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http://www.medscape.com/viewarticle/410809
Pulmonary Hypertension Associated With HIV Infection

Leonardo Seoane, MD, Judd Shellito, MD, David Welsh, MD, Bennet P.
Deboisblanc, MD, Section of Pulmonary/Critical Care Medicine,
Louisiana State University Health Sciences Center, New Orleans

South Med J 94(6):635-639, 2001. © 2001 Southern Medical Association
Abstract and Introduction
Abstract
Pulmonary hypertension occurs with increased frequency among patients
with human immunodeficiency virus (HIV) infection. Although the
pathogenesis of HIV-associated pulmonary hypertension remains unknown,
it appears to occur independently of other risk factors associated
with pulmonary vasculopathy, such as chronic hepatitis C infection and
intravenous drug use. Signs and symptoms are typical of those
immunocompetent patients with primary pulmonary hypertension, but
because many HIV-infected patients are receiving intensive medical
supervision, the diagnosis of pulmonary hypertension is often made at
an earlier stage. Acute responses to epoprostenol are similar to those
among non-HIV-infected individuals, but the benefits of long-term,
intravenous treatment with epoprostenol in HIV-infected patients is
unknown. Future investigations should define the true incidence of
pulmonary hypertension and the long-term effects of epoprostenol on
survival among HIV-infected individuals. Physicians should be alert to
possible pulmonary hypertension in persons infected with HIV.

Introduction
Human immunodeficiency virus has been associated with multiple
infectious and noninfectious pulmonary diseases. As a result of better
prophylaxis against opportunistic infections and longer survival,
noninfectious complications, such as lymphocytic interstitial
pneumonia, non-Hodgkin's lymphoma, and pulmonary hypertension, are
becoming more prominent.[1,2] We review the literature concerning
HIV-associated pulmonary hypertension, and we suggest therapeutic
options and future areas of study.

Kim and Factor[3] first reported pulmonary hypertension associated
with HIV infection in a hemophiliac with membranoproliferative
glomerulonephritis. Other cases of pulmonary hypertension were
described among HIV-infected hemophiliacs, suggesting a causative role
of treatment with low-purity factor VIII.[4] However, as subsequent
nonhemophilia cases were described, suspicion rose that the pulmonary
hypertension might be directly related to HIV infection.[5-7]

Many patients with HIV-associated pulmonary hypertension have other
known risk factors for pulmonary hypertension, such as intravenous
drug abuse or chronic liver disease. This initially cast doubt on an
HIV-mediated pathogenesis. Illicit intravenous drugs derived from
tablets or pills contain insoluble microcrystals that can cause
angiocentric foreign body granulomatous inflammation, thrombosis, and
pulmonary hypertension when injected long-term.[8] However, fewer than
5% of intravenous drug abusers inject tablet derivatives, making this
explanation for most cases of HIV-associated pulmonary hypertension
unlikely.[9] Furthermore, in a recent review of HIV-associated
pulmonary hypertension by Mesa et al,[10] none of the 33 reported
cases with known histology had pathologic evidence of foreign body
granulomatosis.

Portal hypertension and cirrhosis have also been associated with
pulmonary hypertension.[11] In a prospective study[12] of 507 patients
with portal hypertension, prevalence of pulmonary hypertension was 2%,
with the majority of patients having plexogenic pulmonary arteriopathy
on biopsy or autopsy. Liver disease could account for only a minority
of cases of HIV-associated pulmonary hypertension, since only 15% of
patients in whom HIV-associated pulmonary hypertension has been
reported have a history of hepatitis, evidence of cirrhosis, or portal
hypertension.[10]

Epidemiology
It has been estimated that the incidence of pulmonary hypertension
among HIV-positive persons is several thousand times greater than
among the general population. The incidence of primary pulmonary
hypertension (PPH) in the general population has been reported to be
one to two cases per million yearly.[13] Two studies, evaluating more
than 1,200 patients each, have estimated the incidence of symptomatic
pulmonary hypertension to be approximately 1 in 200 HIV-infected
patients or 0.5%.[14,15] The true incidence may be underestimated,
since it was determined from symptomatic cases. The observed
male-to-female ratio among the HIV cases has been 1.6:1, in contrast
to the female predominance of PPH. Associated HIV risk factors have
included intravenous drug use in 42%, homosexual transmission in 25%,
hemophilia in 13%, heterosexual transmission in 10%, nonhemophiliac
blood transfusion in 4%, multiple risk factors in 3%, and vertical
transmission by maternally acquired infection in 4%.[10]

Clinical Findings and Natural History
There appears to be no correlation between either CD4 count or the
stage of HIV infection and the prevalence or severity of pulmonary
hypertension. Among reported cases, CD4 cell counts have ranged from 0
to 937/mm3 (mean, 269/mm3).[16] The most common symptoms among
patients with HIV-associated pulmonary hypertension have been dyspnea,
syncope, fatigue, chest pain, and nonproductive cough. Physical signs
have usually included an increased pulmonic component of the second
heart sound and a murmur of tricuspid regurgitation. In advanced
cases, peripheral edema, ascites, and hepatomegaly have been
present.[10,16,17]

Petitpretz et al[18] compared 20 patients with HIV-associated
pulmonary hypertension with 93 control patients who had PPH. The HIV
group was younger (32 ± 5 vs 42 ± 13 years), less severely impaired
(New York Heart Association [NYHA] class I or II, 50% vs 25%), and had
lower peak pulmonary artery pressures at initial diagnosis (50 ± 11 vs
62 ± 15 mm Hg). The lower pulmonary artery pressures and better
initial NYHA class may relate to earlier diagnosis in the group under
close surveillance for HIV-associated complications. The reported
interval between onset of symptoms and diagnosis was only 6 months for
the HIV group and was 30 months for the PPH group. No significant
difference in survival from the time of diagnosis between the two
groups was observed.

Opravil et al[19] compared 19 HIV-infected persons with a pulmonary
hypertension diagnosis to 19 HIV-infected persons without pulmonary
hypertension. Cases and controls were matched for CD4 counts (range, 1
to 740/mm3), age, sex, risk factors, hospital center, and stage of HIV
infection. Pulmonary hypertension was the cause of death in 8 of the
17 patients who died during the study. The researchers determined
pulmonary hypertension to be an independent predictor of mortality
(relative risk, 2.14; 95% confidence interval, 1.0 to 4.5; P < .05)
among HIV patients. The median survival from the time of diagnosis was
1.3 years for the pulmonary hypertension group vs 2.6 years for the
group without pulmonary hypertension. Although autoimmune diseases
have been associated with pulmonary hypertension, there was no
difference in autoimmune serologies between the two groups. Therefore,
an autoimmune phenomenon in the pathogenesis of HIV-associated
pulmonary hypertension would be unlikely.[19]

In contrast to the observations of Petitpretz et al,[18] survival in
other reported cases of HIV-associated pulmonary hypertension has been
worse than reported survival for patients with PPH. In the review by
Mesa et al,[10] the 1-year survival rate among patients with
HIV-associated pulmonary hypertension was 51%, while the 1-year
survival rate reported by the National Institutes of Health registry
for PPH was 68%.[20,21]

Pathophysiology
Histopathologic changes in the pulmonary blood vessels of patients
with clinically diagnosed PPH may consist of arterial, capillary, or
venular lesions.[22] Hypertensive pulmonary arteriopathy occurs most
commonly and includes medial hypertrophy, intimal fibrosis, plexogenic
arteriopathy, and in situ thrombosis. Only hypertensive arteriopathy
and veno-occlusive disease have been described in HIV-associated
pulmonary hypertension. Of the reported cases of HIV-associated
pulmonary hypertension with available pathology, 78% (36 of 46) had
plexogenic pulmonary arteriopathy. Eleven percent had medial
hypertrophy and intimal fibrosis without plexiform lesions, 7% had
pulmonary veno-occlusive disease, and 4% had in situ thrombosis as the
prominent histologic finding.[16]

The etiology of PPH remains unknown, but its development is thought to
require both a genetic predisposition and a precipitating event. At
the core of the pathogenesis is evidence of endothelial cell
dysfunction manifested by enhanced vasoconstrictor synthesis,
diminished vasodilator production, and enhanced thrombogenesis.[23-28]
Cool et al[27,28] identified endothelial cells as the predominant
component of plexiform lesions and concentric obliterative vascular
lesions. Furthermore, plexiform lesions with proliferating endothelial
cells and perivascular inflammatory cells, made up of T lymphocytes
and macrophages, have been shown to predominate in PPH and
HIV-associated pulmonary hypertension lesions.[27] Initially, it was
thought that HIV might play a direct role by infecting and injuring
endothelial cells. However, evidence for direct involvement by the
virus has been lacking. Mette et al[29] were not able to identify
either HIV-1 p24 antigen or the HIV gag RNA in pulmonary arteries of
patients with HIV-associated pulmonary hypertension.

It has been suggested that the increased incidence of pulmonary
hypertension in patients with HIV might be due to an indirect role of
the virus, stimulating the host to release proinflammatory cytokines
or growth factors, which would result in pulmonary hypertension in
genetically predisposed individuals.[26,30] Ehrenreich et al[31] have
shown increased production of endothelin-1, a potent pulmonary
vasoconstrictor, by cells stimulated by glycoprotein 120. These
investigators have also demonstrated an elevation of endothelin-1 in
HIV patients. Exogenous tat-protein, an HIV gene product, has been
shown to activate endothelial cells.[32] Humbert et al[33] have shown
increased expression of platelet-derived growth factor-a (PDGF-), in
persons with HIV infection and pulmonary hypertension but not in
HIV-infected persons without pulmonary hypertension. They have
suggested a role for PDGF-, which induces smooth muscle and fibroblast
proliferation, in the pathophysiology of pulmonary hypertension.[33]
Chalifoux et al[34] studied macaque monkeys infected with the simian
immunodeficiency virus, an animal model of HIV infection. They
observed perivascular inflammatory cells and pulmonary artery
inflammation in the absence of evidence of direct pulmonary artery
retroviral infection. Gillespie et al[35] described a murine model of
HIV-induced pulmonary hypertension. The mice had endothelial
proliferation similar to that described in the macaque monkeys.

Genetic risk factors are poorly understood. Morse et al[36] described
an increased incidence of HLA-DR6 and HLA-DR52 genes in patients with
HIV-associated pulmonary hypertension. The HLA-DR6 subtype has also
been associated with diffuse infiltrative lymphocytosis syndrome. This
syndrome, which has been characterized by an exaggerated CD8
lymphocytic response to HIV-1 infection, resembles Sjögren's disease
and has been associated with a prolonged survival in HIV-infected
individuals.[36]

The gene responsible for familial PPH has been mapped to the 2q33
chromosome.[37-39] Recent studies by Deng et al[40] have shown that
mutations in the bone morphogenetic protein type II receptor (BMPR2)
gene cause familial PPH. Mutations in the BMPR2 gene have also been
found in 26% of sporadic cases of PPH.[40] However, the age of disease
onset is variable within families and between subjects carrying
identical mutations. These findings suggest that additional factors,
either environmental or genetic, are required for the pathogenesis of
the disease.[41] Further studies evaluating BMPR2 gene mutations among
patients with HIV-associated pulmonary hypertension may help elucidate
the molecular pathology and the relationship between genetic and
environmental factors in the development of pulmonary hypertension.
This may allow for future genetic screening of HIV-infected
individuals.

Treatment and Future Objectives
Few reports describe the efficacy of treatment for pulmonary
hypertension in HIV. In the study by Opravil et al,[19] 7 of the 19
patients studied received symptomatic treatment with diuretics, 3 with
calcium channel blockers, and 1 with anticoagulation. Eight patients
were treated with zidovudine or didanosine after the diagnosis of
pulmonary hypertension was established. Baseline and posttreatment
pulmonary artery pressures were obtained in 13 patients, 7 of whom
were treated with antiretroviral agents. Among patients who received
antiretroviral therapy, mean pulmonary artery pressure dropped 3.2 mm
Hg, while it rose an average of 19 mm Hg among those not receiving
antiretroviral therapy. However, the median survival was 2 years for
both groups. These investigators did not report if any of the patients
receiving antiretroviral therapy also received adjunctive therapy with
calcium channel blockers or anticoagulants. However, there have been
case reports of progression of pulmonary hypertension despite
effective antiretroviral therapy and a low viral load.[42]

Rich et al[43] estimated that approximately 25% of patients with PPH
may respond favorably to calcium channel blockers with both a
reduction in pulmonary vascular resistance and a drop in pulmonary
artery pressure. Few data are available on the prevalence of
vasodilator responsiveness among patients with HIV-associated
pulmonary hypertension. In one series, none of the five cases of
HIV-associated pulmonary hypertension responded to calcium channel
blockers, and intolerable side-effects occurred in four of the
cases.[44]

Domiciliary, continuous intravenous epoprostenol improves
hemodynamics, symptoms, and survival in PPH patients with NYHA class
III or IV symptoms.[45,46] Petitpretz et al[18] showed that acute
hemodynamic responses during a short-term vasodilator trial with
epoprostenol were similar in both HIV-associated pulmonary
hypertension and PPH. However, no long-term follow-up was reported.
Stricker et al[47] reported two cases of HIV-associated pulmonary
hypertension treated with inhaled epoprostenol. Both patients had a
pulmonary artery catheterization to confirm response to inhaled
epoprostenol. The authors reported a reduction in NYHA class and
reduction in pulmonary artery pressures at 7 months of follow-up.
Other less invasive treatments, such as inhaled iloprost, oral
beraprost, and subcutaneous uniprost, are currently being studied in
PPH patients. They may be an attractive alternative for persons with
HIV because of the possible risk of infection with continuous
intravenous epoprostenol in this patient group. Patients with
HIV-associated pulmonary hypertension are currently being enrolled in
a study with uniprost,[48] and protocols are being developed to
include patients with HIV-associated pulmonary hypertension in a study
using endothelin-1 inhibitors.[49] Potential drug interactions between
these agents and highly active antiretroviral therapy (HAART) are
unknown.

Additional studies are needed to better define the effect of HAART on
HIV-associated pulmonary hypertension. With the increased use of HAART
for HIV, it will be interesting to note whether a measurable change
occurs in prevalence of HIV-associated pulmonary hypertension.
Investigations of the effects of vasodilators on the natural history
of HIV-associated pulmonary hypertension are also needed. Especially
important is understanding the effects, if any, of therapy with
prostacyclin and its analogues on HIV viral load and on HAART.

In the interim, without supporting evidence, we recommend screening
with transthoracic echocardiogram for all HIV-infected persons with
unexplained shortness of breath or syncope. Furthermore, we recommend
the initiation of combination antiretroviral therapy in all
HIV-infected patients with pulmonary hypertension irrespective of CD4
counts or viral load. Initiation of continuous intravenous
epoprostenol for all patients with NYHA class III or IV symptoms who
fail to respond to calcium channel blockers seems prudent.

Key Points

   * Many patients with HIV-associated pulmonary hypertension have
other known risk factors for the condition, such as intravenous drug
abuse or chronic liver disease.

   * The incidence of pulmonary hypertension in HIV-positive persons
is several thousand times greater than in the general population.

   * There appears to be no correlation between either CD4 count or
the stage of HIV infection and the prevalence or severity of pulmonary
hypertension.

   * The etiology remains unknown, but its development is thought to
require both a genetic predisposition and a precipitating event.

   * Few reports describe the efficacy of treatment for pulmonary
hypertension in HIV, and there have been reports of progression
despite effective antiretroviral therapy and a low viral load.

   * Screening with transthoracic echocardiogram for all HIV-infected
persons with unexplained shortness of breath or syncope is
recommended.

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 42. Pellicelli AM, Palmieri F, D'Ambrosio C, et al: Role of human
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 43. Rich S, Kaufmann E, Levy PS: The effect of high dose
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 45. Shapiro SM, Oudiz RJ, Cao T, et al: Primary pulmonary
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intravenous epoprostenol infusion. J Am Coll Cardiol 1997; 30:343-349
 46. Barst RJ, Rubin LJ, McGoon MD, et al: A comparison of continuous
intravenous epoprostenol (prostacyclin) with conventional therapy for
primary pulmonary hypertension. Primary Pulmonary Hypertension Study
Group. N Engl J Med 1996; 334:296-302
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HIV-associated pulmonary hypertension (Letter). Ann Intern Med 1997;
127:1043
 48. McAllister RG, Crow JW, Wade M, et al: International multicenter
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Reprint Address
Reprint requests to Leonardo Seoane, MD, 1901 Perdido St, Suite 3205,
New Orleans, LA 70112.

There is indeed a correlation with HIV infection.  The definition is
"abnormally high blood pressure in the arteries of the lungs." The
disorder is usually diagnosed with various scans after auscultation of
the lungs (when they listen to your breathing) and based on symptoms
(like an unproductive cough).

You might wish to be evaluated for the presence of sleep apnea.

If you are overweight, work to bring your weight down through diet and
I cannot emphasize enough the need for exercise. If you don't exercise
on a routine basis, start now. Start slowly and easily--maybe just 3
push ups at the same time each day--when you get up perhaps. Or before
bed (although this may result in difficulty sleeping).

If you smoke, stop. (Yeah, easier said than done, I know.)

Another more extensive article below.

        George M. Carter

***
Pulmonary hypertension and cor pulmonale.
William R. Auger, MD
William R. Auger, MD, Division of Pulmonary and Critical Care (8381),
University of California, San Diego, Medical Center, 200 West Arbor
Drive, San Diego, CA 92103, USA.

An ever-expanding body of information has provided new insights into
the pathophysiologic mechanisms contributing to pulmonary hypertensive
disease. The pulmonary endothelial cell has been shown to have a
central role in both the maintenance of normal vascular tone and in
the pathogenesis of small vessel changes. The relationship between
endothelium-derived mediators such as nitric oxide, prostacyclin, and
endothelin-1 is likely to be important in the development of abnormal
vasomotor tone and structure in the pulmonary vascular bed. Stimulated
by this evolving understanding of pulmonary vascular physiology,
recent literature abounds with references to novel therapeutic
strategies in the care of patients who have both primary and secondary
forms of pulmonary hypertension. Advances in surgical technologies
have also expanded the therapeutic options for selected groups of
pulmonary hypertensive patients. This article highlights recent
developments in the understanding of pulmonary vascular
pathophysiology and examines strategies for evaluation and treatment
of pulmonary hypertension and cor pulmonale.

Current Opinion in Pulmonary Medicine 1995, 1:303-312

Introduction

Throughout the past decade, there have been considerable advances in
the diagnostic approach to patients who have pulmonary hypertension
and cor pulmonale. Many of these advances have resulted from a greater
understanding of the cellular pathophysiologic processes contributing
to the vascular abnormalities associated with this disease. This
understanding has been particularly true in the development of novel
vasodilator therapies. This same period has also seen significant
gains in surgical options for certain patient groups: organ
transplantation for patients suffering from debilitating small-vessel
pulmonary hypertension disease, and pulmonary thromboendarterectomy as
the treatment of choice for individuals who have chronic
thromboembolic pulmonary hypertension. As a result, for many suffering
from pulmonary hypertensive disease, the previously inevitable natural
history of progressive clinical deterioration has been replaced with
new hope.

This article briefly reviews normal physiologic control of the
pulmonary vessel as background for a discussion of the possible
mechanisms underlying the pathologic state, in the setting of both
primary and secondary pulmonary hypertensive disorders. Evaluation of
pulmonary hypertension and some of the more promising therapeutic
strategies in the care of patients who have this disorder are also
reviewed.

Regulation of normal pulmonary vascular tone

Under normal conditions, pulmonary circulation is a low-pressure
vascular circuit. During substantive augmentation of cardiac output,
mean pulmonary artery pressure remains low, which is a consequence of
vascular recruitment and flow-dependent vessel dilatation. Therefore
even during exercise, vessel resistance to blood flow, and hence right
ventricular %cstress%c, is limited.

In a recent review of the use of vasodilators in pulmonary
hypertension, Peacock [1] examined the central role of the pulmonary
endothelial cell in the maintenance of a normally low pulmonary
vascular tone. The endothelium has been shown to elaborate a number of
vasoactive mediators. Prostacyclin (prostaglandin I2),
endothelium-derived relaxing factor or nitric oxide, and
endothelium-derived hyperpolarizing factor constitute the principal
vasodilators. Endothelin-1, platelet-activating factor, and
angiotensin II are potent vasoconstrictors produced by the endothelial
cell. The balance between these mediators, their respective effects on
smooth muscle cells, and the conditions under which one class of
mediators predominates remain subjects of intense investigation. It
appears, however, that basal production of nitric oxide and
prostacyclin under physiologic conditions is responsible for
maintaining appropriate vessel diameters in response to changing flow
conditions [2-4]; this role is in contrast to a limited expression of
endothelin-1 under normal conditions [5] .

The effects of these various vasoactive mediators on vascular smooth
muscle cells is presented in Figure 1. An increase in cytosol calcium
is requisite for smooth muscle contraction, with endothelin-1 exerting
its stimulating effect through a specific smooth muscle cell receptor.
Nitric oxide acts on cytosol guanylate cyclase to increase cyclic GMP
levels, prompting a decrease in intracellular calcium levels through
activation of a high-conductance potassium channel [6]. Prostacyclin
achieves a similar effect on intracellular calcium levels through
stimulation of adenylate cyclase. Suggested by this illustration is
that smooth muscle activation can occur directly or via stimulation of
the endothelial cell. Not represented is the possible interaction
between endothelium-derived vasoactive substances [4]. For example,
nitric oxide, through the production of cyclic GMP in the endothelial
cell, inhibits endothelin-1 production. Conversely, suggestive of
feedback regulation, endothelin-1 can promote the release of nitric
oxide.

The vasoactive properties of these endothelial-derived mediators is
only part of their physiologic portfolio. Prostacyclin and nitric
oxide not only exhibit vasorelaxant activity, they both inhibit
vascular smooth muscle cell proliferation and platelet aggregation. In
contrast, endothelin-1 has been shown to be a smooth muscle cell
mitogen. As a result, the balance between endothelial-derived
mediators has implications not only with respect to vascular tone, but
also in the control of smooth muscle growth and local coagulability.

Pathophysiology of pulmonary hypertension

Secondary basis

By definition, pulmonary hypertension is present when mean pulmonary
arterial pressure exceeds 25 mm Hg at rest or 30 mm Hg with exercise
[7]. An increase in pulmonary vascular resistance may result from a
number of disease states involving the pulmonary parenchyma or the
airways, or from abnormal control of ventilation. Chronic obstructive
pulmonary disease (COPD), interstitial pulmonary fibrosis, chronic
alveolar hypoventilation, and obstructive sleep apnea syndromes [8]
are illustrative of primary disorders that can be complicated by the
gradual development of pulmonary hypertension and cor pulmonale.
Hypoxemia

A common denominator in the cause of this secondary pulmonary
hypertension is longstanding alveolar hypoxia. Pulmonary pressure
elevation can be further exacerbated by accompanying polycythemia (an
increase in blood viscosity) and hypercarbia (respiratory acidosis).
Though this topic is extensively examined elsewhere in this section, a
rise in pulmonary arterial pressure in the setting of chronic hypoxia
is believed to be related to 1) persistent vasoconstriction and 2)
pulmonary arterial remodeling. A recent in-depth review of this topic
by Vender [9] emphasizes that a hypoxic-induced increase in vascular
tone may result from an imbalance between the vasodilating and
vasoconstricting influences on the pulmonary vascular smooth muscle
cell. Much of the available data suggest a defect in pulmonary
dilatation, perhaps secondary to a decrease in the synthesis and
release of endothelium-derived relaxing factor or nitric oxide
[10,11]. Unlike the reversal of pulmonary vasoconstriction with
correction of acute hypoxia, oxygen supplementation typically fails to
normalize pulmonary hemodynamics in the chronic hypoxic situation [12]
. This would imply a limited degree of reversible vasospasm, and may
reflect irreversible vascular changes. As in other forms of pulmonary
hypertension, these structural changes result from perivascular
deposition of collagen and elastin, hypertrophy and hyperplasia of
smooth muscle cells, and abnormal muscularization of downstream,
precapillary vessels. Vender [9] characterized these vascular changes
as adaptive, with no clear relationship to tissue injury and repair.
Vascular disease

There are numerous secondary causes of pulmonary hypertension in which
the pathologic insult affecting the pulmonary vessels is not a
consequence of lung parenchymal or airways disease. In most cases, the
basis for the increase in pulmonary pressures and cor pulmonale can
generally be ascribed to a process related to the underlying disease
state. For example, small-vessel pulmonary arterial changes may
ultimately develop from an augmented pulmonary flow state
(Eisenmenger's physiology), as seen in left to right intracardiac
shunts [13] . Long-term pulmonary venous hypertension, as in mitral
stenosis or chronic congestive heart failure [14] or secondary to
large pulmonary vein obstruction from mediastinal fibrosis [15], may
also lead to a substantive increase in pulmonary arterial pressure.
Small-vessel vascular injury, in some cases due to an inflammatory or
immune-mediated mechanism, can result in severe pulmonary
hypertension. This result can be seen as a manifestation of certain
collagen vascular diseases, such as progressive systemic sclerosis,
mixed connective tissue disease, or Sjogren's syndrome [16].

There is also a group of disorders for which occlusion or narrowing of
the large- to medium-sized pulmonary arteries is the presumed basis
for the increase in vascular resistance. Included in this category are
extensive compression from mediastinal or hilar pathology (eg,
carcinoma, adenopathy, or fibrosis), nonspecific arteritis (Takayasu's
disease) [17] , primary pulmonary vascular tumors, and major-vessel
chronic thromboembolic disease [18]. Although the logical assumption
is that the cause of pulmonary hypertension in this group relates to a
progressive decline in the cross-sectional area of the pulmonary
vascular bed, there is mounting evidence from the experience with
chronic thromboembolic patients that a relatively high flow state in
unobstructed vessels or a possible mediator involvement may be
contributing to the development of pulmonary hypertension and account
for the pulmonary hypertensive lesions in the nonobstructed pulmonary
arterial bed [19] .

Primary basis

In the case of primary pulmonary hypertension (PPH), in which an
etiology for the small-vessel obliterative changes is by definition
elusive, a substantive amount of investigative energies have been
directed to the possibility of an intrinsic imbalance between factors
favoring vasoconstriction over vasodilatation. At the center of
attention has been the role of the pulmonary endothelium in either the
generation of this imbalance or in the sustainment of the increased
vascular tone [20] . For example, the expression of endothelin-1 in
normal and in pulmonary hypertensive patients was examined by Stewart
et al. [21] . Measuring arterial (postpulmonary) and venous
(prepulmonary) endothelin-1 levels, it was demonstrated that the
pulmonary vascular bed is a clearance site for endothelin under normal
conditions (ie, arterial endothelin-1 levels were lower than paired
venous levels). In patients who have pulmonary hypertension from
secondary causes, arterial and venous endothelin-1 levels were both
elevated, with the ratio of paired samples centering around unity.
This result suggests either a loss of the normal clearance capability
of the pulmonary vascular bed or a balance between reduced clearance
and increased endothelin-1 production. Striking were the endothelin-1
measurements in PPH patients. In this group, arterial endothelin-1
levels exceeded measured venous levels, implying a net production or
release of endothelin from the pulmonary endothelium (Figure 2). These
investigators expanded their observations with the use of
immunocytochemistry and in situhybridization techniques. In patients
who have pulmonary hypertension, endothelin-1 immunoreactivity was
greatest in individuals with primary disease, was localized to the
endothelium of vessels with marked morphologic changes, and appeared
to positively correlate with the degree of pulmonary vascular
resistance [5,20,21] .

Conversely, there is growing evidence to suggest that endothelial
dysfunction may manifest as a reduction in the capability to produce
factors that would favor vasodilatation. Evidence that suggested a
reduction in prostacyclin synthesis in PPH patients relative to a
control population was reported by Rich et al. [22]. More recently,
Christman et al. [23] measured metabolites of thromboxane A2 , a
vasoconstrictor, and prostacyclin in patients who had PPH and
secondary forms of pulmonary hypertension, comparing these results
with a non-pulmonary hypertensive control population. In the pulmonary
hypertensive group, thromboxane A2 metabolites were increased, whereas
the excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha , a
prostacyclin derivative, was significantly reduced as compared with
the control group. Ten PPH patients were examined, and in eight of
these patients, the ratio of thromboxane A2 metabolites to
prostacyclin metabolites was substantially greater than in the control
group. This observation suggests an imbalance between the factors
promoting vasoconstriction over vasodilatation (Figure 3). Because
thromboxane A2 can activate platelets, the observed imbalance also has
theoretical appeal to explain the presence of small-vessel thrombotic
arteriopathic changes in pulmonary hypertensive patients. Additional
support for endothelial dysfunction leading to a reduction in
vasodilating factors comes from the in vitro demonstration of impaired
endothelium-derived nitric oxide production in patients who have COPD
[10]. Additionally, Stewart [20] has demonstrated that the infusion of
L -arginine (substrate for nitric oxide synthesis) can produce
significant reductions in pulmonary vascular resistance in pulmonary
hypertensive patients. However, these individuals with primary disease
were the least responsive relative to patients who have secondary
forms of pulmonary hypertension.

The implication of these observations is that a sustained increase in
pulmonary vascular tone may result from a primary perturbation of the
pulmonary endothelium, where an aberrant signal promotes
vasoconstricting mediators or suppresses a vasodilating milieu.
However, it has also been suggested that this apparent vasodilator to
vasoconstrictor imbalance may simply represent a marker of established
disease [21]. Equally speculative is the role played by these
vasoactive substances in vascular remodeling. As noted previously,
endothelin-1 may promote smooth muscle cell growth, whereas
prostacyclin and nitric oxide may exert an opposing effect.

Reasonably, other factors are likely to be operative in the genesis of
the small vessel changes seen in PPH [24]. Botney et al. [25]
described the possible role of transforming growth factor beta in this
pathologic process. In the characterization of plexiform lesions,
Tuder et al. [26] provide compelling evidence that deregulated growth
of endothelial cells accounts for this vascular lesion. The presence
of inflammatory cells at the periphery of these plexiform vessels also
led to the speculation that cytokines with chemotactic potential, such
as interleukin-1, and various growth factors, such as transforming
growth factor- beta and fibroblast growth factor, may play a role in
pulmonary vessel remodeling [26].

Cor pulmonale

Regardless of the cause, the cardiac response to a gradual increment
in pulmonary vascular resistance is the development of right
ventricular hypertrophy or cor pulmonale. Laskey et al. [27] have
recently detailed right ventricle performance characteristics in
pulmonary hypertensive patients. In addition to describing the pattern
of pulmonary arterial pressure and flow generation in these patients,
they underscored the long-appreciated abnormal cardiac response to
exercise in the setting of pulmonary hypertension [28]. This inability
to appropriately augment cardiac output during exertion also reflects
the effects of right ventricle dilatation and volume overload on the
left ventricle. The increase in right ventricle volume, by shifting
the intraventricular septum toward the left ventricle, has been found
to significantly compromise left ventricle chamber size and function.
If pulmonary vascular resistance is not somehow relieved, the
progression of these cardiac perturbations eventuate in right
ventricular failure and hemodynamic collapse.

The observations addressing right ventricle recovery following lung
transplantation for PPH and pulmonary thromboendarterectomy for relief
of chronic thromboembolic pulmonary hypertension have been intriguing.
Several reports have documented dramatic improvement in right atrial
and ventricle size and function following the successful reduction of
pulmonary vascular resistance in the postoperative period [29-31] .
Implicit in these findings is that, even in longstanding pulmonary
hypertension and cor pulmonale, clinically relevant irreversible right
ventricle pathology (ie, fibrosis) is not typically present. This
presumption has been substantiated by a recent study examining
endomyocardial biopsy specimens from patients who have chronic
thromboembolic pulmonary hypertension [32].

Evaluation of pulmonary hypertension

In the evaluation of the patient with pulmonary hypertension and cor
pulmonale, historical information should be gathered with the intent
of identifying a disorder with a known association with pulmonary
vascular disease. In most instances, for example, the presence of
COPD, pulmonary fibrosis, a sleep disorder, or collagen vascular
disease will antedate the occurrence of pulmonary vascular problems.
The same is true for patients who have HIV-related pulmonary
hypertension [33]. However, certain historical information can also be
helpful when the cause of elevated pulmonary pressures is less
obvious. For example, although present in only 40% to 50% of chronic
thromboembolic pulmonary hypertensive patients, a history of
thromboembolic disease, no matter how remote, should be sought.
Intravenous drug use and the ingestion of certain diet medications
(eg, fenfluramine [34]) have also been associated with development of
pulmonary hypertension. If the patient's place of residence is a
region endemic for histoplasmosis, this information is helpful in
directing the clinician to the possibility of fibrosing mediastinitis.
Also, although extremely rare, a family history of pulmonary
hypertension should be explored with any individual presenting with
PPH [35].

Diagnostic approach

Symptoms specifically attributed to the presence of pulmonary
hypertension and cor pulmonale are nonspecific and dependent on the
stage of the disease. A gradual decline in exercise tolerance is
typically the initial manifestation of isolated pulmonary hypertensive
disease. A nonproductive cough, atypical chest pains, profound
exertional dyspnea, fluid retention, cyanosis, presyncopal symptoms,
and syncopal spells are features of progressive pulmonary hypertension
and right ventricular dysfunction.

Findings on physical examination in pulmonary hypertension are
similarly reflective of the stage of the disease. Unless the pulmonary
hypertension or right ventricular dysfunction is marked, the physical
examination results can be deceptively normal. With progression of the
disease, accentuation of pulmonary valve closure, widening or fixed
splitting of the second heart sound, tricuspid regurgitation, jugular
venous distention, hepatomegaly, ascites, and peripheral edema can be
found to various degrees. The finding of pulmonary flow murmurs [18]
is particularly useful in differentiating between large- and
small-vessel pulmonary vascular disease. Auscultation of these
high-pitched, systolic murmurs in the lung fields suggests the
presence of partially obstructing lesions involving the large
pulmonary vessels.

Routine studies such as chest radiography and electrocardiography are
particularly useful in the evaluation of pulmonary hypertensive
patients in establishing the presence of pulmonary, mediastinal, or
cardiac problems. Additional utility of these studies is in the
detection of changes over time, such as an increase in heart size or a
progression of right ventricular hypertrophy, by electrocardiographic
criteria. Pulmonary function tests are similarly helpful in
establishing the presence of significant lung restriction or airflow
obstruction.

Echocardiography, though technically difficult in some patients who
have significant obstructive lung disease, has evolved as an important
noninvasive means of assessing the degree of pulmonary hypertension,
tricuspid regurgitation, and right heart enlargement. Contrast
administration during transthoracic or transesophageal
echocardiography has also been found useful in the detection of
intracardiac shunts [36] .

Worsley et al. [37] emphasized the value of lung ventilation-perfusion
(V/Q) scans in the evaluation of pulmonary hypertension. They observed
that high-probability V/Q scan results are very sensitive (though less
specific) for detecting chronic thromboembolic pulmonary hypertension.
PPH patients were found to have low-probability scan results almost
exclusively, and the majority of patients who have nonthromboembolic
secondary pulmonary hypertension exhibited low- to
intermediate-probability V/Q study results. In the latter group,
high-probability scan results were obtained in two patients: one who
had sarcoid lymphadenopathy obstructing the pulmonary vessels and the
other who had a primary pulmonary artery sarcoma. With rare exceptions
[38,39], the lung scan in small-vessel pulmonary vascular disease will
appear normal or demonstrate peripheral mottling. This appearance is
in distinction to the unmatched segmental or larger perfusion deficits
observed in pulmonary vascular diseases that involve the more proximal
pulmonary vascular bed, the most notable example being large-vessel
chronic thromboembolic disease. This distinction becomes critical
because patients in the latter group warrant more definitive
diagnostic procedures, such as pulmonary angiography, to establish the
cause of their pulmonary hypertension.

Currently, imaging of the pulmonary vascular bed is best achieved
using pulmonary angiography. Because major-vessel chronic
thromboembolic pulmonary hypertension has been shown to be surgically
remediable, establishing this diagnosis in pulmonary hypertensive
patients exhibiting an abnormal V/Q scan result has become
increasingly relevant. It is important to recognize that the
angiographic patterns created by organized thrombi (webs, intimal
irregularities, vascular narrowing, or pouches) are distinct from the
intraluminal filling defects of acute thromboembolic disease or from
the distal hypovascularity (pruning) witnessed in small-vessel
pulmonary hypertension [40]. Although there are risks in performing
pulmonary angiography in pulmonary hypertensive patients, particularly
those who have elevated right ventricular end diastolic pressures
[41], the National Institutes of Health registry experience with PPH
patients [7] and University of California, San Diego, Medical Center's
experience with chronic thromboembolic patients [42] suggest that this
procedure can be performed safely by experienced angiographers taking
certain precautions.

In certain settings, other imaging modalities can prove valuable in
the evaluation of pulmonary hypertension and cor pulmonale. Because
there are competing diagnoses to account for some of the angiographic
patterns in chronic thromboembolic disease, pulmonary angioscopy has
proven beneficial not only in distinguishing between diagnostic
possibilities but also in establishing the proximal extent of
organized thromboembolic disease [43]. The major difficulty with this
diagnostic tool is its limited availability. As it pertains to imaging
the pulmonary vascular bed, the utility of magnetic resonance imaging
[44] and computed tomographic scanning [45] continues to evolve.
Computed tomographic imaging is particularly useful in defining
pathology in the hila, mediastinum, or lung parenchyma that could
account for or be contributing to a patient's pulmonary hypertension.

Therapy of pulmonary hypertension and cor pulmonale

General comments

Several recent reviews have discussed the therapeutic approach to
pulmonary hypertension complicating chronic lung disease [46-48].
Considerable discussion focuses on the effectiveness of long-term
oxygen therapy, noting that this treatment has been shown to improve
survival in COPD patients (Nocturnal Oxygen Therapy Trial) [49].
Although it is known that survival rates are adversely impacted when
pulmonary hypertension develops in this patient population, there is
no clear relationship between improved survival with supplemental
oxygen and an improvement in pulmonary hemodynamics. However, measures
directed at preventing hypoxemia in an effort to reduce hypoxia-driven
pulmonary vasoconstriction remain a logical therapeutic step [50].

Vasodilator therapy in this same patient population is without proven
efficacy as it relates to an improvement in functional status or
survival. Although a reduction in pulmonary vascular resistance can
result, the use of vasodilators in COPD may be complicated by
worsening hypoxemia, primarily as a result of altering adaptive V/Q
relationships. The role of more selective pulmonary vasodilators, such
as nitric oxide, remains an area of ongoing investigation. The
postulated benefit with its use is to augment perfusion in ventilated
lung regions, potentially achieving both a reduction in pulmonary
resistance and improvement in oxygenation. Continuous inhalation of
nitric oxide has been shown to reverse acute hypoxic vasoconstriction
in animals [51,52]. An experience in patients who have chronic lung
disease has also begun to unfold. In a case report, Channick et al.
[53] demonstrated the effectiveness of inhaled nitric oxide in a
patient with severe pulmonary fibrosis. In addition to a marked
reduction in pulmonary vascular resistance, there was a dramatic rise
in PO 2. Using low concentrations of nitric oxide (15 ppm) in 14
hypoxic COPD patients, Moinard et al. [54] were able to show prompt
improvement in pulmonary hemodynamics without provoking significant
changes in PO2. However, in some patients there was an increase in the
percentage of ventilation in poorly or unperfused areas consistent
with a known bronchodilatory effect of nitric oxide. Of interest was
the observation that in the four patients who were also exposed to
100% oxygen, the pulmonary hemodynamic response to inhaled nitric
oxide during the course of the study was comparably better. Despite
these preliminary observations, the appropriate application of inhaled
nitric oxide in chronic lung disease remains speculative. Currently,
outstanding issues related to chronic administration and potential
toxicity make its long-term use as yet impractical.

In cases in which the pathophysiologic basis for pulmonary vascular
involvement is clearly definable, specific therapies can be directed
to improve vascular resistance and right ventricle dysfunction. In the
absence of chronic lung disease, such therapeutic strategies can be
particularly beneficial. For example, if vessel inflammation is felt
to be a substantive contributor to an increase in pulmonary vascular
resistance (ie, collagen vascular disease, early stages of
interstitial lung disease, or Takayasu's arteritis), a trial of
corticosteroids is appropriate. The treatment of patients who have
chronic alveolar hypoventilation using assisted ventilatory devices or
of obstructive sleep apnea patients using nasal continuous positive
airway pressure can effectively prevent the hypoxemia and hypercarbia
responsible for augmenting pulmonary vascular resistance.

Chronic thromboembolic pulmonary hypertension

Major-vessel chronic thromboembolic pulmonary hypertension has been
increasingly recognized as potentially curable with pulmonary
thromboendarterectomy [55]. Based on available information, this form
of pulmonary hypertension is not as rare as once thought, and in fact,
it is likely more prevalent than PPH. The published results from Moser
et al. [18] have shown that marked improvement in pulmonary
hemodynamics and functional status can be achieved in the majority of
surgically treated patients. Consequently, establishing the diagnosis
and distinguishing this disorder from small-vessel pulmonary vascular
disease is essential in identifying pulmonary hypertensive patients
who may benefit from surgical intervention.

Primary pulmonary hypertension

The effectiveness of vasodilators has been most extensively examined
in patients who have PPH. Although a number of vasodilators have been
studied over the years [56,57] , the use of calcium channel
antagonists in this patient population has gained considerable
popularity. This class of drugs has been shown to produce significant
reductions in pulmonary vascular resistance in approximately 20% to
30% of patients; this relatively low percentage is likely a reflection
of the variable role pulmonary vasoconstriction plays in any given
patient. In 1992, Rich et al. [58] reported their experience with 64
PPH patients receiving high-dose calcium channel blockers. Seventeen
patients (26%) experienced a decline in pulmonary vascular resistance
of 20% or more, a positive response that was sustained for up to 5
years in all but one patient. In the patients who had a response, not
only were quality-of-life measures improved, but 5-year survival was
considerably higher (94% vs 38%) relative to patients who did not have
a response and to historical control subjects.

Throughout the past several years, the intravenous infusion of
prostacyclin has also shown promise as a therapeutic option for
patients who have PPH. The rationale for its use stems not only from
its vasodilating properties, but also from its ability to inhibit
platelet aggregation and smooth muscle proliferation. Though initially
used as a short-term measure to establish a vasoreactive component of
patients' elevated pulmonary pressures, clinical trials of long-term
infusions, even in patients who did not have a response initially,
have shown considerable promise in improving both the hemodynamics and
functional status of these patients [59,60] . In a study of 18
patients who had PPH (13 with New York Heart Association class III and
four with New York Heart Association class IV status), Barst et al.
[61] examined the effects of long-term continuous infusion of
prostacyclin, regularly incrementing doses to tolerance. Group
analysis revealed an overall improvement in exercise capacity, an
increase in cardiac index (18%) and reduction in pulmonary vascular
resistance (26%) at 6 months relative to baseline (a result sustained
at 12 months), and a significant improvement in survival relative to
that calculated from prediction equations. However, several
complications arose related to the administration of the drug,
including two deaths, seven episodes of nonfatal sepsis, and nine
episodes of thrombosis of the delivery system. Despite those problems,
this study again raises the issue of the appropriate role of
prostacyclin in the care of PPH patients. Once considered an option
for individuals in whom calcium channel antagonists failed, or as a
therapy to %cbridge%c a patient to transplantation, in selected
patients long-term infusion of prostacyclin may become a reasonable
alternative to transplantation.

Attention has also focused on the potential utility of inhaled nitric
oxide in patients who have PPH. Because it is a gas, a significant
advantage of this pulmonary vasodilator over prostacyclin is the
absence of a systemic vascular effect [62] . Pepke-Zaba et al. [63]
examined the effects of inhaled nitric oxide (40 ppm) in eight
pulmonary hypertensive patients, noting a decline in pulmonary
vascular resistance (5% to 68%) in all patients. In the same group, a
dose-dependent fall in pulmonary vascular resistance with infusion of
prostacyclin was also achieved in six of the eight patients. However,
a significant decline in systemic vascular resistance was observed
during the prostacyclin infusion, an effect not seen during nitric
oxide inhalation. Channick et al. [64] showed similar results in 16
PPH patients. If vasoresponsivity is defined as a greater than 20%
fall in mean pulmonary arterial pressure and a more than 30% reduction
in pulmonary vascular resistance, 31% of patients (five of 16)
administered 40 ppm nitric oxide showed a significant decline in
vascular resistance. In 11 of the 16 patients, a reduction in right
atrial pressure was also noted, implying an improvement in right
ventricular function. Prostacyclin infusion in these same individuals
resulted in four responses; with one exception, the same patients who
showed a response to nitric oxide also showed a response to
prostacyclin. As is the case with nitric oxide application in chronic
lung disease, the utility of this novel vasodilator in patients who
have primary pulmonary vascular disease is, at present, limited to
establishing a vasoresponsive element.

For PPH refractory to medical therapies, lung transplantation has
become a therapeutic option. Transplantation of a single lung in these
patients has become an alternative to transplantation of double lung
or heart-lung block. The satisfactory pulmonary hemodynamic outcomes
with this procedure have been noted [31,65]. Additional advantages to
this approach include the elimination of coronary occlusive disease
complicating heart-lung transplantation and the ability to expand
limited donor resources: a heart-lung block benefiting several
patients instead of one. Although experience continues to grow and the
data from individual transplantation centers will vary, recently
published information from the Registry of the International Society
for Heart and Lung Transplantation [66] reveals survival trends
favoring either double lung or single lung transplantation versus
heart-lung transplantation for PPH. One-year survival (approximately
70%) was comparable between double and single lung transplant
recipients; however, early survival (1 to 3 months) was better for
patients receiving bilateral lungs [66].

Acknowledgment

I would like to thank Maureen Faraguna for her tireless efforts in the
preparation of this manuscript.

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COPD-chronic obstructive pulmonary disease; PPH-primary pulmonary
hypertension; V/Q-ventilation-perfusion.

[Figure 1]

Fig. 1. The various mechanism responsible for control of pulmonary
vascular tone. ACh-acetylcholine; ANP-atrial natriuretic peptid;
EDHF-endothlium-derived hyperpolarizing factor; PGI2-prostacyclin;
PI-phosphoinositide; PKC-protein kinase C; SNP-sodium nitroprussode
(Modified from Peacock [1].)

[Figure 2a]

Fig. 2. Measures of arterial and venous plasma immunoreactive
endothelin-1 (irET) in control subjects (panel A ) and in patients who
have secondary (panel B ) and primary (panel C ) pulmonary
hypertension. Dashed linesrepresent normal range, mean +or- 2 SD.
CAD-coronary artery disease; CHD-congenital heart disease;
CVD-collagen vascular disease; LD-lung disease; PTE-pulmonary
thromboembolic disease; VHD-valvular heart disease. (FromStewart et
al. [21]; with permission.)

[Figure 2b]

Fig. 2. Measures of arterial and venous plasma immunoreactive
endothelin-1 (irET) in control subjects (panel A ) and in patients who
have secondary (panel B ) and primary (panel C ) pulmonary
hypertension. Dashed linesrepresent normal range, mean +or- 2 SD.
CAD-coronary artery disease; CHD-congenital heart disease;
CVD-collagen vascular disease; LD-lung disease; PTE-pulmonary
thromboembolic disease; VHD-valvular heart disease. (FromStewart et
al. [21]; with permission.)

[Figure 2c]

Fig. 2. Measures of arterial and venous plasma immunoreactive
endothelin-1 (irET) in control subjects (panel A ) and in patients who
have secondary (panel B ) and primary (panel C ) pulmonary
hypertension. Dashed linesrepresent normal range, mean +or- 2 SD.
CAD-coronary artery disease; CHD-congenital heart disease;
CVD-collagen vascular disease; LD-lung disease; PTE-pulmonary
thromboembolic disease; VHD-valvular heart disease. (FromStewart et
al. [21]; with permission.)

[Figure 3]

Fig. 3. Ratio of urinary 11-dehydrothromboxane B2 (stable metabolic of
thromboxane A2) to 2,3-dinor-6-keto-prostaglandin F1 alpha
(prostacyclin metabolite) in patients who have primary pulmonary
hypertension (PPH), who have chronic obstructive pulmonary disease
(COPD), and in normal control subjects T bars represent group means
+or- SE. (From Christman et al. [23]; with permission.)

Copyright 1995 by Current Science.

I would like to know too.  I don't know if there is a correlation between
hypertension and HIV but my guess is that may be drugs might have something
to do with it.  I have hypertension that is regularly 150/90.  Many times
the systolic is no more than 120 but the diastolic seems to remain high.  I
take 100mg Atenelol, have been taking for about twenty years and I'm
starting to find these readings alarming.  I've asked my doctors about the
diastolic pressure and they always tell me that they're more concerned about
the systolic.  I'd like to know what the high diastolic readings mean.
Anyone?

Doug