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Alternative Concepts for
Pulmonary Hypertension Terminology, Over the past couple of months a number of new ideas have been developed which provide alternative bases for revising pulmonary hypertension terminology, classification and diagnosis. These ideas include Dr. Lewis Rubin’s concept of Intrinsic Pulmonary Vascular Disease (IPVD), Dr. Gerald Simonneau’s set of pathophysiology-based categorizations and Dr. Norbert Voelkel’s just-discovered genotypic/morphotypic distinctions. Pulmonary hypertension (PH) is an abnormally high elevation in pulmonary artery pressure (greater than 25 mmHg at rest) and pulmonary vascular resistance (greater than 3 mmHg/l/min). This hemodynamic abnormality is common to a variety of syndromes. It causes an increase in right ventricular afterload, thereby impairing right ventricular function and ultimately leading to inactivity and death if not successfully treated. At least since a 1973 WHO meeting on the subject, Primary Pulmonary Hypertension (PPH) has been defined as PH without an identifiable cause and Secondary Pulmonary Hypertension (SPH) has been defined as PH due to an identifiable cause. This classification is increasingly falling out of favor due to the similar clinical path of many forms of SPH with PPH, overlapping histopathological features among the two classifications, and correlations of PPH occurrence with certain other diseases and exogenous ingested substances, even if the precise cause remains unclear. Dr. Lewis Rubin has suggested differentiation of PH based on the intrinsic site of the disease. In this schema Intrinsic Pulmonary Vascular Disease (IPVD) would be reserved for those disorders in which the pulmonary circulation is the intrinsic site of the disease. If the vascular disease is not intrinsic to the pulmonary circulation, but results instead from pulmonary parenchymal or airway disease, then the PH would be called Pulmonary Vascular Disease due to Respiratory Disorders (PVDRD). From a clinical standpoint, IPVD tends to be more severe and life-threatening than PVDRD, and to also share certain pathologic features (medial hypertrophy, intimal proliferation, concentric laminar fibrosis and plexiform and thombotic lesions). It is not clear, however, to what extent these pathologic features also occur in PVDRD. Dr. Rubin’s classification of pulmonary vascular disease by site of primary injury would result in the following table:
An alternative classification schema for chronic pulmonary hypertension has been developed by Prof. Gerald Simonneau of the Antoine-Beclere Hopitaux de Paris. As with Dr. Rubin, Dr. Simonneau divides chronic pulmonary hypertension into four categories based on a mixture of pathological and clinical factors. While the categorization, explained below, is different from Dr. Rubin’s, what the two schemes share in common is a regrouping of much of what was once known as SPH into a new category which includes PPH. In other words, it is now believed that PPH is not really distinct from much of SPH, at least as far as the pathophysiology and treatment of pulmonary hypertension is concerned. Of course, problems other than pulmonary hypertension, e.g., heart structure defects, still need to be separately addressed for the newly co-grouped SPH diseases. Prof. Simonneau divides chronic pulmonary hypertension into four categories: Proliferative Pulmonary Hypertension (PPH – an expansion of the original PPH acronym), Hypoxic Pulmonary Hypertension (HPH), Obstructive Pulmonary Hypertension (OPH) and Passive Pulmonary Hypertension (no acronym offered). He appears to differentiate the categories based on the severity of the mean PAP, the extent of vascular remodeling, and the presence or absence of mechanical obstruction or compression. His schema is as follows: Proliferative Pulmonary Hypertension (PPH) PH characterized by major vascular wall remodeling of small pulmonary arteries (i.e., thickened media and intima and plexiform lesions), strongly suspected endothelial dysfunction and mean pulmonary artery pressures in excess of 40 mmHg.
Hypoxic Pulmonary Hypertension (HPH) PH characterized by less vascular wall remodeling of small pulmonary arteries (i.e., just some medial hypertrophy), not causative of mortality and mean pulmonary artery pressures below 30 mmHg. Chronic parenchymal lung diseases Obstructive Pulmonary Hypertension (OPH) PH related to the mechanical obstruction of pulmonary vessels by emboli or extrinsic compression. Clots (chronic thromboembolism) Passive Pulmonary Hypertension (no acronym) PH due to left ventricular failure or left atrial hypertension, with medial hypertrophy and intimal fibrosis. Yet another basis for a classification schema is suggested by Drs. Rubin Tuder’s and Norbert Voelkel’s recent discovery (University of Colorado Health Sciences Center) that the plexiform lesion endothelial cells in patients with primary pulmonary hypertension (PPH) are monoclonal whereas those in patients with SPH are polyclonal. Dr. Tuder notes that: "To determine whether the endothelial cell proliferation in plexiform lesions in PPH is monoclonal or polyclonal, we assessed the methylation pattern of the human androgen-receptor gene (HUMARA) in proliferated endothelial cells in plexiform lesions from female PPH patients (n=4) compared to secondary pulmonary hypertension (SPH) (n=4). In PPH, 17 out of 22 lesions (77%) were monoclonal. However, in secondary PH, all 19 lesions examined were polyclonal. Smooth muscle cell hyperplasia in pulmonary vessels (n=11) in PPH and SPH was polyclonal in all but one of the examined vessels. The monoclonal expansion of endothelial cells provides the first marker that allows the distinction between primary and secondary PH." A final consideration for a classification schema may be the work of Dr. Brian Christman of Vanderbilt which shows significant differences in the ratio of metabolites of thromboxane to prostacyclin in the urine of PPH and SPH patients. The ratio is significantly higher in the PPH patients. Each of the approaches – causative, clinical, histopathological, genotypic and metabolite measurements – have advantages and disadvantages for segregating cases of pulmonary hypertension. Perhaps what is most important is a diagnosis that provides meaningful guidance as to what type of therapy is most likely to prove safe and effective for patients. In that regard, the problem with pathology-based criteria is the difficulty of obtaining tissue specimens. Based on clinical utility, one might also consider a two-fold classification schema of (1) Prostacyclin Mediated Pulmonary Hypertension (PMPH) for what Dr. Rubin calls IPVD and what Dr. Simonneau calls Proliferative and Obstructive Pulmonary Hypertension, and (2) Oxygen Mediated Pulmonary Hypertension (OMPH) for what Dr. Rubin calls Pulmonary Vascular Diseases Due to Respiratory Disorders and what Dr. Simonneau calls Hypoxic Pulmonary Hypertension. |
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