High Cardiac Output By Microfistulas: A New Pulmonary Hypertension Mechanism in Patients with Myelofibrosis and the Impact of the Treatment with Ruxolitinib

Background: Pulmonary Hypertension (PH) is a well-known complication of the advanced phase of Myeloproliferative Diseases (MPD) such as Polycythemia Vera (PV), Essential Thrombocytopenia (ET) and Myelofibrosis (MF). Although initially attributed to increased pulmonary vascular resistance (group 1 PH of the WHO classification), this entity was classified in 2009 in group 5 PH (unknown mechanism and miscellaneous PH). Our aim was to describe the prevalence and possible causes of PH in a series of patients with MF.

Methods: We studied a series of patients with Primary MF or Secondary MF to other MPD with cardiac ultrasound, right heart catheterization and scintigraphy after intraarterial infusion of Tc99-labeled albumin macroaggregates.

Results: We studied 11 consecutive patients with MF (7 male, mean age 58 years, 4 with MF post-PV, 4 post-TE and 3 Primary MF) during the period 2009-2014. All of them had mutations of JAK-2 gene, fibrosis in bone marrow biopsy and visceromegaly (all with intermediate-2 or higher IPSS). Median NTproBNP levels were 4597 pg/ml (range 175-5700). Echocardiogram showed high systolic pulmonary pressure in most cases, with a mean of  54 ± 17 mmHg (range 35-80). Right heart catheterization showed high cardiac output (HCO) in all patients (table 1).

After ruling out other causes of HCO, a scintigraphy was performed after administration of Tc99-labeled albumin macroaggregates in descending thoracic aorta. In every case, a percentage of the labeled macroaggregates (6.1 ± 2.0% of the radioactivity) were plugged in the pulmonary capillary bed, what is diagnostic of the presence of microfistulas in infradiaphragmatic territory.

In two of these patients, scintigraphies were performed at diagnosis and after been treated with the anti-JAK drug Ruxolitinib (Novartis Pharma). A favourable impact of this drug was obtained in the two cases, probably due to a reduction of spleen volume.

Conclusion: Most patients with MF show pulmonary hypertension associated with high cardiac output caused by microfistulas, without significant increase in pulmonary resistance. This finding has important clinical implications, because pulmonary vasodilators (once recommended) should be contraindicated, since they could cause worsening of the clinical picture. Ruxolitinib could resolve PH in MF and a prospective study in this sense could be indicated.

 

Patient	1	2	3	4	5	6	7	8	9	10	11
Pulmonary Artery Pres. (S/D/Mean)	58/38/ 42	69/41/ 50	48/29/ 40	84/26/ 45	57/17/ 30	22/17 / 19	51/16 / 28	22/9 / 13	25/8 / 14	71/23 / 39	30/7 / 15
Pulmonary wedge pres.	28	37	27	13	9	7	13	7	8	12	6
Cardiac output (l/min)	12.5	8.0	11	7.1	8	7.3	8.7	6.7	7.45	6	7.8
Cardiac index (l/m/m2)	5.5	4.0	6.6	3.6	5	4	4.8	4.0	4.5	3.9	5.1
Pulmonary vascular resistance (Wood U.)	1.2	1.4	1.2	4.5	2.6	3	1.7	0.9	0.8	4.5	1.1