Pre-surgery optimization of patients' expectations to improve outcome in heart surgery: Study protocol of the randomized controlled multi-center PSY-HEART-II trial.

The PSY-HEART-I trial indicated that a brief expectation-focused intervention prior to heart surgery improves disability and quality of life 6 months after coronary artery bypass graft surgery (CABG). However, to investigate the clinical utility of such an intervention, a large multi-center trial is needed to generalize the results and their implications for the health care system. The PSY-HEART-II study aims to examine whether a preoperative psychological intervention targeting patients' expectations (EXPECT) can improve outcomes 6 months after CABG (with or without heart valve replacement). EXPECT will be compared to Standard of Care (SOC) and an intervention providing emotional support without targeting expectations (SUPPORT). In a 3-arm multi-center randomized, controlled, prospective trial (RCT), N = 567 patients scheduled for CABG surgery will be randomized to either SOC alone or SOC and EXPECT or SOC and SUPPORT. Patients will be randomized with a fixed unbalanced ratio of 3:3:1 (EXPECT: SUPPORT: SOC) to compare EXPECT to SOC and EXPECT to SUPPORT. Both psychological interventions consist of 2 in-person sessions (à 50 minute), 2 phone consultations (à 20 minute) during the week prior to surgery, and 1 booster phone consultation post-surgery 6 weeks later. Assessment will occur at baseline approx. 3-10 days before surgery, preoperatively the day before surgery, 4-6 days later, and 6 months after surgery. The study's primary end point will be patients' illness-related disability 6 months after surgery. Secondary outcomes will be patients' expectations, subjective illness beliefs, quality of life, length of hospital stay and blood sample parameters (eg, inflammatory parameters such as IL-6, IL-8, CRP). This large multi-center trial has the potential to corroborate and generalize the promising results of the PSY-HEART-I trial for routine care of cardiac surgery patients, and to stimulate revisions of treatment guidelines in heart surgery.

Genetic Ablation of PDGF-Dependent Signaling Pathways Abolishes Vascular Remodeling and Experimental Pulmonary Hypertension.

OBJECTIVE: Despite modern therapies, pulmonary arterial hypertension (PAH) harbors a high mortality. Vascular remodeling is a hallmark of the disease. Recent clinical studies revealed that antiremodeling approaches with tyrosine-kinase inhibitors such as imatinib are effective, but its applicability is limited by significant side effects. Although imatinib has multiple targets, expression analyses support a role for platelet-derived growth factor (PDGF) in the pathobiology of the disease. However, its precise role and downstream signaling events have not been established. APPROACH AND RESULTS: Patients with PAH exhibit enhanced expression and phosphorylation of ß PDGF receptor (ßPDGFR) in remodeled pulmonary arterioles, particularly at the binding sites for phophatidyl-inositol-3-kinase and PLCγ at tyrosine residues 751 and 1021, respectively. These signaling molecules were identified as critical downstream mediators of ßPDGFR-mediated proliferation and migration of pulmonary arterial smooth muscle cells. We, therefore, investigated mice expressing a mutated ßPDGFR that is unable to recruit phophatidyl-inositol-3-kinase and PLCγ (ßPDGFR(F3/F3)). PDGF-dependent Erk1/2 and Akt phosphorylation, cyclin D1 induction, and proliferation, migration, and protection against apoptosis were abolished in ßPDGFR(F3/F3) pulmonary arterial smooth muscle cells. On exposure to chronic hypoxia, vascular remodeling of pulmonary arteries was blunted in ßPDGFR(F3/F3) mice compared with wild-type littermates. These alterations led to protection from hypoxia-induced PAH and right ventricular hypertrophy. CONCLUSIONS: By means of a genetic approach, our data provide definite evidence that the activated ßPDGFR is a key contributor to pulmonary vascular remodeling and PAH. Selective disruption of PDGF-dependent phophatidyl-inositol-3-kinase and PLCγ activity is sufficient to abolish these pathogenic responses in vivo, identifying these signaling events as valuable targets for antiremodeling strategies in PAH.

5-HT2B receptor antagonists inhibit fibrosis and protect from RV heart failure.

OBJECTIVE: The serotonin (5-HT) pathway was shown to play a role in pulmonary hypertension (PH), but its functions in right ventricular failure (RVF) remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist) or SB204741 (5-HT2B receptor antagonist) on right heart function and structure upon pulmonary artery banding (PAB) in mice. METHODS: Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg bid) or SB204741 (5 mg/kg day). Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI), and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues. RESULTS: Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. CONCLUSION: 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF.