Andrea M. D’Armini

Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2)

Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of inoperable and persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). In the 16-week CHEST-1 study, riociguat showed a favourable benefit–risk profile and improved several clinically relevant end-points in patients with CTEPH. The CHEST-2 open-label extension evaluated the long-term safety and efficacy of riociguat. Eligible patients from CHEST-1 received riociguat individually adjusted up to a maximum dose of 2.5 mg three times daily. The primary objective was the safety and tolerability of riociguat; exploratory efficacy end-points included 6-min walking distance (6MWD) and World Health Organization (WHO) functional class (FC). Overall, 237 patients entered CHEST-2 and 211 (89%) were ongoing at this interim analysis (March 2013). The safety profile of riociguat in CHEST-2 was similar to CHEST-1, with no new safety signals. Improvements in 6MWD and WHO FC observed in CHEST-1 persisted for up to 1 year in CHEST-2. In the observed population at 1 year, mean±sd 6MWD had changed by +51±62 m (n=172) versus CHEST-1 baseline (n=237), and WHO FC had improved/stabilised/worsened in 47/50/3% of patients (n=176) versus CHEST-1 baseline (n=236). Long-term riociguat had a favourable benefit–risk profile and apparently showed sustained benefits in exercise and functional capacity for up to 1 year. Riociguat shows favourable benefit–risk profile in CTEPH patients, with benefits in 6MWD and WHO FC for up to 1 year http://ow.ly/Co04L

Orthotopic heart transplantation: Standard versus bicaval technique

We compared orthotopic heart transplantation (HT) by bicaval technique with the standard technique. Between January 1995 and December 1997, 117 patients underwent 118 HTs; 71 patients (15 women and 56 men) had 72 HTs by standard technique and 46 patients (9 women, 37 men) underwent HT using bicaval procedures. Preoperative parameters were similar in both groups; 5 patients who underwent the standard technique and no patients who underwent bicaval procedures required permanent pacemakers (p = NS). Isoproterenol infusion was significantly longer in the standard technique. Major perioperative arrhythmias (ventricular tachycardia and fibrillation, asystole) appeared in 8.2% and 7.0% of standard and bicaval HTs, respectively; atrial fibrillation appeared in 13.1% and 4.6%, respectively (p = NS). At 1 month, mitral and tricuspid regurgitation rates were higher in the standard group (p = NS); at 1 year only tricuspid regurgitation was still higher (p = NS). Right atrial pressure, Wood units, cardiac output, and cardiac index were examined (p = NS). At multivariate analysis, interaction between preoperative Wood units and transplant type was elicited for Wood units at 1 month and for right atrial pressure at 1, 3, and 6 months. In the high resistance subgroup, the patients who underwent bicaval procedures had higher resistances at 1 month. In the low resistance subgroup, right atrial pressure was higher in patients who underwent standard techniques at 1, 3, and 6 months follow-up. Thus, bicaval HT was found to be safe, without surgically related complications, it provoked significantly less blood loss, and required less isoproterenol use. No significant advantages were observed in conduction disturbances and major arrhythmias or regarding the need for temporary or permanent pacemakers.

Arterial baroreflex modulation of heart rate in patients early after heart transplantation: lack of parasympathetic reinnervation

BACKGROUND Orthotopic heart transplantation results in cardiac denervation. The presence of cardiac parasympathetic reinnervation in humans has been widely debated based on the application of differing indirect measures of autonomic control. However no attempt has been made to analyse the reflex heart rate response to baroreceptor stimulation whose occurrence is generally considered a reliable marker of the ability to activate cardiac vagal reflexes. This study tested the hypothesis that the presence of donor heart RR interval lengthening following phenylephrine induced blood pressure increase would be an index of parasympathetic reinnervation. METHODS Baroreflex sensitivity (BRS) was assessed in 30 patients (mean age 51+/-12 years) 1-24 months after heart transplantation carried out by the standard Lower-Shumway technique. In 6 patients the recipient atrium rate response (P-P interval) to baroreceptor stimulation by phenylephrine was also simultaneously determined by transesophageal recording. RESULTS None of the 30 patients showed prolongation of RR intervals in the donor heart. The average BRS value was -0.28+/-0.54 ms/mmHg (range -1.3-0.7 ms/mm Hg). In the 6 patients in whom BRS was obtained at both the recipient atrium (P-P) and donor heart (R-R) the changes were 7.6+/-5.7 ms/mm Hg and -0.38+/-0.58 ms/mm Hg respectively (p = 0.02), thus confirming that the absent RR interval lengthening in the donor heart is the consequence of efferent vagal fiber interruption. CONCLUSIONS The absence of any RR interval prolongation following phenylephrine induced baroreceptor stimulation demonstrates that vagal efferent reinnervation of the donor heart does not occur up to 24 months in patients operated via the standard Lower-Shumway procedure. It is also suggested that analysis of baroreceptor reflexes is a more specific method in the examination of cardiac parasympathetic reinnervation.

The spectrum of aortic complications after heart transplantation.

BACKGROUND The connection between the donor and the recipient aorta is a potential source of early and late complications as a result of infection, compliance mismatch, and technical and hemodynamic factors. Moreover, the abrupt change in systolic pressure after heart transplantation involves the entire thoracic aorta in the risk of aneurysm formation. The aim of this study was to analyze the types of aortic complications encountered in our heart transplantation series and to discuss etiology, diagnostic approach, and modes of treatment. METHODS Of the 442 patients having orthotopic heart transplantation and the 11 patients having heterotopic heart transplantation at our center, 9 (2%) sustained complications involving the thoracic aorta. These 9 patients were divided into four groups according to the aortic disease: acute aortic rupture (2 patients); infective pseudoaneurysm (3 patients); true aneurysm and dissection of native aorta (2 patients); and aortic dissection after heterotopic heart transplantation (2 patients). Surgical intervention was undertaken in 8. RESULTS Five (83%) of 6 patients who underwent surgical treatment for noninfective complications survived the operation, and 4 are long-term survivors. One patient who underwent a Bentall procedure 71/2 years after heterotopic heart transplantation died in the perioperative period of low-output syndrome secondary to underestimated chronic rejection of the graft. One patient with pseudoaneurysm survives without surgical treatment but died several years later of cardiac arrest due to chronic rejection. Both patients operated on for evolving infective pseudoaneurysm died in the perioperative period. CONCLUSIONS Infective pseudoaneurysms of the aortic anastomosis are associated with a significant mortality. In noninfective complications, an aggressive surgical approach offers good long-term results. The possibility of retransplantation in spite of complex surgical repair should be considered in the late follow-up after heart transplantation, due to the increasing incidence of chronic rejection.

Tezosentan and Right Ventricular Failure in Patients with Pulmonary Hypertension Undergoing Cardiac Surgery: The TACTICS Trial

OBJECTIVE To evaluate the efficacy of tezosentan in reducing the incidence of right ventricular (RV) failure and associated mortality in patients with pre-existing pulmonary hypertension. The primary endpoint was the proportion of patients with RV failure during weaning from cardiopulmonary bypass (CPB), assessed 30 minutes after the end of CPB. DESIGN Multicenter, double-blind, randomized, placebo-controlled trial. SETTING Thirty-one cardiac surgical centers in 14 countries. PARTICIPANTS Two hundred seventy-four patients with pulmonary hypertension aged ≥ 18 years scheduled to undergo cardiac surgery. INTERVENTION Intravenous tezosentan (5 mg/h) during surgery and up to 24 hours afterwards (1 mg/h), or matched placebo. MEASUREMENTS AND MAIN RESULTS One-hundred thirty-three patients received tezosentan and 141 placebo. RV failure occurred in 30 patients (10.9%), 37% of whom died. There was no difference in the incidence of RV failure between the two treatment groups (relative risk reduction: 0.07 [95% CI-0.83, 0.53; P = 0.8278]). CONCLUSION A reduction in RV failure with tezosentan was not observed in this study.(Current Controlled Trials, identifier NCT00458276).

Pulmonary arterial compliance and exercise capacity after pulmonary endarterectomy.

Patients with chronic thromboembolic pulmonary hypertension (CTEPH), despite successful pulmonary endarterectomy (PEA), can continue to suffer from a limitation in exercise capacity. The objective of this study was to assess whether pulmonary arterial compliance is a predictor of exercise capacity after PEA. Right heart haemodynamics, treadmill incremental exercise test, spirometry, carbon monoxide transfer factor, arterial blood gas and echocardiographic examinations were retrospectively analysed in a population of CTEPH patients who underwent PEA at a single centre. Baseline and 3-month haemodynamic data were available in 296 patients; 5-year follow-up data were available in 68 patients. In a multivariable model the following parameters were found to be independent predictors of exercise capacity after surgery: age, sex, pulmonary arterial compliance, tricuspid annular plane excursion, arterial oxygen tension and carbon monoxide transfer factor (p<0.0001); the model showed good discrimination (Harrell’s c=0.84) and calibration (shrinkage coefficient=0.91). Poor exercise capacity at 3 months was loosely associated with higher death rate during subsequent survival (Harrell’s c=0.61). In conclusion, after successful PEA, reduced pulmonary arterial compliance is an important determinant of exercise capacity in association with the age and sex of the patients, and the extent of recovery of both cardiac and respiratory function. However, exercise capacity does not explain a large proportion of the effect of surgery on subsequent survival. Pulmonary arterial compliance is an important determinant of exercise capacity after pulmonary endarterectomy http://ow.ly/rDj1B

Heart transplantation in chemotherapeutic dilated cardiomyopathy

Anthracycline cardiotoxicity can induce dilated cardiomyopathy (DCM). Nine patients (four men) experienced postchemotherapy DCM: age at time of tumour diagnosis ranged from 1-45 years (mean 13.5 +/- 19 years); interval time between tumour and HT was 3-23 years (mean 10.8 +/- 6.6) and age at HT ranged from 10-65 years (30.8 +/- 20.1). Interval between end of chemotherapy and beginning of cardiac symptoms was 5.71 +/- 4.6 years. Mean age at DCM diagnosis was 19.2 +/- 19.7 (range 1-50 years). Interval between start of chemotherapy and DCM ranged from 1 month to 10 years (mean 3.15 +/- 3.6 years). Tumours were Ewing sarcoma (7-year-old boy), paratesticular rabdomyosarcoma (1-year-old boy), Wilms tumor with pulmonary metastasis (3-year-old girl), bilateral breast carcinoma (45-year-old woman), uterine leiomyosarcoma (44-year-old woman), acute myelocytic leukemia (1.5-year-old boy and 17-year-old girl), and chronic myelocytic leukemia (5-year-old boy). All patients had high pulmonary resistance values. One patient with chronic myelocytic leukemia (14 year-old at HT) died due to graft failure on the first postoperative day. At follow-up (mean, 80.4 +/- 69.3 months) two patients died: a 32-year-old woman (acute myelocytic leukemia) 1 year after HT for sepsis and a 68-year-old woman who had breast adenocarcinoma recurrence 81 months after HT. The remaining patients are alive, in good condition with no difference in survival from other transplanted patients (P =.757). Patients with end-stage postchemotherapy DCM without evidence of tumour recurrence can safely undergo HT.

Use of responder threshold criteria to evaluate the response to treatment in the phase III CHEST-1 study

BACKGROUND In the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase - Stimulator Trial 1 (CHEST-1) study, riociguat improved 6-minute walking distance (6MWD) vs placebo in patients with inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. In this study, the proportion of patients who achieved responder thresholds that correlate with improved outcome in patients with pulmonary arterial hypertension was determined at baseline and at the end of CHEST-1. METHODS Patients received placebo or riociguat individually adjusted up to 2.5 mg 3 times a day for 16 weeks. Response criteria were defined as follows: 6MWD increase ≥40 m, 6MWD ≥380 m, cardiac index ≥2.5 liters/min/m(2), pulmonary vascular resistance <500 dyn∙sec∙cm(-5), mixed venous oxygen saturation ≥65%, World Health Organization functional class I/II, N-terminal pro-brain natriuretic peptide <1,800 pg/ml, and right atrial pressure <8 mm Hg. RESULTS Riociguat increased the proportion of patients with 6MWD ≥380 m, World Health Organization functional class I/II, and pulmonary vascular resistance <500 dyn∙sec∙cm(-5) from 37%, 34%, and 25% at baseline to 58%, 57%, and 50% at Week 16, whereas there was little change in placebo-treated patients (6MWD ≥380 m, 43% vs 44%; World Health Organization functional class I/II, 29% vs 38%; pulmonary vascular resistance <500 dyn∙sec∙cm(-5), 27% vs 26%). Similar changes were observed for thresholds for cardiac index, mixed venous oxygen saturation, N-terminal pro-brain natriuretic peptide, and right atrial pressure. CONCLUSIONS In this exploratory analysis, riociguat increased the proportion of patients with inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy achieving criteria defining a positive response to therapy.

Deltoido-pectoralis approach to axillary vessels for full-flow cardiopulmonary bypass

Axillary artery has been proposed as a safe and effective alternative for arterial cannulation in surgical procedures involving ascending aorta and/or aortic arch, and is nowadays the site of choice in many centres. Advantages of axillary artery cannulation include antegrade flow and the possibility of selective mono-hemispherical brain perfusion during circulatory arrest. Experiences with the axillary vein cannulation, however, are scarce. Here we report our preliminary experience with axillo-axillary cardiopulmonary bypass, through both axillary artery and vein cannulation (using echo-guided Seldinger technique) at deltoido-pectoralis groove. We have used such an approach in 5 cases of redo surgery on ascending aorta and we have not had any inconvenience during cardiopulmonary bypass. Full flow was maintained in all patients (in 2 with vacuum assisted drainage) including 2 cases with deep hypothermic circulatory arrest. In conclusion such an approach seems to be feasible and effective and can be safely performed providing that accurate TE echo monitoring is provided.

Left ventricular aneurysm resection with port-access surgery: a new mini-invasive surgical approach

BACKGROUND In recent years port-access and endovascular extra-corporeal circulation techniques have allowed valvular and coronary operations to be performed by mini-thoracotomy. Experience with the technique suggested application to resection of ventricular aneurysms, which are usually approached through a median sternotomy with the use of traditional cardiopulmonary bypass. METHODS We performed a left port-access mini-thoracotomy, with 6 to 8 cm skin incisions, in 7 patients undergoing endoventricular pericardial patch repair for anterior left ventricular aneurysm. Cardiopulmonary bypass was effected using the Heartport system. The mean interval between myocardial infarction and operation was 60.4 +/- 57.7 months. Three patients developed sustained ventricular tachicardia. Mean preoperative ejection fraction was 34% +/- 11%. Associated procedures were coronary bypass grafting in 2 patients and cryosurgery in 3 patients. RESULTS All patients survived to discharge and are alive and well after an average 14.5 months. They are all in NYHA class I-II. Postoperative echocardiograms revealed an average ejection fraction of 48.0% +/- 7.5% (p = 0.006 compared with preoperative value). The 3 patients who had cryosurgery did not demonstrate any recurrence of arrhythmias. CONCLUSIONS Left ventricular aneurysm can be successfully treated through port-access mini-thoracotomy with endovascular cardiopulmonary bypass, avoiding median sternotomy. This mini-invasive approach allows effective ventricular remodeling. Revascularization and antiarrhythmia surgery can also be done at the same time. In case of severely reduced ventricular function this approach permits fibrillatory arrest without aortic cross-clamping. The results are also good in terms of hospitalization time and long-term survival.