Sergio Caravita

Sildenafil therapy for interferon-β-1a-induced pulmonary arterial hypertension: a case report.

Interferon (IFN) therapy is nowadays widely used in clinical practice. In the literature, there are very few reports of the association between IFN therapy and pulmonary arterial hypertension (PAH), and current guidelines do not mention IFNs as a risk factor for PAH. We describe a patient with multiple sclerosis who developed severe PAH after treatment with IFN-β-1a and the clinical response to sildenafil. Furthermore, we stress the need to further investigate the link between IFNs and PAH.

Acute high-altitude exposure reduces lung diffusion: Data from the HIGHCARE Alps project

The causes and development of lung fluid, as well as the integrity of the alveolar-capillary membrane at high altitude, are undefined. This study was conceived to see whether fluid accumulates within the lung with acute high altitude exposure, and whether this is associated with alveolar capillary membrane damage. We studied lung carbon monoxide diffusion (DLCO), its components - membrane diffusion (DM) and capillary volume (VC) and alveolar volume (VA) measured in 43 healthy subjects in Milan (122 m) and after 1 and 3 days at Capanna Regina Margherita (4559 m). DLCO measurement was adjusted for hemoglobin and inspired oxygen. We also measured plasma surfactant derived protein B (SPB) and Receptor of Advanced Glycation End-products (RAGE) as markers of alveolar-capillary membrane damage, and ultrasound lung comets as a marker of extravascular lung water. 21 subjects received acetazolamide and 22 placebo. DLCO was lower at Capanna Regina Margherita (day 1: 24.3 ± 4.7 and day 3: 23.6 ± 5.4 mL/mmHg/min), than in Milan (25.8 ± 5.5; p<0.001 vs. day 1 and 3) due to DM reduction (Milan: 50.5 ± 14.6 mL/mmHg/min, Capanna Regina Margherita day 1: 45.1 ± 11.5 mL/mmHg/min, day 3: 43.2 ± 13.9 mL/mmHg/min; p<0.05 Milan vs. day 3) with a partially compensatory VC increase (Milan: 96 ± 37 mL, Capanna Regina Margherita day 1: 152 ± 66 mL, day 3: 153 ± 59 mL; p<0.001 Milan vs. day 1 and day 3). Acetazolamide did not prevent the fall in DLCO albeit, between day 1 and 3, such a trend was observed. Regardless of treatment lung comets increased from 0 to 7.2 ± 3.6 (p<0.0001). SPB and RAGE were unchanged. Lung fluid increased at high altitude without evidence from plasma measurements, supporting alveolar-capillary damage.

Sex and acetazolamide effects on chemoreflex and periodic breathing during sleep at altitude.

OBJECTIVE Nocturnal periodic breathing occurs more frequently in men than in women with various clinical and pathophysiologic conditions. The mechanisms accounting for this sex-related difference are not completely understood. Acetazolamide effectively counteracts nocturnal periodic breathing, but it has been investigated almost exclusively in men. Our aim was to explore possible determinants of nocturnal periodic breathing in a high-altitude setting both in men and in women. We hypothesized that increased hypoxic chemosensitivity in men could be associated with the development of nocturnal periodic breathing at altitude more frequently than in women, and that acetazolamide, by leftward shifting the CO2 ventilatory response, could improve nocturnal periodic breathing at altitude in a sex-independent manner. METHODS Forty-four healthy lowlanders (21 women), randomized to acetazolamide or placebo, underwent cardiorespiratory sleep studies at sea level off treatment and under treatment on the first night after arrival at a 4,559-m altitude. Hypoxic and hypercapnic chemosensitivities were assessed at sea level. RESULTS Men, more frequently than women, exhibited increased hypoxic chemosensitivity and displayed nocturnal periodic breathing at altitude. Acetazolamide leftward shifted the CO2 set point and, at altitude, improved oxygenation and reduced periodic breathing in both sexes, but to a larger extent in men. Hypoxic chemosensitivity directly correlated with the number of apneas/hypopneas at altitude in the placebo group but not in the acetazolamide group. CONCLUSIONS The greater severity of periodic breathing during sleep displayed by men at altitude could be attributed to their increased hypoxic chemosensitivity. Acetazolamide counteracted the occurrence of periodic breathing at altitude in both sexes, modifying the apneic threshold and improving oxygenation. TRIAL REGISTRY EU Clinical Trials Register, EudraCT; No.: 2010-019986-27; URL: https://www.clinicaltrialsregister.eu.

Long-term effects of intermittent Iloprost infusion on pulmonary arterial pressure in connective tissue disease

BACKGROUND Intravenous periodic Iloprost is proven effective in the treatment of Raynaud phenomenon (RP) related to connective tissue disorder (CTD). Its well known that synthetic prostaglandins are effective drugs for the treatment of pulmonary arterial hypertension (PAH), and that PAH is frequently associated with CTD. OBJECTIVE The aim of the study is to evaluate in the chronic effect of cyclic intravenous Iloprost on pulmonary arterial pressure. METHODS We studied 17 consecutive patients with CTD (14 systemic sclerosis, 3 mixed CTD) and RP, at the entry and after at least 6months of treatment of RP with cyclic Iloprost. On both occasions, in all patients we performed transthoracic Doppler echocardiography and we determined NT-proBNP plasma levels, NYHA functional class, 6 Minute-Walk Distance (6MWD). RESULTS At follow-up (8.2±1.9months; range 6-12) mean values of pulmonary arterial systolic pressure (PASP) significantly decreased (from 32.2±9.2 to 29.2±7.6mmHg, p<0.04) and mean values of 6MWD significantly increased (from 407.5±101.5 to 448.3±89.9m, p<0.01). Moreover, we observed a significant direct correlation between PASP and NT-proBNP values and a significant inverse correlation both between NT-proBNP and 6MWD values and between PASP and 6MWD values. CONCLUSION Our results suggest that cyclic intravenous Iloprost may protect against the development or worsening of PAH in patients with CTD and RP.

Pulmonary hypertension and ventilation during exercise: Role of the pre-capillary component

BACKGROUND Excessive exercise-induced hyperventilation and high prevalence of exercise oscillatory breathing (EOB) are present in patients with post-capillary pulmonary hypertension (PH) complicating left heart disease (LHD). Patients with pre-capillary PH have even higher hyperventilation but no EOB. We sought to determine the impact of a pre-capillary component of PH on ventilatory response to exercise in patients with PH and left heart disease. METHODS We retrospectively compared patients with idiopathic or heritable pulmonary arterial hypertension (PAH, n = 29), isolated post-capillary PH (IpcPH, n = 29), and combined post- and pre-capillary PH (CpcPH, n = 12). Diastolic pressure gradient (DPG = diastolic pulmonary artery pressure - pulmonary wedge pressure) was used to distinguish IpcPH (DPG <7 mm Hg) from CpcPH (DPG ≥7 mm Hg). RESULTS Pulmonary vascular resistance (PVR) was higher in PAH, intermediate in CpcPH, and low in IpcPH. All patients with CpcPH but 1 had PVR >3 Wood unit. Exercise-induced hyperventilation (high minute ventilation over carbon dioxide production, low end-tidal carbon dioxide) was marked in PAH, intermediate in CpcPH, and low in IpcPH (p < 0.001) and correlated with DPG and PVR. Prevalence of EOB decreased from IpcPH to CpcPH to PAH (p < 0.001). CONCLUSIONS Patients with CpcPH may have worse hemodynamics than patients with IpcPH and distinct alterations of ventilatory control, consistent with more exercise-induced hyperventilation and less EOB. This might be explained at least in part by the presence and extent of pulmonary vascular disease.

Hemodynamic phenotyping of pulmonary hypertension in left heart failure

Increased pulmonary venous pressure secondary to left heart disease is the most common cause of pulmonary hypertension (PH). The diagnosis of PH due to left heart disease relies on a clinical probability assessment followed by the invasive measurements of a mean pulmonary artery pressure (PAP) ≥25 mm Hg and mean wedged PAP (PAWP) >15 mm Hg. A combination of mean PAP and mean PAWP defines postcapillary PH. Postcapillary PH is generally associated with a diastolic pulmonary pressure gradient (diastolic PAP minus mean PAWP) <7 mm Hg, a transpulmonary pressure gradient (mean PAP minus mean PAWP) <12 mm Hg, and pulmonary vascular resistance ⩽3 Wood units (WU). This combination of criteria defines isolated postcapillary PH. Postcapillary PH with elevated vascular gradients and pulmonary vascular resistance defines combined post- and precapillary PH (Cpc-PH). Postcapillary PH is associated with a decreased survival in proportion to increased pulmonary vascular gradients, decreased pulmonary arterial compliance, and reduced right ventricular function. The Cpc-PH subcategory occurs in 12% to 13% of patients with PH due to left heart disease. Patients with Cpc-PH have severe PH, with higher diastolic pulmonary pressure gradient, transpulmonary pressure gradient, and pulmonary vascular resistance and more pronounced ventilatory responses to exercise, lower pulmonary arterial compliance, depressed right ventricular ejection fraction, and shorter life expectancy than isolated postcapillary PH. Cpc-PH bears similarities to pulmonary arterial hypertension. Whether Cpc-PH is amenable to therapies targeting the pulmonary circulation remains to be tested by properly designed randomized controlled trials.

Pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a devastating disease with significant disability and mortality, and it has much higher prevalence than previously thought. During the past 15 years, we have witnessed remarkable advances in our understanding of pathogenesis, in diagnostic process and in the development of disease-specific treatments for PAH. Nowadays, the diagnosis is more clearly defined, non-invasive markers of disease severity can be widely applied, and finally we can adopt evidence-based treatment. Newer drugs availability has resulted in radical change in the management of this disease. The article reviews established approaches to evaluation and treatment of this disorder.

Pulmonary vascular function and exercise capacity in black sub-Saharan Africans.

Sex and age affect the pulmonary circulation. Whether there may be racial differences in pulmonary vascular function is unknown. Thirty white European Caucasian subjects (15 women) and age and body-size matched 30 black sub-Saharan African subjects (15 women) underwent a cardiopulmonary exercise test and exercise stress echocardiography with measurements of pulmonary artery pressure (PAP) and cardiac output (CO). A pulmonary vascular distensibility coefficient α was mathematically determined from the natural curvilinearity of multipoint mean PAP (mPAP)-CO plots. Maximum oxygen uptake (V̇o2max) and workload were higher in the whites, while maximum respiratory exchange ratio and ventilatory equivalents for CO2 were the same. Pulmonary hemodynamics were not different at rest. Exercise was associated with a higher maximum total pulmonary vascular resistance, steeper mPAP-CO relationships, and lower α-coefficients in the blacks. These differences were entirely driven by higher slopes of mPAP-CO relationships (2.5 ± 0.7 vs. 1.4 ± 0.7 mmHg·l(-1)·min; P < 0.001) and lower α-coefficients (0.85 ± 0.33 vs. 1.35 ± 0.51%/mmHg; P < 0.01) in black men compared with white men. There were no differences in any of the hemodynamic variables between black and white women. In men only, the slopes of mPAP-CO relationships were inversely correlated to V̇o2max (P < 0.01). Thus the pulmonary circulation is intrinsically less distensible in black sub-Saharan African men compared with white Caucasian Europeans men, and this is associated with a lower exercise capacity. This study did not identify racial differences in pulmonary vascular function in women.

Blood pressure response to six-minute walk test in hypertensive subjects exposed to high altitude: effects of antihypertensive combination treatment

ABSTRACT Background Limited evidence exists on blood pressure (BP) responses to exercise in hypertensive subjects exposed to high altitude, and on the effects of antihypertensive treatment in this setting. We aimed to asses BP response to submaximal exercise in hypertensive lowlanders acutely exposed to high altitude, and the effects of a calcium antagonist–angiotensin receptor blocker combination in this condition. Methods 89 mild-hypertensive participants in HIGHCARE-ANDES study performed a six-minute walk test in 3 conditions: at sea-level off-treatment; at sea-level after 6weeks of double-blind treatment with telmisartan 80mg+slow release nifedipine 30mg or with placebo; on the first full day of permanence at 3260m altitude under randomized treatment. Results The distance walked in 6min was reduced by about 10% at high altitude in both groups (p Conclusions In mild hypertensives, acute exposure to high altitude enhances the BP response to exercise. Such an enhanced response is effectively reduced by telmisartan/nifedipine combination therapy, without affecting exercise performance.

Hyperparathyroidism in celiac disease: always secondary?

It is well known that in celiac disease, malabsorption of calcium leads to secondary hyperparathyroidism as a response to hypocalcemia, and that secondary hyperparathyroidism is probably also due to concomitant vitamin D deficiency [1]. In patients with celiac disease, bone loss and derangement are extremely frequent, and there are recent data that show in celiac disease the release of proinflammatory cytokines activating osteoclasts may contribute to osteopenia and osteoporosis. Although the risk of fractures in celiac disease patients seems only slightly increased, it remains a clinical concern. Furthermore, osteomalacia in celiac patients is sometimes seen even if its exact prevalence remains unknown. A possible association between primary hyperparathyroidism and celiac disease has been reported recently [2, 3]. Here, we describe and discuss two cases of patients who simultaneously had both clinical conditions. Patient A: A 45-year-old woman hospitalized for severe osteomalacia, with inability to walk, history of nephrolithiasis, and iron-deficiency anemia unresponsive to oral iron therapy, was diagnosed with celiac disease which was confirmed by characteristic histologic changes on duodenal biopsy. At the time of her diagnosis, laboratory findings were as follows: hemoglobin 8.5 g/dL with mean corpuscular volume (MCV) 66 fl (83–97); serum calcium 2.38 mmol/L (2.1–2.55); phosphorus 0.53 mmol/L (0.87–1.45); parathyroid hormone (PTH) 478 pg/mL (11–64); 25-hydroxyvitamin D 3 ng/mL (9–38); ferritin 2 ng/mL (12–200); vitamin B12 168 pg/mL (211–911). The patient was started on a gluten-free diet, calcitriol 0.75 lg, calcium lactate-gluconate/calcium carbonate 2,000 mg daily and parenteral administration of iron and vitamin B12. With the start of the therapy, there was a marked improvement in the overall clinical picture with normalization of blood counts, and after 9 months, a return to the normal range of levels of antigliadin antibodies IgA—from 359.6 ng/mL to 5.5 ng/mL (0–5.9)—and antiendomysial antibodies IgA—positive from 1:2,560 to 1:5 (\1:5). However, despite correction of vitamin D deficiency (25-hydoxyvitamin D increased to 31 ng/mL), PTH levels remained high, 393 pg/mL, with evidence of hypercalcemia, 2.7 mmol/L and persistence of hypophosphatemia, 0.47 mmol/L. Her therapy was stopped (at that time calcitriol 0.25 lg, calcium lactate-gluconate/calcium carbonate 500 mg daily) and an ultrasound examination of the neck was performed with evidence of a hypoechoic oval structure, 1.8 cm in diameter, near the left lower pole of a normal thyroid gland, which suggested the possibility of an enlarged parathyroid gland. The patient underwent a technetium-99 m-labeled sestamibi scintigraphy that revealed a focus of activity consistent with a single left inferior parathyroid adenoma. The excision of the left parathyroid gland was carried out by an endocrine surgeon and then the histopathological examination showed a parathyroid adenoma. Thereafter, the patient experienced a progressive increase in bone mass density (with normal serum levels related to osteo-calcium metabolism), and she is now leading a normal life albeit with gluten-free diet. Patient B: A 42-year-old woman was examined for evaluation of a syndrome characterized by generalized weakness, anxiety and depression, and iron deficiency anemia unresponsive to oral iron therapy. By clinical S. C. Wu S. Caravita M. B. Secchi (&) Azienda Ospedaliera Istituti Clinici di Perfezionamento, U.O.C. Medicina Interna, Ospedale Bassini, via Massimo Gorki 50, 20092 Cinisello Balsamo, Milan, Italy e-mail: beatrice.secchi@fastwebnet.it