History and exam
Key diagnostic factors
common
age 20 to 50 years
The age distribution of IPAH has evolved over time. The mean age at diagnosis was 36 years among patients entered into the US National Institutes of Health registry in the 1980s.[6] Contemporary registries from France and the US described a mean age at diagnosis of 50 years.[8][9] A significant proportion of patients (9% in the French registry) were older than 70 years.[8] Another registry of six European countries found that the median age of IPAH diagnosis was 71 years.[10] In the UK and Ireland, registry data from 2001 to 2009 showed an increase in the average age of IPAH diagnosis, from 45 to 52 years.[11]
dyspnoea
Seen in 60%, particularly with exertion.[6]
accentuated pulmonic component (P2) to the second heart sound
uncommon
family history
First-degree relative with the disease is seen in 6%.[6]
Other diagnostic factors
common
uncommon
stimulant use
Particularly methamphetamine. Stimulant use was seen in 28.9% in one study.[40]
syncope
chest pain
Patients may present with or without chest discomfort.[39]
near syncope
Patients may have syncope or near syncope as cardiac output becomes fixed and eventually falls.[37]
early diastolic, high-pitched murmur in the pulmonary area
jugular vein distension
Prominence of the jugular A or V waves. Hepatojugular reflux may be present as well.[39]
Risk factors
strong
family history
The prevalence of familial cases of pulmonary arterial hypertension (PAH) was 6% and 3.9%, respectively, in the US and French registries.[6][32] The transmission is autosomal dominant and shows genetic anticipation, variable expression, and a lifetime penetrance of 10% to 20%.[13][33] If one family member has IPAH, the likelihood of a first-degree relative being affected is approximately 0.6% to 1.2%. If there is a second case in the family, the lifetime risk rises to 5% to 10%.[33]
female sex
Both the early US registry and the French registry showed a female-to-male ratio of 1.7:1 and 1.6:1, respectively.[6][8] A more contemporary US registry showed a much higher female preponderance, with a female-to-male ratio of 3.9:1.[9] Another registry of six European countries found that in younger patients the female-to-male ratio of IPAH was 2.3:1, while the female-to-male ratio in older adult patients was almost even, at 1.2:1.[10] Whether there are hormonal or other reasons for sex-specific differences in PAH is not yet understood.[7][33]
bone morphogenetic protein receptor type 2 (BMPR2) mutations
Mutations in the gene encoding for BMPR2, a member of the transforming growth factor-beta superfamily, cause familial PAH.[12] The exact prevalence of BMPR2 mutations in the IPAH population is unknown, with reports ranging from 11% to 40%.[13] These mutations lead to changes in intracellular signalling pathways that result in proliferative and anti-apoptotic effects in the pulmonary vasculature.[13]
weak
drugs and toxins
In addition to appetite suppressants, various other classes of drugs have been associated with the development of PAH. These include amphetamine-like agents (methamfetamine, amfetamine), tyrosine kinase inhibitors (dasatinib, bosutinib, ruxolitinib, nintedanib, imatinib), antiviral medications (sofosbuvir, simeprevir, daclatasvir), alkylating agents (busulfan, cyclophosphamide, carboplatin, melphalan), immunosuppressive agents (abatacept, leflunomide, thalidomide, mycophenolic acid, everolimus, ciclosporin), antineoplastic agents (docetaxel, doxorubicin, etoposide, trastuzumab, vinblastine, vincristine), antimetabolites (gemcitabine), proteasome inhibitors (bortezomib, carfilzomib), interleukin (IL)-1 inhibitors (anakinra, canakinumab), programmed cell death protein (PD)-1 inhibitors (nivolumab), stimulants (modafinil), and interferons (alfa-2b, beta-a, pegylated alfa-2a, pegylated alfa-2b).[3][34]
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