Possible Effectiveness of Combination Therapy in Patients with Severe Pulmonary Hypertension

Masahito Sakuma
Tohoku University Graduate School of Medicine, Sendai, Japan

Previous work by this group showed that epoprostenol (Epo) was associated with a satisfactory response in 44.4% of treated patients with pulmonary hypertension (PH) and NYHA class I and mild NYHA class II heart failure. An unsatisfactory response was seen 38.9% of patients and early death in 16.7% of patients. This indicates that chronic Epo therapy improves quality of life but not does not improve clinical status in one-half of patients. Nitric oxide (NO) inhalation is another important therapeutic tool of PH. NO inhalation has been shown to reduce right arterial pressure and increase cardiac output.

This group investigated the feasibility of combination therapy of Epo and NO inhalation for primary pulmonary hypertension (PPH), by assessing inhaled NO levels in patients with PH treated chronically with Epo. Protocol 1 examined the hemodynamic effects in 10 patients with PPH (age 34 years±10.7 years; 2 males) after chronic treatment with Epo (32.0±15.8 ng/kg/min) for 19.1±15.6 months. NO inhalation was performed during catheterization. Mean pulmonary artery pressure and right artery pressure were significantly reduced (54.9 to 51.9 mm Hg, p=0.02; 8.5 to 7.0 mm Hg, p=0.02, respectively). Cardiac output increased from 4.56 to 5.04 (p=0.03) and pulmonary vascular resistance decreased from 905 to 733 (p=0.005). The ratio of pulmonary vascular to systolic vascular resistance was reduced from 0.63 to 0.57 (p=0.01).

Protocol 2 compared the hemodynamic effect of NO inhalation before and after chronic treatment with Epo. Six women with PPH (age range 24 to 53 years) were treated with Epo (dose range 17.3-49 ng/kg/min) for 3 to 24 months. Cardiac output and heart rate were increased after chronic treatment with Epo. Pulmonary vascular resistance was significantly reduced from 1.2% before Epo therapy to minus 18.95 after Epo therapy (p<0.05).

The investigators conclude that NO inhalation has an additional effect on the pulmonary circulation during chronic use of Epo and this suggests that Epo improves pulmonary vascular responsiveness to NO inhalation. The combination of Epo infusion and augmentation of NO or the effects of NO (NO inhalation, NO donor or phosphodiesterase V inhibitor which enhances the effects of both intrinsic and extrinsic NO) might improve the prognosis in patients with PH more than either therapy alone. The best combination therapy for PH must be examined in addition to assessing newer medications.

Inhibition of Type 5 Phosphodiesterase: Promising Therapy for Pulmonary Hypertension

Hiroshi Watanabe
Hamamatsu University School of Medicine, Hamamatsu, Japan

Oral sildenafil, a type 5 phosphodiesterase inhibitor, may be valuable as a vasodilator in patients with primary and secondary pulmonary hypertension, according to a study performed at Hamamatsu University School of Medicine. Figure 1 illustrates the role of sildenafil in regulating vascular tone.

The study examined the hemodynamic efficacy and safety of short- and long-term treatment with sildenafil in 10 patients with primary and secondary pulmonary hypertension: 2 with primary pulmonary hypertension, 5 with connective tissue disease, and 3 with congenital heart disease. Patients received sildenafil 50 mg orally during cardiac catheterization. Pulmonary arterial pressure, systemic arterial pressure, cardiac output and other parameters were measured before and after sildenafil administration. Patients who had a positive hemodynamic response were then maintained on sildenafil 25 mg orally BID. Long-term hemodynamic effects were evaluated by repeat cardiac catheterization after 3 months.

Seven of the 10 patients responded to sildenafil. After the first administration, sildenafil decreased mean pulmonary arterial pressure by 27%, increased cardiac index by 18%, and reduced pulmonary artery resistance by 41%. It did not affect systemic artery pressure, reported Watanabe. Figure 2 shows the acute dynamic effects of sildenafil in a patient with primary pulmonary hypertension, and Figure 3 illustrates this in a patient with secondary pulmonary hypertension.

After 3 months of treatment, sildenafil increased cardiac index by 15%, reduced mean pulmonary arterial pressure by 26%, and reduced pulmonary artery resistance by 37%.

“The responders were maintained on 24 mg oral sildenafil twice a day with remarkable improvement,” he said. New York Heart Association functional class returned from III to II, and serum brain natriuretic peptide (BNP) levels dropped by 50%. Follow-up cardiac catheterization after 3 months showed that the hemodynamic efficacy of sildenafil was well-preserved.

The 3 nonresponders were patients with congenital heart disease who had secondary pulmonary hypertension for more than a decade and demonstrated mean arterial pressures of more than 70 mm Hg. “These probably are the factors that limited the efficacy of sildenafil,” Watanabe said.

“The results of this study indicate that sildenafil satisfies the recommended criteria for an agent to treat pulmonary hypertension, which includes a more than 25% reduction in mean pulmonary arterial pressure and a 33% fall in pulmonary vascular resistance,” he concluded. Positive responses to vasodilating agents in pulmonary hypertension are known to improve long-term clinical outcomes. The data presented suggest that oral sildenafil may be a valuable vasodilator in patients with primary and secondary pulmonary hypertension. Although the twice-daily dosing was effective, longer-acting formulations may be needed for more stable control of pulmonary artery pressure.

Living-Donor Lobar Lung Transplantation for End-Stage Primary Pulmonary Hypertension

Hiroshi Date
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

In living-donor lobar lung transplantation (LDLLT), an alternative to cadaver lung transplantation, two healthy donors donate the right or left lower lobe of their lung and these are transplanted into a recipient as a whole right and left lung. Because of the limited amount of lung tissue that is transplanted in this procedure, it is best suited to children or adults who are small in size. It has been most exclusively performed for cystic fibrosis. Although LDLLT has been successfully performed in pediatric primary pulmonary hypertension (PPH), its use in adult PPH has not been proven.

These investigators evaluated the effects of LDLLT for pediatric and adult patients with end-stage PPH. From January 2001 to December 2002, 9 patients were studied (2 male, 7 female; average age 19 years, range 8-31 years; 4 children, 5 adults). This group has successfully used LDLLT in 11 other patients with other indications. Currently all patients are still living. Eight of the patients had bilateral transplantation, while 1 child had unilateral transplantation, because the mother was the only available donor. All 17 donors (7 fathers, 6 mothers, 4 brothers) have returned to their normal daily life. The mean graft size was 69.9±5.5% of the predicted value of the recipient.

The pathology of the excised lungs was PPH in 7 patients (H-E grade 3 in 1 patient, H-E grade 6 in 6 patients), pulmonary capillary hemangiomatosis in 1 patient, and pulmonary veno-occlusive disease in 1 patient.

At 2 to 3 months post-transplant, mean pulmonary arterial pressure was reduced from 61.7±5 mm Hg pre-transplant to 16.1±1.8 mm Hg (p=0.0001). Cardiac index increased from 1.9±0.1 L/min/m2 pre-transplant to 2.9±0.2 post-transplant (p=0.0001). The reduced pulmonary arterial pressure was sustained at 1 year, while the cardiac index was further improved (Figure 1). The changes on chest x-ray in 1 recipient is shown in Figure 2. Pulmonary function testing showed steady improvement during the first year, with forced vital capacity reaching 2000 ml (17% of predicted value).

Rho-Kinase is an Important Therapeutic Target for the Treatment of Pulmonary Hypertension

Kohtaro Abe
Kyushu University Graduate School of Medicine, Fukuoka, Japan

This group recently demonstrated that Rho-kinase, a target of the small GTPase Rho, is substantially involved in the pathogenesis of arteriosclerosis in animal models. They propose that this mechanism may also be involved in primary pulmonary hypertension (PPH).

In adult male Sprague-Dawley rat model of monocrotaline- (MCT) induced PPH, 4 groups were studied (control, MCT, prevention protocol (fasudil treatment from day 0), treatment protocol (fasudil treatment from day 21). Fasudil is a long-term oral treatment that is metabolized to hydroxyfasudil, a specific Rho-kinase inhibitor.

In the prevention protocol, survival was very poor in the monocrotaline group (27%) while it was greatly improved in the low dose (83%) and high dose (93%) fasudil groups. In the treatment protocol, even though treatment began after the establishment of PPH, fasudil significantly and dose-dependently improved prognosis (43% low dose, 86% high dose) compared to the MCT group.

Fasudil prevented MCT-induced PH and right ventricular (RV) hypertrophy at day 21 and day 63 in the prevention group. Clinically important, fasudil caused a marked regression of MCT-induced PH and RV hypertrophy in the treatment group. Histology showed that medial wall thickening seen in the MCT group was markedly suppressed in the fasudil-treated groups in both protocols. Pulmonary vascular lesion formation was prevented or markedly regressed with fasudil.

In terms of mechanisms, long-term fasudil treatment in the prevention protocol was associated with 1) suppression of MCT-induced vascular smooth muscle (VSMC) proliferation, 2) macrophage accumulation, 3) enhanced apoptosis of VSMC, 4) prevention of MCT-induced endothelial dysfunction of pulmonary arteries, 5) suppression of MCT-induced VSMC hypercontractions in response to serotonin, 6) significant suppression of MCT-induced Rho-kinase activity, and 7) upregulation of eNOS in the lungs.

Hence, these results demonstrate the proliferation and hypertrophy of VSMC, adhesion and migration of inflammatory cells, injury and thrombosis of the endothelium, and hypercontraction of VSMC—all of these mechanisms are involved in the pathogenesis of MCT-induced PH in rats. They further demonstrated that inhibition of Rho-kinase is effective for the prevention and treatment of PH in this model.

In a clinical study of 10 patients with severe PH (3 primary, 7 secondary), they showed that 30-minute intravenous fasudil treatment did not affect pulmonary artery pressure, nor did oxygen inhalation, nitric oxide inhalation, or nifedipine. Pulmonary vascular resistance was not ameliorated by oxygen inhalation, nitric oxide inhalation, or nifedipine, but was significantly suppressed by fasudil. Systemic hypertension was not induced by fasudil treatment.

Their work shows that Rho-kinase is substantially involved in the pathogenesis of MCT-induced and hypoxia-induced PH (shown in a separate study) in rats. Rho-kinase may also be involved in the pathogenesis of PH in humans. Rho-kinase may be a novel therapeutic target in the treatment of PH.