt; 0.0001), LA enlargement (+0.090, P = 0.001), tricuspid regurgitation velocity &gt; 2.8 m/s (+0.082, P = 0.0085), left ventricular hypertrophy (+0.0159, P &lt; 0.0001) and left ventricular global longitudinal strain (+0.0198, P &lt; 0.0001). Indexing LA reservoir strain to estimated LA pressure (E/e') as a surrogate for LA compliance further improved diagnostic performance (AUC 0.772, P &lt; 0.0001; +0.053 compared to LA reservoir strain alone, P = 0.003). Conclusion Left atrial reservoir strain may provide enhanced diagnostic accuracy beyond conventional echocardiographic measures to discriminate HFpEF from NCD. Further study is required to verify the diagnostic utility of LA strain.

Background Optimal management of patients with severe mitral stenosis ( MS ) and low transmitral gradient is incompletely understood. Methods and Results We examined 101 consecutive patients with severe rheumatic MS (mitral valve area ≤1.5 cm 2 ) who underwent balloon valvuloplasty. Low gradient was defined as mean transmitral gradient <10 mm Hg and low flow as stroke volume index ≤35 mL/m 2 by echocardiography. Symptoms and mortality data were collected. Systolic, diastolic, and arterial function were characterized by measuring left ventricular (LV) end‐systolic elastance, LV stiffness constant (β), diastolic capacitance (predicted LV end‐diastolic volume at a common LV filling pressure of 30 mm Hg), and effective arterial elastance. Low gradient (<10 mm Hg) was present in 55 patients, including low flow/low gradient in 11 and normal flow/low gradient in 44 patients, and high gradient was present in 46 patients. Participants with low‐flow/low‐gradient (LG) MS were older with higher rates of atrial fibrillation (64%) and subvalvular thickening, higher afterload, and decreased LV compliance with lower ejection fraction (57±10% versus 65±4% versus 63±6%, P =0.002) but similar end‐systolic elastance compared with patients with normal‐flow/ LG and high‐gradient MS . The normal‐flow/ LG group had larger mitral valve area and lower left atrial pressure by catheterization, as well as favorable long‐term outcomes compared with the low‐flow/ LG and high‐gradient MS group. A total of 40% of patients with LG MS had no symptomatic benefit from valvuloplasty compared with 18% of patients with high‐gradient MS ( P =0.02). Conclusions Presence of low gradient in patients with severe MS was associated with lesser symptomatic benefit from valvuloplasty. In the subset with low stroke volume index, this may be related to independent ventricular‐vascular uncoupling, decreased LV compliance, and high prevalence of atrial fibrillation in addition to intrinsic MS .