Metabolic Syndrome Exacerbates Pulmonary Hypertension due to Left Heart Disease.

RATIONALE: Pulmonary hypertension (PH) due to left heart disease (LHD), or group 2 PH, is the most prevalent form of PH worldwide. PH due to LHD is often associated with metabolic syndrome (MetS). In 12% to 13% of cases, patients with PH due to LHD display vascular remodeling of pulmonary arteries (PAs) associated with poor prognosis. Unfortunately, the underlying mechanisms remain unknown; PH-targeted therapies for this group are nonexistent, and the development of a new preclinical model is crucial. Among the numerous pathways dysregulated in MetS, inflammation plays also a critical role in both PH and vascular remodeling. OBJECTIVE: We hypothesized that MetS and inflammation may trigger the development of vascular remodeling in group 2 PH. METHODS AND RESULTS: Using supracoronary aortic banding, we induced diastolic dysfunction in rats. Then we induced MetS by a combination of high-fat diet and olanzapine treatment. We used metformin treatment and anti-IL-6 (interleukin-6) antibodies to inhibit the IL-6 pathway. Compared with sham conditions, only supracoronary aortic banding+MetS rats developed precapillary PH, as measured by both echocardiography and right/left heart catheterization. PH in supracoronary aortic banding+MetS was associated with macrophage accumulation and increased IL-6 production in lung. PH was also associated with STAT3 (signal transducer and activator of transcription 3) activation and increased proliferation of PA smooth muscle cells, which contributes to remodeling of distal PA. We reported macrophage accumulation, increased IL-6 levels, and STAT3 activation in the lung of group 2 PH patients. In vitro, IL-6 activates STAT3 and induces human PA smooth muscle cell proliferation. Metformin treatment decreased inflammation, IL-6 levels, STAT3 activation, and human PA smooth muscle cell proliferation. In vivo, in the supracoronary aortic banding+MetS animals, reducing IL-6, either by anti-IL-6 antibody or metformin treatment, reversed pulmonary vascular remodeling and improve PH due to LHD. CONCLUSIONS: We developed a new preclinical model of group 2 PH by combining MetS with LHD. We showed that MetS exacerbates group 2 PH. We provided evidence for the importance of the IL-6-STAT3 pathway in our experimental model of group 2 PH and human patients.

Multimarker Approach to Improve Risk Stratification of Patients Undergoing Transcatheter Aortic Valve Implantation.

Background: A blood multimarker approach may be useful to enhance risk stratification in patients undergoing TAVI. Objectives: The objective of this study was to determine the prognostic value of multiple blood biomarkers in transcatheter aortic valve implantation (TAVI) patients. Methods: In this prospective study, several blood biomarkers of cardiovascular function, inflammation, and renal function were measured in 362 patients who underwent TAVI. The cohort was divided into 3 groups according to the number of elevated blood biomarkers (ie, ≥ median value for the whole cohort) for each patient before the procedure. Survival analyses were conducted to evaluate the association between blood biomarkers and risk of adverse event following TAVI. Results: During a median follow-up of 2.5 (IQR: 1.9-3.2) years, 34 (9.4%) patients were rehospitalized for heart failure, 99 (27%) patients died, and 113 (31.2%) met the composite endpoint of all-cause mortality or heart failure rehospitalization. Compared to patients with 0 to 3 elevated biomarkers (referent group), those with 4 to 7 and 8 to 9 elevated biomarkers had a higher risk of all-cause mortality (HR: 1.54 [95% CI: 0.84-2.80], P = 0.16, and HR: 2.81 [95% CI: 1.53-5.15], P < 0.001, respectively) and of the composite endpoint (HR: 1.65 [95% CI: 0.95-2.84], P = 0.07, and HR: 2.67 [95% CI: 1.52-4.70] P < 0.001, respectively). Moreover, adding the number of elevated blood biomarkers into the clinical multivariable model provided significant incremental predictive value for all-cause mortality (Net Reclassification Index = 0.71, P < 0.001). Conclusions: An increasing number of elevated blood biomarkers is associated with higher risks of adverse clinical outcomes following TAVI. The blood multimarker approach may be helpful to enhance risk stratification in TAVI patients.

Multimarker Approach to Identify Patients With Higher Mortality and Rehospitalization Rate After Surgical Aortic Valve Replacement for Aortic Stenosis.

OBJECTIVES: This study sought to evaluate whether a multimarker approach might identify patients with higher mortality and hospitalization rates after aortic valve replacement (AVR) for aortic stenosis (AS). BACKGROUND: The society valve guidelines include accepted triggers for AVR in patients with severe asymptomatic AS, but circulating biomarkers do not have a clear role. METHOD: From a prospective registry of patients undergoing cardiac surgery between 2000 and 2012, 665 treated with surgical AVR (441 isolated) were evaluated. Seven biomarkers were measured on blood samples obtained before AVR. Biomarker levels were adjusted to account for the influence of age, sex, body mass index, and renal function; the median was used to determine an elevated value. Endpoints included all-cause mortality and all-cause and cardiovascular hospitalizations. Mean follow-up was 10.7 years and 299 (45%) died. RESULTS: Patients with 0 to 1, 2 to 3, 4 to 6, and 7 biomarkers elevated had 5-year mortality of 10%, 12%, 24%, and 33%, respectively, and 10-year mortality of 24%, 35%, 58%, and 71%, respectively (log-rank p < 0.001). The association between an increasing number of elevated biomarkers and increased all-cause mortality was observed among those with minimal symptoms (New York Heart Association functional class I or II) and those with a low N-terminal pro-B-type natriuretic peptide (p < 0.01 for both). Compared with those with 0 to 1 biomarkers elevated, patients with 4 to 6 or 7 biomarkers elevated had an increased hazard of mortality after adjustment for clinical risk scores (p < 0.01) and a 2- to 3-fold higher rate of all-cause and cardiovascular rehospitalization after AVR. Similar findings were obtained when evaluating cardiovascular mortality. Among patients with no or minimal symptoms, 42% had ≥4 biomarkers elevated. CONCLUSIONS: Among patients with severe AS treated with surgical AVR, an increasing number of elevated biomarkers of cardiovascular stress was associated with higher all-cause and cardiovascular mortality and a higher rate of repeat hospitalization. A multimarker approach may be useful in the surveillance of asymptomatic patients with severe AS to optimize surgical timing.