Firstly a major determinant of some forms of idiopathic PH (the cases of familial PH) is genetic. A variety of gene mutations and polymorphisms have been related to the pathogenesis of PH without reaching definite conclusions (1). Probably additional triggers are required for the development of the condition.
However primary PH can be considered a possibly heritable cardiovascular disease, an area in which the WG is much interested. Secondly, chronic non idiopathic PH may be a component of the complex, largely ignored yet, pathophysiology of the so called heart failure with preserved left ventricular ejection fraction (HFPEF). Two recent papers deal with these two completely different forms of PH.
Idiopathic PH: a devastating disease
Idiopathic PH is a devastating disease characterized by a sustained elevation of mean pulmonary artery pressure to >25 mm Hg at rest or >30 mm Hg with exercise and with a mean wedge pressure <15 mm Hg. Although the pathogenesis of primary PH is unknown, there is consensus that after an endothelial dysfunction/injury, a strong imbalance between antithrombotic/prothrombotic, vasodilatation / vasoconstriction, and growth inhibition/promitogen forces develops.
Three major pathways are recognized to play a role in this imbalance: the prostacyclin, nitric oxide, and endothelin pathways, which involve several mediators.
Each of these pathways has been targeted with 3 different drug categories, namely, epoprostenol or other prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. These agents have been tested against placebo or control, providing a consistent evidence of benefit on the clinical end points of functional capacity, albeit failing to support a survival advantage. The disease leads to progressive hypoxemia, right ventricular failure, and death, occurring from a few months to a few years after diagnosis.
A meta-analysis of all randomized controlled trials performed with such drugs published up to October 2008 have been published on the European Heart Journal (2). The main outcome measure was all-cause mortality. Twenty-one trials were included in the primary analysis (3140 patients) and two additional studies (59 patients) were included in the sensitivity analysis.
Average duration of the trials was 14.3 weeks (only!). During the short follow-up period all-cause mortality rate in the control group was 3.8%. Active treatments were associated with a reduction in mortality of 43% (RR 0.57; 95% CI 0.35–0.92; P = 0.023); the sensitivity analysis confirmed a reduction in mortality of 38% (RR 0.62; 95% CI 0.39–1.00; P = 0.048).
The cause-specific hospitalizations were reduced by 68%. Significant, although small to moderate, improvements in the hemodynamic central pattern, including pulmonary pressures and cardiac index, were also reported. The authors conclude that the results of this meta-analysis suggest, besides a clinical improvement, a benefit on survival in the patients treated with the targeted therapies approved for PH.
As acknowledged by the authors the limitations of this meta-analysis include the prolonged period of time between the publication of the first and the last RCT (about 18 years), the different duration of the trials (ranging from 8 to 36 weeks), the lack of blindness in some studies, the pooling of multiple active treatment arms (potential alteration of the trial structure), the report of secondary outcome parameters only in part of the RCTs (possible reporting bias), and potential heterogeneity in the conduct of the trials and in the definition of hospitalization for pulmonary arterial hypertension in different RCTs (no individual patients data were reviewed).
Actually, all trials reported so far in PH were short, small and (consequently) based on surrogate end-points (usually the six minutes walking distance). A longer follow-up is the prerequisite for evaluating the relationship (if any) between surrogate and hard end points. Despite PH being a rare disease, the various groups currently working in the field—as well as all other groups with the same expertise—should make an additional effort to plan and conduct large, pragmatic, and clinically-oriented clinical trials.
Left-sided heart failure (HF) is known to cause PH
Left-sided heart failure (HF) is known to cause PH, but the development and severity of PH in HF is highly variable, and contributing factors are not fully understood. There is now growing appreciation that PH is common and may be severe in elderly patients with HF with preserved left ventricular ejection fraction (HFpEF). However, the true prevalence and severity of PH in HFpEF from the general community remain unknown. Common to left ventricular failure regardless of EF, increased left-sided filling pressure leads to pulmonary venous hypertension (HTN). Beyond this post-capillary contribution to PH, a reactive increase in pulmonary arterial tone or intrinsic arterial remodelling can result in a superimposed pre-capillary component of pulmonary arterial hypertension.
This was confirmed in a community-based study of 244 HFpEF patients (age 76 ± 13 years; 45% male) followed up using Doppler echocardiography over 3 years (3). Control subjects were 719 adults with HTN without HF (age 66 ± 10 years; 44% male).In HFpEF, PH was present in 83% vs 8% in controls and the median (25th, 75th percentile) pulmonary arterial systolic pressure (PASP) was 48 (37, 56) mm Hg. PASP increased with pulmonary wedge pressure (PCWP) (r = 0.21; p < 0.007). Adjusting for PCWP, PASP was higher in HFpEF than in hypertensive patients without clinically incident HF (p < 0.001). The PASP distinguished HFpEF from hypertension without HF with an area under the receiver-operating characteristic curve of 0.91 (p < 0.001) and strongly predicted mortality in HFpEF (hazard ratio: 1.3 per 10 mm Hg; p < 0.001).
In fact, the greater severity of PH in HFpEF may be caused by an additional pre-capillary component of pulmonary arterial hypertension, which might be related to a progressive desensitization or loss of production of regulatory endothelial agents (NO, prostaglandins) and mediated by reactive increases in pulmonary arterial tone or development of a congestive arteriopathy characterized by pulmonary arteriolar remodelling, medial hyperplasia, and intimal fibrosis, as shown to occur in patients with mitral stenosis or systolic HF.
Conclusion:
The individual propensity to develop such responses may lead hypertensive patients to develop HFpEF. The presence of a pre-capillary component in addition to post-capillary PH in HFpEF raises the potential that aside from therapies aimed at reducing pulmonary venous congestion, those aimed at pulmonary arterial hypertension may also have a role in the treatment of HFpEF. To date, there are no proven therapies in HfpEF.
Update on Tako-Tsubo syndrome
Finally, a short up-date. The last “paper of the month” that I posted on the web a few months ago dealt with the Tako-Tsubo syndrome. I reported and discussed a few findings supporting the hypothesis that the transient and regional myocardial dysfunction that characterizes the syndrome would be sympathetically mediated.
Recently a paper from J. Abraham et al, published in the JACC (4) reports 9 cases of “stress cardiomyopathy”, precipitated immediately by the intravenous administration of epinephrine (6 cases) or dobutamine (3 cases), evaluated by coronary angiography, and with serial echocardiography and cardiac enzymes. Interestingly these cases reproduced the classical features of the left ventricular ballooning syndrome (including normal coronary angiography and mild enzyme elevation) showing all 3 previously described variants: with apical (3 cases), midventricular (2 cases) and basal (4 cases) asynergy. The left ventricular ejection fraction, initially dropped to 35% in average (IQR:35%-40%), recovered in one week (median 7 days, IQR 4 to 13 days).
These findings further strongly support an excessive symptomatic stimulation or individual hypersensitivity to cathecholamines as central to pathogenesis of this unique syndrome.
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