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Systemic Arterial Hypertension

Hypertension is a hemodynamic derangement. The elevated blood pressure in systemic arterial hypertension may be associated with an increased cardiac output or vascular resistance (the hallmark of the disease).

Classification of the various forms of hypertension based on causes are shown in table 2.

Reference:.Froblich,E.D.MD,Hurst's The Heart.Pathophysiology of Systemic Arterial Hyper tension,pp1391-1401.


The major hemodynamic alteration in hypertension is an increased vascular resistance, which is achieved through an active increase in the state of tone of vascular smooth muscle in both arterioles and the venules.

This state of vessel tone can be achieved whether the myocyte is stimulated by enhanced adrenergic input (elevated circulating levels) of humoral agents (e.g. catecholamines, angiotensin II, vasopressin, serotonin), local vasoactive peptides (e.g.angiotensin II, vasoactive intestinal polypeptide, endothelium), or ions (e.g. calcium); by reduced amount of vasoconstrictors; or by an increase in vasodilating agents (acetylcholine, adenosine, prostaglandins), local vasoactive peptide (e.g. insulin, calcitonin gene-related peptide), or ions (e.g. potassium, magnesium, Krebs intermediate metabolites).

Whatever the myocyte stimulus, there is an increased availability of calcium ions for the mechanical coupling that permits the enhanced state of contractility of vascular smooth muscle. Also, an increased wall to lumen diameter of the arterial and arteriolar wall, serves to augment vascular responsiveness to constrictive stimuli and perpetuates the hypertension.

Fluid Volume Partitions

The intravascular (plasma) volume contracts in patients with essential hypertension and is associated with a greater degree of interstitial fluid. If a the blood pressure is lowered by a vasodilator drug, the capillary hydrostatic and renal arterial perfusion pressure would diminish, causing the interstitial fluid to migrate intravascularly to expand the intravascular space and reducing the effectiveness of the antihypertensive agent. But with the addition of a diuretic, intravascular volume would again contract, thereby restoring the anthypertensie effect.

Recently, the angiotensin converting enzyme and the calcium channel inhibitor therapies have prevented the expanded intravascular volume and pseudotolerance has been of less concern.

Reference:.Froblich,E.D.MD,Hurst's The Heart.Pathophysiology of Systemic Arterial Hyper tension,pp1391-1401.


Epidemiologic studies have demonstrated a high direct correlation between dietary sodium intake of populations and the prevalence of hypertension. The reduction in sodium intake to levels below the current recommendation of 100 mmol per day and the dietary approaches to stop hypertension diet (DASH) both lower blood pressure substantially with greater effects in combination than singly.

Reference:Sacks,F.,and Others:Effects on blood pressure of reduced dietary sodium and theDASH diet,N England J Med Vol.344,No.I, Jan.4,2001,pp3-9 ;
Reference:.Froblich,E.D.MD,Hurst's The Heart.Pathophysiology of Systemic Arterial Hyper tension,pp1391-1401.

Complications of Hypertensive Disease

a. Left ventricular hypertrophy.

The left ventricle increases its mass and wall thickness progressively as a result of the progressive overload and increased left ventricular wall stress imposed by the increasing arterial pressure and total peripheral resistance. Ultimately a stable state is reached and subsequently diastolic dysfunction occurs, associated with a fourth heart sound, atrial enlargement, and reduced left ventricular distention.

Ultimately left ventricular systolic function is impaired and cardiac failure occurs, if arterial pressure and ventricular afterload are not reduced.

The best means of preventing of preventing morbidity and mortality is to prevent left ventricular hypertrophy, using early and continuous antihypertensive therapy.

b. Myocardial ischemia and infarction.

Both of these complications may occur due to increased LV pressure and LV chamber diameter leading to increased oxygen demand in pure LV hypertensive heart disease. Also, hypertension acclerates the onset of coronary atherosclerosis.

c. Aortic dissection (to see the entire photographs of figures below click on the tumbnails: 50, 51b, 51c, 51d, 51e, 51f, 51g, 51h, 51i, 51j, 51k).

Figure 50

Figure 51b

Figure 51c

Figure 51d

Figure 51e

Figure 51f

Figure 51g

Figure 51 h
Figure 51i

Figure 51j

Figure 51k

Currently, the prevalence of this complication has diminished due to the use of antihypertensive therapy (especially beta blocking agents).

A recent study suggest that frequent follow-up monitoring of patients having aortic intramural hematomas of the ascending aorta (AIH) in the intensive care unit with CT, transesophageal echocardiography, and MRI (figures above 51h, 51i, 51j, 51k) along with aggressive medical treatment of their hypertension can be an option to allow timed surgical repair, or prevent progression to dissection and rupture and improve prognosis.

Fig.51i. Serial X-ray computed tomograms (CT) in a patient with proximal aortic intramural hematoma (case no. 18). Initial CT (July 12, 1999) showed characteristic crescentic wall thickening in both the ascending and descending aorta with a large amount of pericardial effusion. After emergent percutaneous pericardiocentesis, medical treatment was chosen by the patient, and CT (July 15, 1999) revealed development of pleural effusion. The patient's condition stabilized rapidly, although the amount of pleural effusion increased (July 29, 1999). One month after the event, complete normalization of the aorta with resorption of pleural effusion was observed (August 9, 1999).

Fig51j. One example of the development of typical aortic dissection in a patient with proximal aortic intramural hematnma (case no. 2). Initially, computed tomography showed dramatic decrease of aortic wall thickening with progressive enlargement of the lumen of the ascending aorta (October 31 and November 12). About two months after the event, she complained of chest pain again and follow-up study revealed development of typical aortic dissection

One predictive factor seems to be the size of the ascending aorta at the first examination. It has been shown that patients with an aortic diameter of less than 5cms. had regression of the hematoma during medical therapy, whereas those with a larger diameter had a tendency to progression to dissection or rupture.

Also, the prognosis of very old patients is acceptable under medical therapy because of severe atherosclerosis apparently limiting the expansion of hemorrhage under blood pressure control.

For patients with AIH, emergent surgery has been the standard practice. But with close monitoring conditions on an intensive unit, treatment strategies may be individualized. Symptomatic patients and those with progression during follow-up and a large ascending aorta should undergo emergent surgery. But other patients whose condition can be stabilized with antihypertensive therapy as well as very old patients may be treated medically with good long-term results.

Reference:Song,J-K,MD,and others,Different Clinical Features of Aortic Intramural Hematoma Versus Dissection Involving the Ascending Aorta,JACC,Vol.37,No.6,2001,1603-1610.

Reference:Mohr-Kahaly,MD,Aortic Intramural Hematoma:From Observation to Therapeutic Strategies,JACC,Vol.37,No.6,2001,1611-1613.

d. Malignant and accelerated hypertension.
This form of hypertension is less common due to the widespread use of antihypertension therapy. It represents a sudden accleration in the vascular disease associated with essential hypertension and if untreated results in over 97 per cent of involved patients dying within one year.

It is associated with necrotizing arteriolitis and severe arteriolar spasm,and reduced blood flow especially to the kidneys, provoking a state of secondary hyperaldosteronism. Vigorous antihypertensive treatment will reverse this positive feedback mechanism.

e. End stage renal disease and nephrosclerosis.
More frequently, essential hypertension is associated with renal arteriolar thickening, fibrinoid deposition in glomeruli, and proteinuria, which follow the development of left ventricular hypertrophy.

f. Parenchymal renal disease.

Hypertension is a frequent complication of most renal diseases, whether glomerulonephritis, polycystic renal disease or others. This type of hypertension should be considered in any case of hypertension with anemia of undetermined cause, particularly if that patient is black.

g. Strokes
Strokes have been dramatically reduced with antihypertenaive therapy, whether hemorrhagic or thrombic, and there has been at least a 50% reduction in fatal strokes.

Reference:.Froblich,E.D.MD,Hurst's The Heart.Pathophysiology of Systemic Arterial Hyper tension,pp1391-1401.

How Blood Pressure Is Measured

Blood Pressure is measured by means of a stethoscope and an inflatable cuff (figure 122b) that compresses the arm until the brachial artery is squeezed shut. Intially the artery walls will be closed and no sounds will be heard through the stethoscope. As air is released from the cuff a thump will be heard. This is the moment when the systolic blood pressure-i.e. the first and higher of the of the two numbers of a person's blood pressure-is recorded. As the cuff pressure continues to drop below the level of the systolic pressure, the artery will begin to open and close, and a rhythmic thumping noise will be audible. When the sound becomes muffled and faint, the diastolic pressure is recorded. As the cuff pressure declines below the diastolic pressure in the artery, the vessel remains open and the sounds disappear completely (figure 122a).

The cuff size must match the patient's arm, meaning a big arm requires a bigger cuff, and a smaller one needs a smaller cuff.

Also, the patient should be sitting or lying with the arm at the level of the heart while the reading is obtained.

The patient should be relaxed. Finally caffeine, nicotine and exercise should be avoided prior to taking the blood pressure. If the reading is high, it should be repeated after 2 to 3 minutes of relaxation and rest or later at another appointment. Also, a 24 hour ambulatory monitor can be done to check the pressure around the clock (figure 123e).

Reference:Harvard Men's Health Watch,Feb.2001,pp.1-4

Current standards

There is no single normal blood pressure; instead blood pressure readings span a spectrum that ranges from ideal at the low end to acceptable in the middle and abnormally high at the top. Interpretations for adults 18 years of age and older are in figure 123a.

Isolated systolic hypertension

Isolated systolic hypertension with a normal diastolic reading is the most common form of hypertension in people 65 and older and its prevalence increases steadidly with age (figure 123b, 123c). In a recent study of 15,693 people age 60 years old or above and with systolic blood pressures of 160 or more and diastolic pressures of 95 or less, without treatment each 10 mmHg rise in systolic blood pressure increased the risk of stroke by 26%, with strokes accounting for much of the excess mortality.

Drug treatment reduced the risk of stroke by 30%,the risk of heart attacks by 23%, and the risk of death by 13%.

Reference:Harvard Men's Health Watch,Feb.2001,pp.1-4

High-Normal Blood Pressure

A recent study found that high-normal blood pressure (systolic pressure of 130 to 139 mm Hg, diastolic pressure of 85 to 89 mm Hg, or both) is associated with an increased risk of cardiovascular disease, emphasizing the need to determine whether lowering such pressures can reduce this risk.

Vasan,R.S. and others,Impact of high normal blood pressure on the risk of cardiovascular disease,N Engl J Med 2001;345:1291-7.,N Engl


Treatment involves two elements, life style modification and drug therapy. Diet should be low in sodium and saturated fat but high in fruits, vegetables, whole grain, and nonfat dairy products. Exercise, weight and stress control, and limiting alcohol to no more than two drinks a day are important.

If these measures don't bring blood pressure down or if there is organ damage or risk factors, then antihypertensive drug therapy is necessary (figure 123d).

Most authorities suggest a diuretic first (table 6), then adding a beta blocker (table 7) particularly for older patients and those with isolated systolic hypertension. Patients with diabetes or congestive heart failure may get better results from angiotensin converting enyzme (ACE) inhibitors (table 9), and with angina may benefit fron calcium channel blockers (table 8).

The alpha1-adrenergic blocking agents (table 10) can be used as monotherary or in combination with other existing progams. They are particularly effective in managing hypertension associated with pheochromocytoma.

There are also alpha2-adrenoreceptor agonists (aldomet, which is the preferred drug with hypertension and ecclampsia; catapres, wytensin, tenex) prescribed as step 2 drugs due to side effects), neuroeffector adrenergic blocking drugs (hylorel, ismelin, and reserpine, which is the least expensive, effective, well tolerated) and direct vasodilators (hydralazine).

loniten reserved for multidrug resistant hypertension; both usually prescribed with a beta-blocker to prevent tachycardia and a diuretic to prevent edema).

Reference:Harvard Men's Health Watch,Feb.2001,pp.1-4

Giffford,R.Jr.,Hurst's The Heart,8th Edition,Treatment of Patients with Systemic Arterial Hypretension.pp1427-1448

Diagnostic Evaluation of the Patient with Systemic Arterial Hypertension

Mild to Moderate Hypertension

The clinician should inquire in the patient's history about the existence of symptoms such as those listed in table 3 , and perform the evaluation procedures and diagnostic tests summarized in table 4.

One should look for clues to reversible causes of the hypertension such as coarctation of the aorta including diminished leg pulses, delay in the femoral pulse, reduced leg blood pressure, a coarse systolic murmur at the left sternal border or rib notching on the chest x-ray (figures 23a, 23b).

Acromegaly, thyroid diseases, Cushing's syndrome and alcoholism should be suspected from the history and general appearance of the patient.

In the evaluation a search for target organ damage and cardiovascular risk factors should be made to include listening for bruits over the carotid,renal and femoral arteries.

The EKG must be inspected for evidence of ischemia, and the cholesterol and other tests recommended in table 4 should be performed.

It is important to examine for congestive heart failure by looking for LVH, rales, ventricular gallop (heart sounds like a gallop), distended neck veins, edema (swollen feet ankles, legs) amongst other signs.

Severe, Accelerated or Malignant Hypertension

Diagnostic criteria for malignant hypertension include a diastolic blood pressure of 125mmHg or more, in conjunction with target organ damage (retinal hemorrhages, papilla edema, heart failure, encephalopathy, and renal insufficiency) and physiologic abnormalities (impaired renal perfusion, elevated plasma renin andaldosterone levels, increased sympathetic tone).

Renal arteriography may be necessary to diagnose renal artery stenosis.Also,a plasma catecholamine level is indicated as well to rule out pheochromcytoma.

Athlete with Hypertension

Marfan's sydrome with aortic regurgitation and hypertrophic cardiomyopathy (figures 39, 39b, 39f) must be considered.

Echocardiography should be considered in athletes with abnormal EKG's suggesting LVH with abnormal ST- and T- wave changes (echocardiographic septal or posterior LV wall thickness of 13mm or more are uncommon in atheletes with physiologic LVH).


Hypertensive Retinopathy

Advanced retinopathy is associated with a poor prognosis.

Hypertensive Cardiovascular Disease

Two major forms of heart disease occur in patients with hypertension:
coronary heart disease (discussed elsewhere on this website) and hypertensive heart disease. The criteria for hypertensive heart disease include the presence of hypertension plus LVH when other causes are excluded.These patients may be susceptible to myocardial ischemia without evidence of coronary disease.

The EKG is one of the tests used to detect LVH (table 5).

EKG evidence of left atrial abnormality often precedes the LV abnormality:
terminal negative atrial forces in V1 above 0.04mm-s, bipeak interval > 0.04s in deeply notched P waves in any lead,ratio of P wave duration to PR interval exceeding 1.6 in leadII,and P wave above 0.3mv height or above 0.12 duration in leadII.

Echocardiographic evidence of LVH (assessing IVS thickness,LV posterior wall and free wall thickness) occurs in 30-40% of hypertensive patients whose EKG and chest appear normal. Thus, the echocardiogram is an early and sensitive indicator of LVH in patients with hypertension.

Hypertensive Cerebrovascular Disease

Cerebrovascular Accidents

Hypertension is the most important risk factor for the development of hemorrhagic or atheroembolic stroke. Microhemorrhage or occlusion of small vessels can result in small areas of infarction (lacunar infarcts), which are associated with neurologic deficits that clear over days to weeks. Multiple lacunas can lead to to multi-infarct dementia. The differentiation between a transient ischemic attack (TIA) and a small lacunar infarct may be difficult but MRI may be able diagnose these lacunas.

Evanescent neurologic symptoms or findings in conjunction with a carotid artery bruit justify carotid duplex Doppler scan and/or angiography in an operable patient.

Hypertensive Encephalopathy

Hypertensive encephalopahy is characterized by acute to subacute changes in neurologic status that occur as a result of elevated arterial pressure (especially malignant hypertension) and are reversed by lowering of the blood pressure with effective antihypertensive therapy within 12 to 72 hours. The CT scan and MRI can help diagnose focal areas of intracerebral hemorrhage or infarction.

Hypertensive Nephrosclerosis

Benign Nephrosclerosis

Malignant Nephrosclerosis


Renovascular Hypertension Prevalence

Renal artery stenosis is the most common curable of hypertension, but probably occurs in 3% or less of hypertensive patients. Below the age of 40, renovascular hyprtension is more frequent in women than men and is less common in the black patients with hyprtension.

Clinical findings

Abdomiminal bruits and severe hypertensive retinopathy are clues to renovascular disease.

Pathological Types of Renal Artery Stenosis

Fibrous dysplasia and atherosclerosis of the renal arteries account for almost all cases of renovascular hypertension.

1. Fibrous Dysplasia

With fibrous dysplasia , hypertension generallly presents before age 35, most often in women. It is usually unilateral when initially diagnosed. In 60% of cases there is an upper abdominal bruit (figure 140 ).

Reference:Safian.R.and others.RENAL ARTERY STENOSIS,N.Engl.J.Med.Vol.344,No.6,Feb.8,2001.pp431-442 ).

2. Atherosclerotic Renovascular Disease

It accounts for two-thirds or more of the patients with renovascular hypertension, occurring predominantly in men over 45 years (figure 140 ). At least two-thirds have bilateral lesions (Progressive atherosclerosis, renal artery stenosis and ischemic nephropathy, figure 141)

Reference:Safian.R.and others.RENAL ARTERY STENOSIS,N.Engl.J.Med.Vol.344,No.6,Feb.8,2001.pp431-442 ).

Diagnostic Tests are not indicated in patients with advanced renal failure and bilateral small kidneys.

Reference:Hall,W.D.,AND OTHERS, Diagnostic Evaluation of the Patient with Systemic Arterial Hypertension,HURST'S 8TH Edition,The Heart,pp.1403-1425.

(Figure126, Reference:Safian.R.and others.RENAL ARTERY STENOSIS,N.Engl.J.Med.Vol.344,No.6,Feb.8,2001.pp431-4420 )

Digital subtraction Angiography or Aortography

When the clinical suspicion is high, it is usually more expedient to proceed directly to arterial DSA or arterigraphy.

Reference:Safian.R.and others.RENAL ARTERY STENOSIS,N.Engl.J.Med.Vol.344,No.6,Feb.8,2001.pp431-442 ).
Reference:Hall,W.D.,AND OTHERS, Diagnostic Evaluation of the Patient with Systemic Arterial Hypertension,HURST'S 8TH Edition,The Heart,pp.1403-1425.

Renal vein Renin Ratio (table2a, Noninvasive Assessment of Renal-Artey Stenosis)

Once the presence of renal arterial disease has been established, the functional significance of the stenosis can be evaluated to help determine if the renal artery lesion is the cause of the hypertension, by measuring the renal vein renin ratio.A renal vein ratio of 1.5 or greater favoring the stenotic side is indicative of a functional significant renal artery lesion.

The renal vein renin ratio is frequently not reliable for predicting surgical response in patients with bilateral renovascular disease (figure 142 )

Reference:Safian.R.and others.RENAL ARTERY STENOSIS,N.Engl.J.Med.Vol.344,No.6,Feb.8,2001.pp431-442 .

Reference:Hall,W.D.,AND OTHERS, Diagnostic Evaluation of the Patient with Systemic Arterial Hypertension,HURST'S 8TH Edition,The Heart,pp.1403-1425.

Captopril Renography

Isotope renography detects the acute reductions of glomerular filtration rate(GFR) following the administration of captopril to patients with functionally significant renal artery stenosis and is often an effective screening procedure for renovascular hypertension. Isotope renography using 99m Tc-DPTA (reflecting largely glomerular filtration rate) is performed immediately before and 60 to 90 min. after the administration of a single 2.5-mg dose of captopril. Following converting enzyme inhibition,both the uptake and excretion of DPTA on the stenotic side are usually decreased from baseline in patients with unilateral renal arterial disease, whereas no consistent decrease is observed in the contralateral uninvolved kidney (figure 124a).

Reference:Goto,A. and others,Captopril-Augmented Renal Scan,N.Engi.J.Med.Vol.344,No.6,Feb.8,2001,p430).

This acute reduction in filtration rate that occurs in the stenotic kidney following converting enzyme inhibition may be due to interruption of angiotensin II-mediated vasoconstriction of the postglomerular efferernt arteriole.

Reference:Hall,W.D.,AND OTHERS, Diagnostic Evaluation of the Patient with Systemic Arterial Hypertension,HURST'S 8TH Edition,The Heart,pp.1403-1425.


Atherosclerotic renal-artery stenosis is a common sign of generalized atherosclerosis (figure 142 ) and is frequently associated with hypertension and excretory dysfunction (figure 141). But the association of renal-artery stenosis with hypertension or renal insufficiency does not establish causation, and although the methods for the diagnosis and treatment of renal insufficiency have improved, the use of invasive diagnostic techniques and treatment early in the course of the disease still has no proven benefit.

Further, there seems to be a shift away from identifying patients with renovascular hyprtension, because of the known benefits of medical therapy and lack of sustained cure after percutaneous or surgical revascularization, and a shift toward identifying patients with renal artery stenosis who are at risk for excretory dysfunction.

Because of this shift, medical therapy and modification of risk factors to limit atherosclerosis are essential in all patients, regardless of whether they have undergone revascularization.

In patients with atherosclerotic renal-artery stenosis who are at risk for excretory dysfunction, percutaneous and surgical techniques may improve or stabilize renal function. The long term results are better in patients who have better renal function at base line, suggesting that deferring revascularization until renal function deteriorates may not be the best approach.

Reference:Safian.R.and others.RENAL ARTERY STENOSIS,N.Engl.J.Med.Vol.344,No.6,Feb.8,2001.pp431-442

Doppler ultrasonography can determine the resistance to flow in the segmental arteries of both kidneys ( high level of resistance indicated by resistance-index values of at least 80) , the values for which can be used to predict patients whose renal function or blood pressure will improve after the correction of renal -artery stenosis. A renal resistance index value of at least 80 reliably identifies patients with renal-artery stenosis in whom angioplasty or surgery will not improve renal function, blood pressure, or kidney survival.

Reference:Radermacher,J. and Others, Use of Doppler Ultrasonography

To Predict The Outcome Ofe used to predict patients whose renal function or blood pressure will improve after the correction of renal-artery stenosis. A renal resistance index value of at least 80 reliably identifies patients with renal-artery stenosis in whom angioplasty or surgery will not improve renal function, blood pressure, or kidney survival.

Reference:Radermacher,J. and Others, Use of Doppler Ultrasonography To Predict The Outcome Of Therapy For Renal-Artery Stenosis,N.Engl. J.Med .2001;344:410-7



PRIMARY pulmonary hypertension predominantly affects women, frequently in the prime of life, and usually leads to death from right ventricular failure within a few years after diagnosis. It is a vascular disease but is oddly confined to the small pulmonary arterioles, where intimal fibrosis and medial hypertrophy lead sequentially to vascular obstruction, elevated pulmonary vascular resistance, pulmonary hypertension, and right ventricular overload. Coagulation at the endothelial surface contributes to obstruction, and thromboembolism may occur as a secondary event. The right ventricle compensates through hypertrophy, and although it can sustain function at high pressures for months to years, decompensation is ultimately manifested in reduced cardiac output and the development of peripheral edema. Many conditions and diseases lead to similar pulmonary vascular lesions and clinical outcomes, including the scleroderma spectrum of diseases, human immunodeficiency virus infection, liver disease, and the use of certain anorectic drugs.These illnesses, along with primary pulmonary hypertension, are now classified as types of pulmonary arterial hypertension.
Primary pulmonary hypertension first came under coordinated scientific scrutiny when the National Institutes of Health created the national Primary Pulmonary Hypertension Patient Registry in 1982, at a time when there was increasing optimism about a role for vasodilator therapy. Although there had been multiple previous reports of benefit from beta-agonists, alpha-blockers, and hydralazine, these responses were usually not sustained, and the relevant studies were not appropriately powered to detect true effects. The discovery that calcium-channel blockers could cause a sustained reduction in pulmonary vascular resistance in about 20 to 25 percent of previously untreated patients led to aggressive approaches to short-term vasodilator testing and long-term vasodilator therapy. Although not every patient with acute vasodilatation has a durable response to therapy, this feature carries a favorable prognosis, and many such patients are treated with calcium-channel blockers alone. It has not been proved that vasoconstriction is a pathogenetic mechanism of primary pulmonary hypertension, but this possibility seems logical and deserves continued study.
What can be done for the 75 percent of patients who do not have a response to short-term vasodilator therapy? The discovery that intravenous epoprostenol (prostacyclin) improved functional capacity, not only in patients with a response to calcium-channel blockers but also in those without a response, was followed by evidence that it also improves survival among both types of patients.This finding has led to widespread use of continuous intravenous epoprostenol therapy in all patients without a response to calcium-channel blockers and in most patients with New York Heart Association class IV heart failure. Beyond the activity of epoprostenol as a potent vasodilator, its mechanisms of benefit are unclear, but they may indude a positive inotropic effect, a small degree of systemic vasodilatation, and antiplatelet effects, which theoretically could reverse vascular damage.
Epoprostenol therapy by continuous infusion through a central catheter is expensive - about $60,000 per year - as well as technically demanding, and it has undesirable side effects. It is widely recognized that simpler effective therapies are needed. Prostacyclin analogues given by continuous subcutaneous infusion, orally, or by intermittent aerosol are under development as alternatives to the intravenous route. Subcutaneous treprostinil was recently approved by the Food and Drug Administration for further clinical trials. The prostacyclins act through an increase in the level of the second messenger, intracellular cyclic AMP (cAMP). Other vasodilators, including inhaled nitric oxide and oral sildenafil, act by means of cyclic guanosine monophosphate (cGMP). Sildenafil increases the cGMP level by inhibiting phosphodiesterase type 5, an enzyme that hydrolyzes cGMP. Clinical studies are needed to test for potential additive effects of simultaneous increases in cGMP and cAMP by combining the two classes of drugs. Safe generation of nitric oxide in vivo might be attained with the use of oral arginine or citrulline, substrates for the generation of nitric oxide, with resultant cGMP levels sustained by concomitant oral sildenafil.
Endothelin-1 is a potent endogenous peptide mediator that has a role in pulmonary arterial hypertension. It is unclear whether it has a primary pathogenetic role or whether it is a secondary mediator that perpetuates disease. Plasma endothelin levels are increased in patients with primary pulmonary hypertension, and endothelin is released in increased amounts in the blood traversing the lung. Endothelin is released by endotheial cells as big endothelin, which is cleaved to pro-endothelin, which, in turn, is converted to endothelin-1 (in systemic and lung vessels) or endothelin-2 (in kidney and gut). Endothelin-1 acts on two receptors - endothein-A receptors and endothein-B receptors. Activation of endothelin-B receptors causes the production of nitric oxide and vasodilatation, and activation of endothelin-A receptors results in vasoconstriction and smooth-muscle growth. The ideal endothein-receptor antagonist is likely to be specific for endothelin-A.
A study using bosentan, a nonspecific endothelin receptor antagonist, to treat pulmonary hypertension is reported in this issue of the Journal. Bosentan had small but measurable beneficial effects in a double-blind, placebo-controlled trial involving 213 patients. The duration of this trial was 16 weeks, which is not sufficient to test for a difference in mortality, but its results suggest that endothelin-receptor blockade has a therapeutic role in some patients with pulmonary arterial hypertension. The effect of bosentan appeared to be limited in most patients, and there was an unacceptable incidence of abnormal hepatic function at the higher dose. Because short-term vasodilator testing was not performed as part of the study, it is not known whether the patients with the best response to the drug were the same patients who might have had a response to other vasodilators. One cannot conclude from this study that bosentan should be the primary drug for the treatment of primary pulmonary hypertension or of other causes of pulmonary arterial hypertension. Follow-up studies are needed to determine the durability of the effect, whether there are differences in survival, what types of complications occur, and whether subgroups of patients have different responses to the drug. It would be useful to measure endothelin levels and to determine whether there are correlations between these levels and clinical effects. Studies should be designed to test whether combining endothelin-receptor antagonists with either inhibitors of phosphodiesterase type 5 or inducers of cAMP results in greater functional improvement than does either class of drug alone.
No current therapies appear to affect the pathogenesis of pulmonary vascular obstructive disease directly. In rare cases, patients receiving epoprostenol have had such dramatic responses that the dose has been reduced, and cessation of drug therapy has been attempted in a few patients, although the outcomes have not been published. The recent discovery that the transforming growth factor beta(TGF-beta) superfamily of receptors is involved in the pathogenesis of pulmonary hypertension should lead over the course of the next several years to specific therapies aimed at the origin of the disease. The evidence suggesting the involvement of TGF-beta receptors is compelling. About half of studied patients with familial primary pulmonary hypertension have mutations in exons of the bone morphogenetic protein receptor II gene (BMPR2), and the majority of others have genetic linkage to areas of chromosome 2 near BMPR2, perhaps in a promoter or upstream regulator or perhaps in intronic DNA. In addition, about 25 percent of patients with sporadic primary pulmonary hypertension have been found to have mutations in BMPR2. Mutations in the gene for activin-receptor-like kinase 1 (ALK1), another receptor in the TGF-beta family, are responsible for pulmonary hypertension in at least some patients with hereditary hemorrhagic telangiectasia. Clusters of endotheial cells carrying somatic TGF-beta 2-receptor mutations are found in plexiform lesions in the pulmonary arterioles of patients with sporadic primary pulmonary hypertension. Studies of these receptor abnormalities in transfected cells, cell cultures from patients' tissues, and transgenic mice are under way, and insights into the relevant mechanisms will certainly emerge during the next several years. Other promising areas of research are potassium-channel function and drugs that interrupt the cycle of growth and repair in diseased pulmonary vessels.
Therapy for primary pulmonary hypertension has progressed from calcium-channel blockers to prostacydin and now includes adjunctive therapy with bosentan and, in some patients, sildenafil. Combination therapies should be tested in the next generation of studies. It now seems conceivable that the continuous intravenous administration of epoprostenol through a central catheter will soon be history. A better understanding of pathogenesis is at hand because the genes associated with many cases of primary pulmonary hypertension have been identified, but the development of therapies based on this knowledge awaits further insights.


Vanderbilt University School of Medicine
Nashville, TN 37232

Newman,J.H.,N Engl Med,Vol.346,No.12,March21,2002 Pp.933-935.