Group 2 Pulmonary Hypertension 

Updated: Jul 30, 2021
Author: Nikhil Barot, MD, MS; Chief Editor: Zab Mosenifar, MD, FACP, FCCP 

Overview

Background

Pulmonary hypertension (PH) is divided into five distinct groups, which are categorized according to similar pathophysiologic changes, clinical presentation, and available therapies. Pulmonary hypertension due to left-sided heart disease (PH-LHD), classified by the World Health Organization (WHO) into group 2 pulmonary hypertension, is the most common cause of pulmonary hypertension and is associated with impaired exercise capacity and reduced survival.[1] It is defined by a mean pulmonary arterial pressure (mPAP) greater than 20 mm Hg and pulmonary capillary wedge pressure (PCWP) greater than 15 mm Hg.[2]

PH-LHD is further categorized by the underlying etiology, including due to systolic dysfunction, diastolic dysfunction, valvular defects, congenital or acquired left-sided heart inflow/outflow tract obstruction, and congenital cardiomyopathies. The pathophysiology is complex and features both a passive and an active mechanism of changes to the pulmonary vasculature.

Pathophysiology

Pulmonary hypertension due to left-sided heart disease (PH-LHD) results from pulmonary venous stretching due to elevated upstream left-sided heart filling pressures. As a result, the right ventricular systolic pressure increases in order to maintain adequate cardiac output.

The term isolated postcapillary pulmonary hypertension (Ipc-PH, formerly called “passive”) is used to describe those patients whose pulmonary hypertension is merely due to passive pulmonary venous congestion.[3] A minority of PH-LHD patients subject to longstanding elevated left-sided heart filling pressures undergo structural and functional pathophysiologic changes in the precapillary vasculature, including remodeling and vasoconstriction resulting in mean pulmonary arterial pressure (mPAP) disproportionately elevated relative to the pulmonary capillary wedge pressure (PCWP). Such patients are described as having combined postcapillary and precapillary pulmonary hypertension (Cpc-PH, formerly called “reactive” or “out of proportion”).[4]

Unlike certain other causes of pulmonary hypertension, particularly WHO group I, which tends to demonstrate more intimal proliferation and plexiform lesions, the pulmonary vasculature of PH-LHD shows greater intimal fibrosis and myofibroblast proliferation.[5] Specifically, the precapillary vasculature of Cpc-PH patients has been noted to have increased capillary endothelial basement membrane thickness, which subsequently leads to narrowing of the pulmonary arteriolar lumen, further worsening pulmonary vascular resistance. Pressure elevation in the pulmonary vessels along with changes in the endothelium result in the release of growth factors that increase elastin production, causing smooth muscle hypertrophy and stiffening of the pulmonary vessel.[6]

Epidemiology

There are approximately 6.5 million people in Europe and 5 million people in the United States with heart failure.[7] About 60% of patients with heart failure with reduced ejection fraction (HFrEF) have been noted to have pulmonary hypertension at presentation. The prevalence of pulmonary hypertension due to diastolic dysfunction is not known.[8]

Prognosis

The development of pulmonary hypertension due to left-sided heart disease (PH-LHD) is associated with a poor prognosis, particularly in relation to patients with LHD without associated development of pulmonary hypertension. Patients with heart failure with reduced ejection fraction (HFrEF) and pulmonary hypertension have a higher mortality rate (28%) than those without pulmonary hypertension (17%) at 28 months.[9, 10] The prognosis for patients with pulmonary hypertension and heart failure with preserved ejection fraction (HFpEF) has not been well studied.

Since patients with combined postcapillary and precapillary pulmonary hypertension (Cpc-PH) have higher pulmonary pressures compared with isolated postcapillary pulmonary hypertension (Ipc-PH) patients, they generally have increased dyspnea, lower exercise tolerance, and shorter survival.[11]

Patient Education

Patients should be educated about the expected symptoms of pulmonary hypertension due to left-sided heart disease (PH-LHD) as well as the importance of strict medication and diet adherence in order to avoid worsening symptoms or hospitalization. Additionally, patients should be encouraged to monitor their weight and fluid intake at daily intervals.

 

Presentation

History

Symptoms of pulmonary hypertension due to left-sided heart disease (PH-LHD) can be nonspecific and progressive. The medical history can reveal a previous diagnosis of myocardial infarction, cardiomyopathy from systolic or diastolic dysfunction, congenital cardiomyopathies or inflow or outflow tract obstruction, systemic arterial hypertension, or pericarditis.

Symptoms include the following:

  • Dyspnea
  • Weakness
  • Fatigue
  • Syncope with exertion due to poor cardiac output response to increased activity
  • Lower extremity swelling from an increase in right-sided filling pressure
  • Hoarseness (Ortner syndrome) from compression of the recurrent laryngeal nerve by an enlarged pulmonary artery
  • Right upper quadrant pain or abdominal swelling from hepatic venous congestion

Physical Examination

Examination of patients with pulmonary hypertension due to left-sided heart disease (PH-LHD) may initially reveal findings consistent with left ventricular heart failure or valvular dysfunction. As the disease progresses, patients demonstrate signs of worsening right-sided heart dysfunction.

Physical examination findings consist of the following:

  • Pulmonary crackles in the presence of volume overload
  • S3 or S4 heart sounds
  • Increased S2 heart sound intensity with development of splitting of S2 sound from right ventricular failure
  • Right ventricular heave
  • Elevated jugular venous pulse from volume overload with prominent A wave
  • Hepatomegaly with hepatic vessel pulsations from hepatic venous congestion
  • Ascites in the presence of right-sided heart failure

Complications

Group 2 pulmonary hypertension is associated with a higher morbidity and mortality when compared with patients with left-sided heart disease alone. Long-term complications include the development of right ventricular failure.

Complications of pulmonary hypertension due to left-sided heart disease (PH-LHD) include the following:

  • Right ventricular failure
  • Ascites
  • Pleural effusion
  • Peripheral extremity edema
  • Hoarseness
  • Syncope
 

DDx

Diagnostic Considerations

In addition to primary lung diseases, other WHO groups of pulmonary hypertension should be considered as alternative or coincident diagnoses before attributing pulmonary hypertension solely to left-sided heart disease. These include, but are not limited to, the following:

  • Chronic thromboembolic pulmonary hypertension
  • Pulmonary arterial hypertension
  • High-output heart failure
  • Pulmonary veno-occlusive disease
 

Workup

Approach Considerations

Initial screening tests with two-dimensional transthoracic echocardiography revealing elevated pulmonary artery systolic pressure (PASP) and/or right ventricular dysfunction should prompt further diagnostic evaluation for underlying pulmonary hypertension.

Invasive testing with right-sided heart catheterization (RHC) is used to confirm the diagnosis of pulmonary hypertension. RHC is also useful for vasodilator testing.

As previously mentioned, a comprehensive workup for other pulmonary hypertension WHO groups 1, 3, 4, and 5 should be undertaken as this can influence the treatment options available.

Laboratory Studies

Baseline complete blood cell count, basic metabolic panel, and liver function tests should be obtained in all patients. Serologic evaluation for other etiologies of WHO groups 1, 3, 4, and 5 pulmonary hypertension should be obtained in order to identify concomitant etiologies. In patients with volume overload, obtaining a brain natriuretic peptide (BNP) level and troponin level can be helpful in establishing baseline values and as a means to monitor degree of chamber stretch and myocardial injury.

Electrocardiography

Electrocardiography findings in pulmonary hypertension are nonspecific but may suggest right ventricular disease. Signs of right ventricular hypertrophy include right axis deviation, incomplete and complete right bundle-branch block, and an R-wave-to-S-wave ratio greater than 1 in lead V1. Additionally, increased P-wave amplitude in lead II is indicative of right atrial enlargement.

Chest Radiography and Computed Tomography

Chest radiography in patients with pulmonary hypertension due to left-sided heart disease (PH-LHD) demonstrates enlarged central pulmonary arteries with or without oligemic lung fields depending on the patient’s underlying volume status (see image below). Signs of right atrial and ventricular dilation can include a diminished retrocardiac space and prominent right-sided heart border. Additionally, an enlarged cardiac silhouette with prominent left-sided heart border can found in group 2 pulmonary hypertension. In the setting of acute exacerbation, edema at the lung bases can be noted. Abnormalities found on chest radiographs can be followed up with computed tomography.

Chest radiograph of a patient with pulmonary hyper Chest radiograph of a patient with pulmonary hypertension due to left-sided heart disease from heart failure with reduced ejection fraction showing enlarged pulmonary arteries, mild pulmonary vascular congestion, and dilated right atrium and left atrium.

Echocardiography

Echocardiography is used to evaluate right ventricular systolic pressure (sometimes expressed as pulmonary artery systolic pressure, [PASP]), chamber size, right and left ventricular systolic and diastolic function, valvular function, and presence of pericardial effusion (see the image below). Doppler echocardiography can be used to estimate PASP using the tricuspid regurgitant jet velocity and right atrial pressure. The efficacy of measuring PASP depends on the ability to locate the tricuspid regurgitant jet. An important aspect to determining WHO group 2 pulmonary hypertension due to left-sided heart disease (PH-LHD) is the measurement of left atrial size in which a dilated left atrium is suggestive of chronic elevated left atrial pressures due to left-sided heart disease. In determining the underlying etiology of pulmonary hypertension, bubbles can be administered to detect intracardiac shunts. In the setting of right ventricular overload, systolic flattening of the intraventricular septum and thickening of the right ventricular free wall may be observed. As a result of chronic right ventricular overload, tricuspid regurgitation, right atrial dilatation, and hypokinesis of the right ventricular free wall may be present.

Transthoracic echocardiograph showing an apical fo Transthoracic echocardiograph showing an apical four-chamber view of the same patient with pulmonary hypertension due to heart failure with reduced ejection fraction. The right atrium and ventricle are notably dilated.

Right-Sided Heart Catheterization

Right-sided heart catheterization (RHC) is used to confirm the diagnosis of pulmonary hypertension and can be used to differentiate group 2 pulmonary hypertension from other underlying etiologies. Measurements obtained from RHC include pulmonary capillary wedge pressure (PCWP), mean pulmonary arterial pressure (mPAP), cardiac output (CO), pulmonary vascular resistance (PVR) reported in Wood units (WU), transpulmonary gradient (TPG), and diastolic pressure gradient (DPG).

TPG is the difference between the mPAP and the mean PCWP (mPCWP), with a normal value being less than 12 mm Hg. The Fifth World Symposium in pulmonary hypertension recommended using DPG, the difference between diastolic PAP and mPCWP, to differentiate isolated postcapillary pulmonary hypertension (Ipc-PH) from combined postcapillary and precapillary pulmonary hypertension (Cpc-PH).[4] The DPG is more specific in identifying pulmonary hypertension due to left-sided heart disease (PH-LHD) patients who have undergone pathophysiologic remodeling since the DPG is less sensitive to changes in pulmonary vascular flow rate (which can be variable due to dynamic changes in stroke volume and cardiac output), resistance, and PCWP. One study found that a DPG greater than 7 mm Hg is an independent predictor of survival in patients with PH-LHD.[12]

On the basis of these measurements during RHC, PH-LHD can be divided into the following two categories:

  • IpcPH (mPAP >20 mm Hg, mPCWP >15 mm Hg, TPG >12 mm Hg, DPG < 7 mm Hg, and/or PVR < 3 WU)
  • CpcPH (mPAP >20 mm Hg, mPCWP >15 mm Hg, TPG >12mm Hg, DPG >7 mm Hg, and/or PVR >3 WU)

Some controversy exists regarding vasodilator testing in the setting of group 2 pulmonary hypertension. Vasoreactivity testing includes the use of prostanoids, nitrous oxide, nitroprusside, or phosphodiesterase-5 inhibitors. Testing is recommended when pulmonary hypertension is out of proportion or in heart transplantation candidates.[5] The goal of testing is to determine if pulmonary hypertension is reversible (reduction in TPG and PVR without change in CO or raising PCWP) with the use of vasodilators. However, there are no current guidelines on the definition for reversibility in group 2 pulmonary hypertension.

Other Tests

Other etiologies of pulmonary hypertension should be evaluated with a ventilation perfusion scan (to assess for chronic thromboembolic pulmonary hypertension), polysomnography (to assess for obstructive sleep apnea), and pulmonary function tests (to assess for restrictive or obstructive pulmonary disease).

 

Treatment

Approach Considerations

Treatment for group 2 pulmonary hypertension consists primarily of treating the underlying left-sided heart disease. Treatment can include pharmacotherapies, surgery, or minimally invasive techniques (valve replacements, bypass grafting, assist devices).[13]

Medical Care

Medication management is further discussed in Medication.

Surgical Care

In cases of left-sided sided disease due to valvular disease (aortic or mitral), consideration should be made for referral to a cardiothoracic surgeon for valve repair. For left-sided disease refractory to medical therapy, heart transplantation should be considered.

Consultations

Referral to a center that specializes in pulmonary hypertension is recommended for further management. With underlying left-sided heart disease, it is recommended to consult with a cardiologist to help with management. In cases of refractory left-sided heart disease, consideration must be made for a referral for cardiac transplantation.

Diet

Currently, there are no direct guidelines regarding diet for group 2 pulmonary hypertension. However, conservative fluid intake (< 1.5-2 L/day) and avoiding excess salt intake (< 3 g/day) are recommended to prevent exacerbation of left-sided heart disease. Additionally, in cases of left-sided disease due to an ischemic etiology, avoidance of foods high in fats and cholesterol is recommended to prevent further worsening of underlying coronary artery disease.

Activity

Patients with group 2 pulmonary hypertension can continue to remain active and to partake in physical activity as tolerated; however, very strenuous activity can worsen symptoms.

Prevention

In cases of left-sided disease due to hypertension, avoidance of high salt intake and optimization of blood pressure can prevent worsening of underlying disease. Additionally, patients should take preventative measures to avoid foods high in cholesterol and fats if the underlying etiology is coronary artery disease. Patients should receive their pneumococcal vaccination and annual influenza vaccination.

Long-Term Monitoring

Patients should see their pulmonary hypertension specialist regularly. A 6-minute walk test (6MWT) is performed at regular intervals to evaluate functional status. Patients should have a transthoracic echocardiography performed at least annually. A significant change in functional status should prompt a repeat echocardiography and/or right-sided heart catheterization.

 

Medication

Medication Summary

The goal of medication treatment of group 2 pulmonary hypertension is to lower filling pressures and provide afterload reduction in patients with heart failure. For management of heart failure with reduced ejection fraction (HFrEF), medication classes consist of diuretics, angiotensin-receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, and beta-blockers. In settings of combined postcapillary and precapillary pulmonary hypertension, pulmonary vasodilators have not consistently been shown to improve symptoms or hemodynamics and some harm has been demonstrated in trials of these medications.

Diuretics

Diuretics are the mainstay of therapy for pulmonary hypertension due to left-sided heart disease (PH-LHD). The most commonly used diuretics are loop diuretics (furosemide, bumetanide, or torsemide). In cases of refractory volume overload, thiazide diuretics can also be used in conjunction with loop diuretics for synergistic effect. The goal of diuretics is to alleviate volume overload and to lower both right- and left-sided filling pressures. A stable dose of diuretic therapy is needed to manage volume and prevent decompensated heart failure.

ARBs and ACE inhibitors

Owing to survival benefit in patients with left ventricular systolic dysfunction, patients should be initiated on an ACE inhibitor or, if unable to tolerate, an ARB. These two classes of medications cause vasodilation, neurohormonal modification, and improvement in left ventricular ejection fraction. Examples of ACE inhibitors include benazepril, lisinopril, ramipril, and enalapril. Examples of ARBs include losartan and valsartan.

Beta-blockers

Beta-blockers inhibit sympathetic activity and have been shown to reduce mortality in patients with heart failure with reduced ejection fraction. Common beta-blockers used are bisoprolol and metoprolol. Additionally, beta-blockers with alpha activity like carvedilol can also reduce afterload.

Prostacyclins

Prostacyclins are pulmonary vasodilators that cause dilation of vascular beds through activation of intracellular adenylate cyclase. A large randomized controlled trial (Flolan International Randomized Survival Trial [FIRST]) evaluated the use of epoprostenol infusion with standard of care in patients with advanced heart failure versus standard of care alone.[14] Although there were improvements in pulmonary vascular resistance (PVR), pulmonary capillary wedge pressure (PCWP), and cardiac output (CO), an increased mortality rate with the use of epoprostenol was observed. The use of prostacylins is contraindicated in PH-LHD owing to an increased risk of mortality.

Endothelin receptor antagonists

Endothelin 1 is a potent endogenous vasoconstrictor that causes vascular smooth muscle hyperplasia in addition to direct vasoconstrictor effects. Endothelin receptor antagonists bind endothelin 1 receptors, causing a decrease in pulmonary arterial pressure through decreases in PVR. Approved for use in group 1 pulmonary arterial hypertension, there have been few trials evaluating their efficacy in group 2 pulmonary hypertension.

The Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure [ENABLE]) study evaluated the use of bosentan in patients with severe heart failure (ejection fraction < 35%, New York Heart Association class III-IV). In this study, 1613 patients were randomized to bosentan versus placebo, with results showing no improvement in outcome between the two groups.[15] However, there was an increased risk of heart failure exacerbation in the bosentan group due to fluid retention.

Phosphodiesterase-5 inhibitors

Phosphodiesterase-5 (PDE-5) inhibitors cause smooth muscle relaxation and antiproliferative effects in the vasculature, leading to a reduction in pulmonary artery pressure in patients with WHO group 1 pulmonary hypertension. In patients with PH-LHD, use of PDE-5 inhibitors has shown mixed results. In one study, exercise capacity and cardiac output improved with the use of sildenafil.[16] Additionally, a smaller study looking at 34 patients with symptomatic heart failure and pulmonary hypertension showed improvement in exercise capacity, quality of life, and fewer hospitalizations for heart failure exacerbations in the sildenafil group compared with placebo.[17]

In a multicenter, randomized controlled study, 216 patients with stable heart failure (ejection fraction >50%) and PH-LHD were randomized to sildenafil or placebo for 24 weeks. The study found there was no difference between clinical status or exercise capacity between the two groups.[18] The use of sildenafil in PH-LHD from valvular disease was evaluated in a study comparing the use of sildenafil (40 mg thrice daily) versus placebo in 200 patients who had been 2 years removed from successful valvular repair or replacement.[19] The study showed an increased rate of heart failure exacerbation leading to hospitalization and a worsening of functional capacity in the sildenafil group. Currently, sildenafil is not yet recommended in WHO group 2 pulmonary hypertension, owing to the lack of long-term studies or consistent results.

Diuretics

Class Summary

Diuretics promote excretion of water and electrolytes by the kidneys. They are used to treat heart failure or hepatic, renal, or pulmonary disease when sodium and water retention has resulted in edema or ascites. They may be used as monotherapy or combination therapy to treat hypertension. Loop diuretics are commonly used. Thiazide diuretics can also be used in concurrently for synergistic effect in cases of refractory volume overload.

Furosemide (Lasix)

Furosemide primarily appears to inhibit reabsorption of sodium and chloride in the ascending limb of the loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis.

Bumetanide (Bumex)

Bumetanide increases excretion of water by interfering with the chloride-binding cotransport system; this, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle. Bumetanide does not appear to act in the distal renal tubule.

Torsemide (Demadex)

Torsemide increases excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. It increases excretion of water, sodium, chloride, magnesium, and calcium. If a switch is made from intravenous to oral administration, an equivalent oral dose should be used.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water and potassium and hydrogen ions.

Chlorothiazide (Diuril)

Chlorothiazide inhibits the reabsorption of sodium and chloride in distal tubules, causing increased excretion of chloride, sodium, and water as well as of potassium, magnesium, phosphate, bicarbonate, and hydrogen ions.

Anigiotensin Receptor Blockers (ARBs)

Class Summary

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system (RAAS) and plays an important role in the pathophysiology of hypertension. Besides being a potent vasoconstrictor, angiotensin II stimulates aldosterone secretion by the adrenal gland; thus, ARBs decrease systemic vascular resistance without a marked change in heart rate by blocking the effects of angiotensin II.

Type I angiotensin receptors are found in many tissues, including vascular smooth muscle and the adrenal gland. Type II angiotensin receptors also are found in many tissues, although their relationship to cardiovascular hemostasis is not known. The affinity of ARBs for the type I angiotensin receptor is approximately 1000 times greater than that for the type II angiotensin receptor. In general, ARBs do not inhibit the angiotensin converting enzyme (ACE), other hormone receptors, or ion channels. They interfere with the binding of formed angiotensin II to its endogenous receptor.

Losartan (Cozaar)

Losartan is appropriate for patients unable to tolerate ACE inhibitors. It may induce a more complete inhibition of the RAAS than ACE inhibitors do, it does not affect the response to bradykinin, and it is less likely to be associated with cough and angioedema. Compared with the ACE inhibitors, losartan is associated with a lower incidence of drug-induced cough, rash, and taste disturbances.

Valsartan (Diovan)

Valsartan is appropriate for patients unable to tolerate ACE inhibitors. It may induce a more complete inhibition of the RAAS than ACE inhibitors do, it does not affect the response to bradykinin, and it is less likely to be associated with cough and angioedema. Compared with ACE inhibitors, losartan is associated with a lower incidence of drug-induced cough, rash, and taste disturbances.

Olmesartan (Benicar)

Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking binding of angiotensin II to the AT-1 receptor in vascular smooth muscle. Its action is independent of pathways for angiotensin II synthesis.

Candesartan (Atacand)

Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors, it does not affect the response to bradykinin, and it is less likely to be associated with cough and angioedema. It is used in patients unable to tolerate ACE inhibitors.

Angiotensin Converting Enzyme (ACE) Inhibitors

Class Summary

These agents minimize an ischemia-induced rise in angiotensin production. Because hypertension may be dependent on angiotensin II, antihypertensives that inhibit renin or angiotensin II are used widely. All drugs in this class have similar action and adverse effects.

Benazepril (Lotensin)

Benazepril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Lisinopril (Prinivil, Qbrelis, Zestril)

Lisinopril prevents conversion of angiotensin I to angiotensin II, resulting in decreased aldosterone secretion and subsequently, a decrease in vasoconstriction.

Ramipril (Altace)

Ramipril partially inhibits both tissue and circulating ACE activity, therefore reducing the formation of angiotensin II in the tissue and plasma. Ramipril has an antihypertensive effect even in patients with low-renin hypertension.

Enalapril (Epaned, Vasotec)

Enalapril is a competitive ACE inhibitor that prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, causing angiotensin II levels and aldosterone secretion to decrease.

Beta-Blockers, Beta-1 Selective

Class Summary

Beta-blockers are especially useful in the concurrent treatment of hypertension and migraine. Dosing is limited by the bradycardia adverse effect. This drug class should not be used in patients with type 1 diabetes, because these drugs blunt the normal warning symptoms of hypoglycemia.

Bisoprolol

Bisoprolol is a selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. It has little or no effect on beta2-receptors at doses of 20 mg or less.

Metoprolol (Lopressor, Toprol XL)

Metoprolol is a selective beta1-adrenergic receptor blocker that decreases the automaticity of contractions. During intravenous administration, carefully monitor blood pressure, heart rate, and the electrocardiogram. No dosage adjustment is required with renal failure.

Beta-Blockers, with Alpha-Blocking Activity

Class Summary

These agents have nonselective beta-adrenoreceptor and alpha-adrenergic blocking activity. Therapy should be initiated at low dosages, which should be increased gradually over several weeks. Patients' conditions may deteriorate over the short term, but they generally improve in the long term with continued therapy.

Carvedilol (Coreg, Coreg CR)

Carvedilol blocks beta1-, alpha-, and beta2-adrenergic receptor sites, decreasing adrenergic-mediated myocyte damage. Effects in hypertension may include vasodilation, reduction in cardiac output, decreased peripheral resistance, exercise- or beta-agonist–induced tachycardia, decreased renal vascular resistance, and increased level of atrial natriuretic peptide.