Heart failure with preserved ejection fraction (HFpEF) patients who develop pulmonary hypertension (PH) have an increased risk of death, with combined pre- and post-capillary PH (CpcPH) having the highest risk. However, the mechanism behind PH development in HFpEF is poorly understood. We aimed to identify transcriptomic associations with PH development in HFpEF. Blood was collected from 30 HFpEF patients: 10 without PH, 10 with isolated post-capillary PH, and 10 with CpcPH. Gene expression measurements were completed using transcriptome-wide RNA sequencing. Gene expression differences were compared using a quasi-likelihood method adjusting for age, sex, race, and smoking-status. Biological pathways were compared using global gene expression differences. A replication in 34 additional heart failure patients and a validation in lung tissue from a representative mouse model were completed using quantitative PCR. Six differentially expressed genes were identified when comparing transcriptomics between subjects with CpcPH and those without PH. When tested in additional subjects, only the association with ID2 replicated. Consistent with clinical findings, Id2 expression was also upregulated in mice with HFpEF and PH. Pathway analysis identified proliferative and mitochondrial pathways associated with CpcPH. Thus, these patients may possess systemic pathophysiological differences similar to those observed in pulmonary arterial hypertension patients.

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Pulmonary hypertension (PH) attributable to left heart disease (LHD) is believed to be the most common form of PH and is strongly associated with increased mortality and morbidity in this patient population. Specific therapies for PH‐LHD have not yet been identified and the use of pulmonary artery hypertension‐targeted therapies in PH‐LHD are not recommended. Endothelin receptor antagonists, phosphodiesterase‐5 inhibitors, guanylate cyclase stimulators, and prostacyclins have all been studied in PH‐LHD with conflicting results. Understanding the mechanisms underlying PH‐LHD could potentially provide novel therapeutic targets. Fibrosis, oxidative stress, and metabolic syndrome have been proposed as pathophysiological components of PH‐LHD. Genetic associations have also been identified, offering additional mechanisms with biological plausibility. This review summarizes the evidence and challenges for treatment of PH‐LHD and focuses on underlying mechanisms on the horizon that could develop into potential therapeutic targets for this disease.

Heart failure (HF) is highly prevalent and a major cause of death in the United States. The effect of HF medications on survival has been predicted by validated models studied in populations predominantly of European descent. This study aimed to identify medications associated with survival in a racially diverse HF population. Patients with HF were recruited and followed from 2001 to 2015. Data were collected from electronic health records and the Social Security Death Index. The primary analysis tested the association between medication dose and all-cause mortality, with a secondary analysis assessing the composite outcome of death or cardiac-related hospitalization. Circulating concentration of the fibrotic marker procollagen type III N-terminal peptide (PIIINP) was also compared with medication doses in patients with concentrations available. The study population consisted of 337 patients, of which 25.2% died and 46% were hospitalized. Increased beta-blocker (BB) dose was significantly associated with survival in the base model [hazard ratio (HR) = 0.71, P = 0.017] and marginally associated in the comprehensive model (HR = 0.75, P = 0.068). BB dose was also associated with decreased risk of the composite end point in the base model (HR = 0.80, P = 0.029) and to a lesser extent in the comprehensive model (HR = 0.83, P = 0.085). Furthermore, increased BB dose was inversely associated with circulating PIIINP concentration (P = 0.041). In conclusion, our study highlights the importance of BB dose escalation for survival and decreased hospitalization in patients with HF, regardless of race or HF type. It also suggests that benefits observed with high-dose BBs could be mediated, at least in part, by decreased cardiac fibrosis.