Acute molecular effects of pressure-controlled intermittent coronary sinus occlusion in patients with advanced heart failure.

AIMS: Cardiac repair has steered clinical attention and remains an unmet need, because available regenerative therapies lack robust mechanistic evidence. Pressure-controlled intermittent coronary sinus occlusion (PICSO), known to induce angiogenetic and vasoactive molecules as well as to reduce regional ischemia, may activate endogenous regenerative processes in failing myocardium. We aimed to investigate the effects of PICSO in patients with advanced heart failure undergoing cardiac resynchronization therapy. METHODS AND RESULTS: Eight out of 32 patients were treated with PICSO, and the remainder served as controls. After electrode testing including left ventricular leads, PICSO was performed for 20 min. To test immediate molecular responses, in both patient groups, coronary venous blood samples were taken at baseline and after 20 min, the time required for the intervention. Sera were tested for microRNAs and growth factors. To test the ability of up-regulated soluble factors on cell proliferation and expression of transcription factors [e.g. Krüppel-like factor 4 (KLF-4)], sera were co-cultured with human cardiomyocytes and fibroblasts. As compared with controls, significant differential expression (differences between pre-values and post-values in relation to both patient cohorts) of microRNA patterns associated with cardiac development was observed with PICSO. Importantly, miR-143 (P < 0.048) and miR-145 (P < 0,047) increased, both targeting a network of transcription factors (including KLF-4) that promote differentiation and repress proliferation of vascular smooth muscle cells. Additionally, an increase of miR-19b (P < 0.019) known to alleviate endothelial cell apoptosis was found, whereas disadvantageous miR-320b (P < 0.023) suspect to impair expression of c-myc, normally provoking cell cycle re-entry in post-mitotic myocytes and miR-25 (P < 0.023), decreased, a target of anti-miR application to improve contractility in the failing heart. Co-cultured post-PICSO sera significantly increased cellular proliferation both in fibroblasts (P < 0.001) and adult cardiomycytes (P < 0.004) sampled from a transplant recipient as compared with controls. Adult cardiomyocytes showed a seven-fold increase of the transcription factor KLF-4 protein when co-cultured with treated sera as compared with controls. CONCLUSIONS: Here, we show for the first time that PICSO, a trans-coronary sinus catheter intervention, is associated with an increase in morphogens secreted into cardiac veins, normally present during cardiac development, and a significant induction of cell proliferation. Present findings support the notion that epigenetic modifications, that is, haemodynamic stimuli on venous vascular cells, may reverse myocardial deterioration. Further investigations are needed to decipher the maze of complex interacting molecular pathways in failing myocardium and the potential role of PICSO to reinitiate developmental processes to prevent further myocardial decay eventually reaching clinical significance.

Patients with severe aortic valve stenosis and impaired platelet function benefit from preoperative desmopressin infusion.

BACKGROUND: Patients with severe aortic valve stenosis have a markedly reduced platelet function as measured by a prolonged collagen adenosine diphosphate closure time (CADP-CT) determined by the platelet function analyzer PFA-100. We hypothesized that such patients may benefit from desmopressin when they present with prolonged CADP-CT due to the specific action of desmopressin on von Willebrand factor (VWF) and CADP-CT. METHODS: In this double-blind, randomized placebo controlled trial, 43 patients undergoing aortic valve replacement (due to severe aortic valve stenosis with CADP-CT>170 seconds) were given desmopressin 0.3 µg/kg or saline intravenously after induction of anesthesia. Measurement of CADP-CT, factor VIII activity, von Willebrand factor antigen, GpIb binding activity, ristocetin cofactor activity, collagen-binding activity, and multimers were performed after induction of anesthesia, one hour after desmopressin infusion, and 24 hours postoperatively. RESULTS: In the majority of patients, baseline values of von Willebrand factor related indices were normal, but increased one hour after infusion of desmopressin by 73% to 90% as compared with placebo. Selective loss of high molecular weight multimers was seen only in a minority of patients. The CADP-CT was greater than 170 seconds in 92% of screened patients, and desmopressin shortened CADP-CT by 48% versus baseline and reduced postoperative blood loss by 42% (p<0.001). CONCLUSIONS: Prolonged CADP-CT indicates platelet dysfunction in severe aortic valve stenosis, and can guide the use of desmopressin as an effective prohemostatic agent in patients with severe aortic valve stenosis.

Impaired recovery of cardiac output and mean arterial pressure after successful defibrillation in patients with low left ventricular ejection fraction.

BACKGROUND: Early defibrillation clearly improves survival from malignant arrhythmia. However, in some cases the cause of death will only be altered from arrhythmic to nonarrhythmic. We evaluated the impact of left ventricular ejection fraction (LVEF) on trend and recovery profile of beat-to-beat cardiac output (CO) and mean arterial blood pressure (MAP) after successful defibrillation. METHODS: We investigated 63 NYHA class I-III patients undergoing threshold testing in the course of insertion of an implantable cardioverter defibrillator (ICD) in monitored anaesthesia care. Preoperatively, LVEF was classified as either normal (>50%), moderately (30-50%) or severely impaired (<30%). CO and MAP were measured continuously throughout the implantation procedure. RESULTS: Arrest time and body mass index were not different between groups. CO in patients with severely and moderately reduced LVEF dropped 21% and 13% below baseline (P<0.05), respectively. MAP also decreased by 26% and 17%, respectively. In contrast, 45% of patients with LVEF>50% showed sympathetic activation that resulted in a 12% and 2% increase in mean values for CO and MAP, respectively. In relation to patients with LVEF<50%, CO and MAP values were significantly higher after defibrillation (P<0.05). Additionally, recovery of CO was prolonged in the groups with ventricular dysfunction (P<0.05). Temporary post-shock pacing was observed in 40% of patients. CONCLUSIONS: A large number of ICD patients with restricted LVEF appears to lack the ability to quickly restore CO and MAP after successful defibrillation. Organ reperfusion may thus still be compromised.

Platelet dysfunction in outpatients with left ventricular assist devices.

BACKGROUND: Thromboembolic and bleeding complications in outpatients with a left ventricular assist device are common and can be detrimental. A meticulous balance between anticoagulant and procoagulant factors is therefore crucial. However, in contrast to routinely performed plasmatic coagulation tests, platelet function is hardly ever monitored although recent reports indicated platelet dysfunction. We therefore differentially evaluated platelet function with four commonly used point-of-care devices. METHODS: In a cross-sectional design platelet function was assessed in 12 outpatients and 12 healthy matched volunteers using thrombelastography platelet mapping, thromboelastometry, platelet function analyzer, and a new whole blood aggregometer (Multiplate). RESULTS: Phenprocoumon produced an international normalized ratio of 3.5. It was associated with a twofold prolongation in the thromboelastometry clotting time (p < 0.001). Platelet function under high shear was severely compromised: collagen adenosine diphosphate closure times were 2.5-fold longer in patients than in volunteers (p < 0.001), and 50% of patients had maximal collagen adenosine diphosphate closure time values. Although antigen levels of von Willebrand factor were 80% higher in patients (p < 0.001), von Willebrand factor-ristocetin was subnormal in 5 of 12 patients. Ristocetin-induced aggregation was also threefold higher in volunteers (p < 0.001), indicating an additional functional defect of platelets affecting the glycoprotein Ib-von Willebrand factor axis. The von Willebrand factor multimer pattern in patients also appeared abnormal. CONCLUSIONS: Multimodal antiplatelet monitoring showed markedly impaired platelet function in patients with a left ventricular assist device. Platelet dysfunction under high shear rates and abnormal ristocetin-induced aggregation is only partly attributable to low von Willebrand factor activity. These findings resemble the acquired von Willebrand syndrome that is associated with microaggregate formation and enhanced bleeding.

Cerebral desaturation during cardiac arrest: its relation to arrest duration and left ventricular pump function.

OBJECTIVE: To determine the impact of brief periods of cardiac arrest (CA) on regional cerebral oxygen saturation (rSO2) in patients with low left ventricular ejection fraction (LVEF <30%). DESIGN: Prospective observational study. SETTING: Cardiac surgery room at a university hospital. PATIENTS: Seventy-seven consecutive patients undergoing elective implantation of a cardioverter/defibrillator in monitored anesthesia care. According to preoperative assessments, left ventricular function was classified as normal (LVEF >50%), moderately impaired (LVEF 30%-50%), or severely reduced (LVEF <30%). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: rSO2 was determined during threshold testing with concomitant induction of CA. In patients with LVEF <30%, mean baseline rSO2 (59%) was already below the lower range of normal despite normal arterial blood pressure, heart rate, and arterial oxygen saturation. rSO2 increased by 6% after 6 L/min oxygen insufflation (p < 0.05) and dropped again in each group after CA, reaching a nadir after successful defibrillation. Patients with LVEF <30% and baseline rSO2 <63% exhibited the lowest values. They also showed the highest incidence (11%) of critical cerebral desaturations (i.e., >20% drop from baseline or rSO2 value <50%). rSO2 in patients with LVEF <30% was always below that determined in patients with LVEF >30% (p < 0.05). There was a strong correlation between rSO2 values before CA and rSO2 nadir (p < 0.05). The drop in rSO2 was only moderately related to the brief CAs (p < 0.05). CONCLUSION: These findings demonstrate that severely compromised left ventricular pump function is associated with diminished rSO2. As these patients seem to be more susceptible to critical desaturations, they may be prone to severe tissue hypoxemia unless adequate oxygen delivery is reestablished rapidly. This may contribute to the poor neurologic outcome after successful resuscitation in patients with LVEF <30%.

The influence of protocol pain and risk on patients' willingness to consent for clinical studies: a randomized trial.

We tested the hypothesis that the risk or discomfort associated with a clinical trial influence patients' decisions to participate. Simultaneously, we evaluated factors likely to influence patients' decisions such as understanding of the risk and discomfort associated with the study, patient age, educational level, and psychological status. With IRB approval, participants, who believed they were being asked to participate in a real trial, were presented one of three sham protocols: no risk or pain (Control, n = 48), pain but no risk (Pain, n = 51), or risk but no pain (Risk, n = 51). Patients were debriefed at the end of the interview. Our major outcome measures were (a) understanding risk or pain associated with the proposed studies, (b) the extent to which patients felt pressured to participate, and (c) willingness to participate. Whereas understanding was similar in all groups (Control, 68%; Pain, 67%; and Risk, 72%), willingness to participate differed significantly (Control, 64%; Pain, 35%; Risk, 26%; P < 0.001). Patients who understood the level of risk or pain associated with the protocols were twice as likely to participate than those who did not (49% versus 24%; P = 0.003). Nine percent agreed to participate in the risky or painful protocols without understanding the risks involved. Patients who felt pressured did not agree to participate. Thus, the consent process protected patients, although for unexpected reasons. Understanding was poor, but patients who did not understand the risks or pain involved or who felt pressured rarely consented. Consequently, relatively few patients unknowingly agreed to participate in risky or painful studies.