Cor pulmonale (Latin cor, heart + New Latin pulm n le, of the lungs) or pulmonary heart disease is enlargement

of the right ventricle of the heart as a response to increased resistance or high blood pressure in the lungs (pulmonary hypertension). Chronic cor pulmonale usually results in right ventricular hypertrophy (RVH), whereas acute cor pulmonale usually results in dilatation. Hypertrophy is an adaptive response to a long-term increase in pressure. Individual muscle cells grow larger(in thickness) and change to drive the increased contractile force required to move the blood against greater resistance. Dilatation is a stretching (in length) of the ventricle in response to acute increased pressure. To be classified as cor pulmonale, the cause must originate in the pulmonary circulation system. Two major causes are vascular changes as a result of tissue damage (e.g. disease, hypoxic injury, chemical agents, etc.), and chronic hypoxic pulmonary vasoconstriction. RVH due to a systemic defect is not classified as cor pulmonale. When untreated, cor pulmonale can lead to right-heart failure and death.

Contents
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1 Overview 2 Pathophysiology 3 Causes 4 Symptoms 5 Diagnosis 6 Epidemiology 7 Complications 8 Investigations 9 Treatment 10 Prevention 11 Footnotes 12 External links

[edit] Overview
The heart and lung are intricately related. Whenever the heart is affected by disease, the lungs will follow and vice versa. Pulmonary heart disease is by definition a condition when the lungs cause the heart to fail.[1]

The heart has two pumping chambers. The left ventricle pumps blood throughout the body. The right ventricle pumps blood to the lungs where it is oxygenated and returned to the left heart for distribution. In normal circumstances, the right heart pumps blood into the lungs without any resistance. The lungs usually have minimal pressure and the right heart easily pumps blood through.[2] However when there is lung disease present, like emphysema, chronic obstructive lung disease (COPD) or pulmonary hypertension- the small blood vessels become very stiff and rigid. The right ventricle is no longer able to push blood into the lungs and eventually fails. This is known as pulmonary heart disease. Pulmonary heart disease is also known as right heart failure or cor pulmonale. The chief cause of right heart failure is the increase in blood pressure in the lungs (pulmonary artery).

[edit] Pathophysiology
There are several mechanisms leading to pulmonary hypertension and cor pulmonale:
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Pulmonary vasoconstriction Anatomic changes in vascularization Increased blood viscosity Idiopathic or primary pulmonary hypertension

[edit] Causes
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Acute: Massive pulmonary embolization Exacerbation of chronic cor pulmonale Chronic: o COPD o Primary Pulmonary Hypertension o Recurrent Pulmonary Embolism o Loss of lung tissue following trauma or surgery o Pierre Robin sequence o End stage Pneumoconiosis o Sarcoidosis o T1-4 Vertebral subluxation o Obstructive sleep apnea o Altitude sickness o Sickle cell anemia o Bronchopulmonary dysplasia (in infants)
o o

[edit] Symptoms

The symptoms of pulmonary heart disease depend on the stage of the disorder. In the early stages, one may have no symptoms but as pulmonary heart disease progresses, most individuals will develop the symptoms like:
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Shortness of breath which occurs on exertion but when severe can occur at rest Wheezing Chronic wet cough Swelling of the abdomen with fluid (ascites) Swelling of the ankles and feet (pedal edema) Enlargement or prominent neck and facial veins Enlargement of the liver Bluish discoloration of face Presence of abnormal heart sounds possible bi-phasic atrial response shown on an EKG due to hypertrophy

[edit] Diagnosis
In many cases, the diagnosis of pulmonary heart disease is not easy as both the lung and heart disease can produce similar symptoms. Most patients undergo an ECG, chest X ray, echocardiogram, CT scan of the chest and a cardiac catheterization. During a cardiac catheterization, a small flexible tube is inserted from the groin and under x ray guidance images of the heart are obtained. Moreover the technique allows measurement of pressures in the lung and heart which provide a clue to the diagnosis.[1]

[edit] Epidemiology
Each year there are about 20,000 deaths and close to 280,000 hospital admissions among individuals who have pulmonary heart disease. The majority of individuals affected by pulmonary heart disease are women less than 65 years of age. Infants who are born with congenital heart disorders (esp. holes in the heart like a VSD) are prone to pulmonary artery disease. In infants the earlier the heart disease is treated, the better the prognosis.[3] While pulmonary heart disease is serious, it is much less common than coronary artery disease.[2]

[edit] Complications
Blood backs up into the systemic venous system, including the hepatic vein. Chronic congestion in the centrilobular region of the liver leads to hypoxia and fatty changes of more peripheral hepatocytes, leading to what is known as nutmeg liver.

[edit] Investigations
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Chest X-Ray - Right ventricular hypertrophy, right atrial dilatation, prominent pulmonary artery, peripheral lung fields show reduced vascular markings. Patients of chronic

obstructive pulmonary disease show features of hyperinflation which include widened intercostal space, increased translucency of lung and flattened diaphragm. ECG - Right ventricular hypertrophy - right axis deviation, prominent R wave in lead V1 & inverted T waves in right precordial leads, Large S in Lead I, II and III; Large Q in lead III, Tall Peaked P waves (P pulmonale) in lead II, III and aVF. All the above features are not found in a single patient but different patients show different combination of these findings. Echocardiogram - Right ventricular dilatation and tricuspid regurgitation is likely

[edit] Treatment
Elimination of the cause is the most important intervention. Smoking must be stopped, exposure to dust, flames, household smoke and to cold weather is avoided. If there is evidence of respiratory infection, it should be treated with appropriate antibiotics after culture and sensitivity. Diuretics for RVF, In pulmonary embolism, thrombolysis (enzymatic dissolution of the blood clot) is advocated by some authorities if there is dysfunction of the right ventricle, and is otherwise treated with anticoagulants. In COPD, long-term oxygen therapy may improve cor pulmonale. Cor pulmonale may lead to congestive heart failure (CHF), with worsening of respiration due to pulmonary edema, swelling of the legs due to peripheral edema and painful congestive hepatomegaly (enlargement of the liver due to tissue damage as explained in the Complications section. This situation requires diuretics (to decrease strain on the heart), sometimes nitrates (to improve blood flow), phosphodiesterase inhibitors such as sildenafil or tadalafil and occasionally inotropes (to improve heart contractility). CHF is a negative prognostic indicator in cor pulmonale. Oxygen is often required to resolve the shortness of breath. Plus, oxygen to the lungs also helps relax the blood vessels and eases right heart failure. Oxygen is given at the rate of 2 litres per minute. Excess oxygen can be harmful to patients because hypoxia is the main stimulus to respiration. If such hypoxia is suddenly corrected by overflow of oxygen, such stimulus to the respiratory center is suddenly withdrawn and respiratory arrest occurs. When wheezing is present, majority of the patients require bronchodilators. A variety of drugs have been developed to relax the blood vessels in the lung. Calcium channel blockers are used but only work in a few cases. Other novel medications that need to be inhaled or given intravenously include prostacyclin derivatives. Cases of COPD with chronic corpulmonale present with secondary polycythemia , if severe it may increase the blood viscosity and contribute to pulmonary hypertension. If hematocrit(PCV) is above 60%, then it is better to reduce the red blood cell count by phlebotomies. Mucolytic agents like bromhexine and carbocisteine help bring out excessive bronchial secretions more easily by coughing. All patients with pulmonary heart disease are maintained on blood thinning medications to prevent formation of blood clots.

When medical therapy fails, one may require a transplant. However, since the lungs are damaged, both the heart and lungs needs to be transplanted. With a shortage of donors this therapy is only done 10-15 times a year in North America.

[edit] Prevention
While not all lung diseases can be prevented one can reduce the risk of lung disease. This means avoiding or discontinuing smoking. Patients with end stage emphysema or chronic obstructive lung disease always end up with right heart failure. When working in environments where there are chemicals, wear masks to prevent inhalation of dust particles.[4]

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Abstrak Cor pulmonale didefinisikan sebagai perubahan dari struktur dan fungsi dari ventrikel kanan yang disebabkan oleh kelainan primer pada sistem pernafasan. Hipertensi pulmonal adalah kelainan yang menghubungkan antara dysfungsi paru dan jantung pada penderita cor pulmonal. Kegagalan jantung kanan yang dsebabkan oleh kelainan primer pada jantung bagian kiri maupun kelainan kongenital jantung tidak dapat disebut sebagai cor pulmonal. Umumnya cor pulmonal memiliki onset yang yang kronik dan progresif lambat. Untuk membantu penegakan diagnosis cor pulmonale, pemeriksaan radiologis yang paling sering digunakan adalah foto roentgen thorak. Kata kunci : foto roentgen thorak, cor pulmonale

HISTORI Pasien laki-laki usia 57 tahun datang dengan keluhan sesak nafas. Pasien mengaku memiliki kebiasaan merokok sejak 20 tahun yang lalu. Pasien juga sering batuk yang kumat-kumatan tanpa diobati maupun diperiksakan ke tenaga kesehatan. Pasien mengaku menderita hipertensi sejak lima tahun yang lalu tetapi pasien malas untuk kontrol. Dari pemeriksaan fisik didapatkan auskultasi paru terdapat ronki basah kasar dan terdapat pelebaran vena jugularis vital sign tekanan darah 200/110 mmHg, nadi 80 x/menit dan respirasi 20 x/menit. Sementara dari foto rontgen dada didapatkan cardiomegali dan peningkatan corakan bronkovaskuler suspek bronkitis. DIAGNOSIS foto rontgen dada didapatkan cardiomegali dan peningkatan corakan bronkovaskuler suspek bronkitis. DISKUSI Kelainan paru yang mendasari terjadinya hipertensi pulmonal diantaranya :

1. vasokonstriksi karena hipoksia, hiperkapnea atau keduanya 2. Peningkatan tekanan alveolar 3. Hipertrofi arterioles Hipertensi pulmonal meningkatkan afterload pada ventrikel kanan, yang kemudian memicu rentetan peristiwa yang mirip dengan kegagalan ventrikel kiri. Etiologi cor pulmonale biasanya disebabkan oleh COPD. Pada pasien dengan COPD, eksaserbasi akut atau infeksi pulmonal dapat memicu terjadinya overload ventrikel kanan. Gejala awalnya cor pulmonale bersifat asimtomatik, walaupun pasien mengalami gejala yang signifikan karena kelainan paru mendasar (misal dispnea, kelemahan saat aktifitas). Kemudian setelah tekanan ventrikel kanan meningkat, gejala fisik baru terlihat (Suara jantung dua yang mengeras, murmur trikuspid dan insufisiensi pulmonal). Pada tahap lanjut dapat terjadi irama galop saat inspirasi, pelebaran vena jugularis, hepatomegali dan edema ekstremitas bawah. Diagnosis Diagnosis cor pulmonale ditegakkan berdasarkan pemeriksaan fisik dan echocardiography. Apabila echocardiography tidak tersedia maka X-rays dada dapat membantu memperlihatkan hipertrophy ventrikel kanan dan pelebaran arteri pulmonal proksimal. EKG dapat memperlihatkan hipertrofi ventrikel kanan (mis, deviasi axis kanan, QR wave pada lead V1, dan gelombang R dominan di lead V1 dan V3) mempunyai korelasi dengan derajat hipertensi pulmonal. Akan tetapi karena hiperinflasi pulmonal pada COPD menyebabkan realigmen dari jantung. Akan tetapi temuan dari x-rays dada, EKG dan pemeriksaan fisik harus tetap di kroscek dengan echocardiography. echocardiography dapat digunakan untuk mengevaluasi fungsi ventrikel kiri dan kanan. Kelemahan dari echocardiography adalah hanya mampu mendeteksi kelainan pada ventrikel kanan yang disebabkan oleh kelainan paru. Terapi Terapi untuk cor pulmonale difokuskan pada kelinan yang mendasarinya, terutama untuk mengurangi hipoksia. Identifikasi dan penatalaksanaan seawal mungkin dapat mencegah perubahan struktural yang ireversibel. Jika terdapat oedem perifer, diuretik masih diperdebatkan untuk diberikan. Pemberian diuretik dapat membantu jika terdapat juga hipertrofi ventrikel kiri dan overload cairan pulmonal, akan tetapi penurunan preload walaupun sedikit dapat menyebabkan cor pulmonal menjadi lebih parah. vasodilator pulmonal (hydralazine, ca channel blockers, nitrous oxide, prostacyclin, phosphodiesterase inhibitors) walaupun sangat membantu untuk penanganan hipertensi pulmonal primer tidak efektif untuk terapi cor pulmonal. Obat lain seperti endothelin receptor blocker, efeknya pada sor pulmonal belum diteliti. pemberian digoxin hanya dapat efektif bila terdapat dysfungsi ventrikel kiri yang terjadi bersamaan dengan dysfungsi ventrikal kanan. Selain itu terdapat beberapa pasien COPD yang sensitif terhadap efek digoxin.

Kesimpulan 1. cor pulmonale merupakan kelainan jantung yang didasari oleh kelainan paru 2. cor pulmonale biasanya disebabkan oleh COPD 3. Gejala cor pulmonale berupa dispnea, kelemahan saat aktifitas,irama galop saat inspirasi, pelebaran vena jugularis, hepatomegali dan edema ekstremitas bawah 4. Diagnosis cor pulmonale ditegakkan berdasarkan pemeriksaan fisik dan echocardiography, tetapi apabila echocardiography tidak tersedia dapat dilakukan pemeriksaan dengan foto roentgen thorak. 5. Terapi untuk cor pulmonale difokuskan pada kelainan yang mendasarinya Cor pulmonale is a serious condition in which the lower right chamber of the heart (the right ventricle) becomes enlarged and eventually fails as a result of chronic lung disease. Normally, little effort is necessary to pump blood from the right ventricle to the lungs, as compared with the force necessary to pump blood from the left ventricle to the remainder of the body. As a result, the heart muscle of the right ventricle is comparatively weaker than that of the left ventricle. When lung function is impaired, as a result of lung disease, the right ventricle must work harder to overcome increased resistance to blood flow from the heart through the branches of the pulmonary artery (pulmonary hypertension). Because it is harder to pump blood to the lungs, blood flow from the right ventricle is slowed down, leading to an accumulation of blood within the right ventricle. Though the heart muscle becomes enlarged (hypertrophied) in an attempt to compensate, it eventually fails (right-sided heart failure). Acute cor pulmonale is an emergency situation arising from a blood clot in the lungs (pulmonary embolism). With prompt medical attention, it is usually reversible. Chronic cor pulmonale develops gradually. It is associated with chronic obstructive lung diseases such as emphysema, silicosis, and pulmonary fibrosis (replacement of normal lung tissue with fibrous scar tissue) following a prolonged infection.

How is it diagnosed?
Cor pulmonale signs and symptoms

Early stages:
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No symptoms (usually).

Later stages:
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Weakness and fatigue. Shortness of breath with exertion. Frequent fainting. Swelling of the ankles and feet caused by fluid retention.

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Distended neck veins. Bluish skin. Chest pain. Enlarged liver and swollen abdomen.

History: Symptoms include shortness of breath with exercise, chronic cough that produces sputum, blue tinge around the mouth and fingernails (cyanosis), wheezing, weakness, tiring easily, and swelling of the lower extremities (edema). Physical exam may reveal distended veins in the neck, enlarged and tender liver, swelling of lower extremities (edema), and abdominal swelling and discomfort due to fluid collection in the abdominal cavity (ascites). Tests to evaluate heart function may include chest x-ray to detect an enlarged right ventricle and pulmonary artery, echocardiogram (a technique in which ultrasound is used to visualize dimensions of the ventricles and exclude left ventricle dysfunction), and electrocardiogram (to record the electrical activity of the heart, identifying right ventricle enlargement). Pulmonary function tests usually confirm the underlying lung disease. Pulmonary angiography (x-ray of blood vessels in the lungs after injection with a contrast medium) can be used to detect pulmonary embolism (blood clot in the lungs), but carries increased risk when performed on individuals with pulmonary hypertension.

How is Cor pulmonale treated?

Treatment is directed at relieving the underlying lung or cardiac disorder that caused the condition. When due to pulmonary embolism, small clots may be dissolved with the use of thrombolytic drugs. Emergency surgery may need to be performed to remove a large embolus. Chronic obstructive lung disease is usually treated by use of bronchodilators to widen airways of the lungs and aid in breathing. Oxygen therapy may also be necessary. In severe cases, the use of a mechanical ventilator may be required to reduce breathing difficulties and ensure adequate oxygen for the body's needs. In addition, treatment may include diuretics (to increase urine production and reduce excess body fluids), salt and fluid restriction, and adequate rest. Unless atrial fibrillation is present, digitalis (a drug that increases the force of the heart's muscle contraction, enabling the heart to pump more blood) is not indicated.
Medications
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Diuretics to prevent fluid accumulation. Digitalis to strengthen the force of heart-muscle contractions. Antibiotics for recurrent infections. Vasodilators to reduce the resistance of the blood vessels to promote improved blood flow.

Abstract

Chronic cor pulmonale involves the enlargement of the right ventricle as a result of pulmonary hypertension due to pulmonary disorders involving the lung parenchyma, bellows function, or ventilatory drive. The right ventricular hypertrophy that occurs in chronic cor pulmonale is a direct result of chronic hypoxic pulmonary vasoconstriction and subsequent pulmonary artery hypertension, leading to increased right ventricular work and stress. We discuss methods by which hypoxic vasoconstriction and reduction in the pulmonary vascular bed lead to the development of pulmonary artery hypertension. This article reviews the interaction of the pulmonary vasculature and right ventricle in the nondiseased state as well as during disease exacerbations. Ventricular dependence and its contribution to the pathophysiology of right ventricular failure are also reviewed. In addition, we provide an overview of specific disease states that can result in the development of chronic cor pulmonale including chronic obstructive pulmonary disease (COPD), interstitial lung disease, sleep apnea, alveolar hypoventilation disorders, and primary pulmonary hypertension. We also review the current diagnostic studies used to evaluate and study cor pulmonale. Objectives: Upon completion of this article, the reader should be able to: (1) recognize the difference in pathophysiology of acute cor pulmonale and chronic cor pulmonale; (2) understand the basic pathophysiology of pulmonary artery hypertension; (3) recognize the interaction between the pulmonary vasculature and the right heart in the development of chronic cor pulmonale; (4) describe the significance of right and left ventricular interdependence in cor pulmonale; (5) list some of the common disease states associated with chronic cor pulmonale; and (6) summarize the evaluation of the patient with chronic cor pulmonale, recognizing the common signs and symptoms as well as the diagnostic studies to order in evaluating cor pulmonale. Accreditation: The University of Michigan is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. Credits: The University of Michigan designates this educational activity for a maximum of 1 category 1 credit toward the AMA Physician's Recognition Award.
Introduction

The term cor pulmonale was introduced in 1931 by Dr. Paul D. White.[1] In 1963, The World Health Organization expert committee proposed a pathologic definition of cor pulmonale as "hypertrophy of the right ventricle resulting from diseases affecting the function and/or structure of the lungs, except when these pulmonary alterations are the result of diseases that primarily affect the left side of the heart, as in congenital heart diseases."[2] In 1970, Behnke and colleagues replaced the concept of hypertrophy with "an alteration in the structure and function of the right ventricle."[3] This definition thus included a variety of disorders ranging from a mild abnormality of the right ventricle to overt right heart failure. The current definition of chronic cor pulmonale is right ventricular hypertrophy, dilation, or both as a result of pulmonary hypertension caused by pulmonary disorders involving the lung parenchyma, impaired pulmonary bellows function, or altered ventilatory drive.[4] The major causative disorders are shown in Table 1 . Acute cor pulmonale usually refers to the development of acute pulmonary hypertension and right ventricular overload from a massive pulmonary thromboembolic event, with subsequent development of right ventricular dilation.[5]

Right ventricular dilation or hypertrophy in chronic cor pulmonale is a direct compensatory effect of chronic pulmonary vasoconstriction and subsequent pulmonary artery hypertension that leads to increased right ventricular work and stress. When the right ventricle can no longer compensate through dilation or hypertrophy, right ventricular failure occurs.[6] In this article, we review the pathophysiology of pulmonary hypertension, the interaction between the pulmonary vasculature and the right heart, and right and left ventricular interdependence in cor pulmonale. We also provide an overview of respiratory disorders that affect right ventricular performance, including chronic obstructive pulmonary disease (COPD), interstitial lung disease, sleep apnea and various hypoventilation syndromes, and primary pulmonary hypertension. Finally, we review some of the diagnostic studies used to investigate cor pulmonale.

Pathophysiology of Pulmonary Artery Hypertension

Pulmonary hypertension is defined operationally as mean pulmonary arterial pressure > 20 mmHg at rest or 30 mmHg with exercise. Increased pulmonary artery pressure and pulmonary vascular resistance may develop in disorders of the lung parenchyma, airways, or pulmonary vasculature and as a result of abnormal control of ventilation.[7]
Hypoxic Vasoconstriction

Hypoxic vasoconstriction of the small arteries and arterioles is likely a defense mechanism that develops acutely to maintain local ventilation-perfusion relationships.[8] Local pulmonary vasconstriction occurs in hypoxic regions, causing blood flow to be shunted away from the hypoxic area to regions of adequate ventilation, thus improving the overall ventilation-perfusion matching within the lung.[5] Although the acute vasoconstrictive response to hypoxia is benefical, chronic hypoxic vasoconstriction leads to narrowing of the pulmonary arteries. Chronic hypoxia induces "muscularization" of the pulmonary arteries, with the smooth muscle cells proliferating longitudinally within the intima of the small pulmonary arteries.[9] As a result, pulmonary vascular resistance increases, and pulmonary hypertension develops. Hypoxic vasoconstriction may affect the pulmonary vascular bed through an imbalance in the production and regulation of nitric oxide (NO), a vasodilator. Impaired NO production or release by endothelial cells in chronic hypoxic vasoconstriction may account for the inability of the pulmonary vasculature to relax.[10] Impaired NO production may also be responsible for the proliferation of vascular smooth muscle cells, medial hypertrophy, and eccentric intimal fibrosis. These structural changes may increase platelet aggregation and in situ thrombi, thereby further increasing pulmonary vascular resistance. Eventually, the cross-sectional area of the pulmonary vascular bed decreases and pulmonary hypertension becomes irreversible.[11] The vascular endothelium also plays a central role in the development of hypoxia-induced pulmonary hypertension through the production and release of various mediators of vascular tone. One such mediator is endothelin1, which is a potent endogenous vasoconstrictor.[12] Endothelin 1 release by endothelial cells is increased in hypoxic states. The presence of

endothelin 1 may increase calcium entry into the vascular smooth muscle cells leading to hypoxic vasoconstriction.[5] In addition, certain endothelial growth factors, such as vascular endothelial growth factor and platelet-derived growth factors A and B are upregulated under conditions of chronic hypoxia. These growth factors are involved in endothelial cell proliferation and vascular injury and remodeling of the pulmonary vascular bed.[13] Angiotensin and angiotensin-converting enzyme (ACE) seem to have some role in the pathogenesis of right ventricular hypertrophy secondary to hypoxia-induced pulmonary hypertension. In rat models, the development of pulmonary artery hypertension and subsequent right ventricular hypertrophy owing to hypoxia is associated with an increase in right ventricular membrane-bound ACE activity.[14] In animals with chronic hypoxia, treatment with ACE inhibitors seems to reduce right ventricular hypertrophy and fibrosis.[15]
Constriction of the Pulmonary Vascular Bed

Occlusion or narrowing of medium-size to large pulmonary arteries is the basis for increased pulmonary vascular resistance in such disorders as hilar or mediastinal compressive metastatic tumors or fibrosis, nonspecific arteritis, primary pulmonary tumors, major vessel chronic thromboembolic disease, and infection (tuberculosis or histoplasmosis). Although the pulmonary artery hypertension is most likely due to a progressive decline in the cross-sectional area of the pulmonary vascular bed there is also some evidence indicating the presence of a high-flow state in the unobstructed vessels or mediator involvement.[16] Constriction of the pulmonary vascular bed may also play a role in pulmonary artery hypertension secondary to COPD.[5] Acidosis and secondary polycythemia also contribute to resistance to blood flow through the restricted pulmonary vascular bed.[17]

Interaction Between the Pulmonary Vasculature and the Right Heart

The right ventricle is a crescent-shaped chamber composed of a concave free wall and a convex interventricular septum[18,19] (Fig. 1). Right ventricular contraction is produced by three main mechanisms: an initial shortening of the trabeculae and papillary muscles forcing the tricuspid valve toward the ventricular apex; a subsequent decrease in the longitudinal axis, causing minimal ejection of blood; and finally, movement of the free wall toward the interventricular septum leading to a contraction followed by a secondary contraction of the circular fibers and resulting in an increased curvature of the interventricular septum. The concave free wall, along with the increased curvature of the interventricular septum, leads to a bellows-like action with subsequent expulsion of blood from the right ventricle. Right ventricular contractions are aided by a passive gradient between the two regions within the chamber, the inflow and outflow areas. Right ventricular contractions are more passive than left ventricular contractions. Because of the thin walls and crescent shape of the right ventricle, it is compliant and can accommodate and eject relatively large amounts of blood with limited myocardial shortening.[20] Therefore, it can accommodate large increases in blood volume rather than pressure, in contrast to the muscular left ventricular pressure pump. If right ventricular afterload is increased because of pulmonary artery constriction, stroke volume rapidly decreases. In contrast, if right ventricular preload is increased or atrial preload is increased by volume expansion, the stroke volume or work remains

constant[21,22] (Fig. 2). Under normal circumstances, the compliant thin-walled right ventricle empties into the pulmonary vasculature, which provides low resistance to outflow.
Figure 1.

(Enlarge Image)

The anatomic relationship of the right ventricle (RV) to the left ventricle (LV) illustrating the crescent shape of the right ventricle and the globular shape of the heart. Left atrium (LA) and right atrium (RA). (From Guyton[24] with permission.)

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Figure 1. The anatomic relationship of the right ventricle (RV) to the left ventricle (LV) illustrating the crescent shape of the right ventricle and the globular shape of the heart. Left atrium (LA) and right atrium (RA). (From Guyton[24] with permission.) Figure 2.

Effect of increasing afterload (A) and preload (B) on the right and left ventricle. (From McFadden and Braunwald[22] with permission.)
(Enlarge

Image) [ CLOSE WINDOW ]

Figure 2. Effect of increasing afterload (A) and preload (B) on the right and left ventricle. (From McFadden and Braunwald[22] with permission.)

In normal persons, the pulmonary vasculature can react to wide fluctuations in flow without much change in pressure so that the right ventricle is not pressure-overloaded. This accommodation is effected by recruitment of previously nonperfused vessels in the superior portions of the lung and distention of the vessels in dependent areas. During periods of intense exercise, pulmonary blood flow may increase up to fivefold, whereas pulmonary vascular resistance may increase only minimally through recruitment of small arterioles and capillaries thereby enabling the pulmonary vascular bed to accommodate an increase in cardiac output while systolic pulmonary artery pressure rarely exceeds 20 mmHg.[23] In fact, two thirds of the lung must be destroyed before pulmonary artery pressure increases at rest. Even after pneumonectomy, pulmonary artery pressure remains near normal as long as no further pulmonary vascular change occurs.[6] The response of the right ventricle to acute increases in pulmonary vascular resistance has been studied in animal models.[24] Figure 3 depicts the changes in mean systemic arterial pressure, mean pulmonary artery pressure, mean right ventricular pressure, and mean right atrial pressure that occur as the main pulmonary artery is progressively constricted over 4 to 5 minutes. During this process, the right ventricle was able to generate increasing pulmonary artery pressure and maintain cardiac output until the mean pulmonary artery pressure was about 40 mmHg, at which point sudden circulatory collapse ensued.

Figure 3.

(Enlarge Image)

Measurement of mean pulmonary pressures in a dog over a 4- to 5-minute period. The right ventricle is unable to generate a mean pulmonary artery pressure > 40 mmHg, leading to sudden circulatory collapse. (From Wiedemann and Matthay[24] with permission.)

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Figure 3. Measurement of mean pulmonary pressures in a dog over a 4- to 5-minute period. The right ventricle is unable to generate a mean pulmonary artery pressure > 40 mmHg, leading to sudden circulatory collapse. (From Wiedemann and Matthay[24] with permission.)

Wiedemann and Matthay described the pathophysiology of such acute circulatory collapse as the "vicious cycle" of acute right failure (Fig. 4).[24] Increasing right ventricular volume (preload) is an important mechanism for maintaining systolic function in the presence of pulmonary artery hypertension. However, as right ventricular volume increases, ventricular wall stress and oxygen demand increase, tricuspid valve insufficiency occurs, and left ventricular diastolic compliance decreases. These events, which impair the performance of the ventricles, eventually cause systemic hypotension. As aortic pressure drops, right coronary artery perfusion is adversely

affected, with further decline in right ventricular function and further right ventricular dilation. Without intervention, these events rapidly spiral into irreversible shock.
Figure 4.

Pathophysiology of acute right heart failure: the vicious cycle. (From Wiedemann and Matthay[24] with permission.)
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Figure 4. Pathophysiology of acute right heart failure: the vicious cycle. (From Wiedemann and Matthay[24] with permission.)

In patients with chronic cor pulmonale, acute decompensation may occur during exacerbations of pulmonary disease when compensatory measures (such as dilation and hypertrophy) fail. Other factors leading to right ventricular failure may include reduced right ventricular preload due to hyperinflation in patients with obstructive lung disease with decreased venous return. Reduced right ventricular filling in these patients may result from increased intrathoracic pressure or decreased intravascular volume owing to diuretic therapy. In patients with restrictive lung disease, loss of distensibility and relative stiffness of the intrathoracic structures may limit cardiac filling leading to right ventricular collapse.[25] Also, poor right ventricular response or

overt failure due to pressure overload may be caused by impairment of right ventricular blood supply. In systemic hypertension, the left ventricle has increased myocardial oxygen demand. In turn, coronary artery perfusion pressure increases with an increase in diastolic pressure to meet this myocardial oxygen demand. In patients with pulmonary artery hypertension, right ventricular myocardial oxygen demand is also increased. Right ventricular myocardial perfusion occurs during both diastole and systole but systolic flow to the right coronary artery is diminished because of elevations in right ventricular pressure.[11] In addition, perfusion pressures may decrease with a reduction in cardiac output. Even with normal coronary arteries, the blood flow to the right coronary artery can be limited at high pulmonary artery pressures, possibly leading to right ventricular failure due to myocardial ischemia.[6]

Right and Left Ventricular Interdependence in Cor Pulmonale

The prevalence of left ventricular dysfunction as a result of right ventricular dysfunction is widely debated.[26-28] In a study by Render and colleagues[26] of patients with moderate to severe COPD, 32% who presented with clinical deterioration had left ventricular dysfunction contributing to their poor exercise tolerance. In a study by Vizza and colleagues,[27] left ventricular dysfunction did occur but less frequently in patients with parenchymal or airway disease than in patients with pulmonary vascular disease (primary pulmonary hypertension and Eisenmenger's syndrome). The increased prevalence of biventricular dysfunction in the patients with pulmonary vascular disease is due to their having more severe pulmonary hypertension than patients with parenchymal or airway disease. These findings suggest that the right ventricle may compromise left ventricular function because of shifting of the interventricular septum in more severe pulmonary hypertension. Left ventricular dysfunction without significant right ventricular impairment was rare in this study.[27] Although the right and left ventricle are anatomically bound through the interventricular septum, changes in the left ventricular size are not likely to affect the function of the right ventricle. However, a large change in the volume of the right ventricle may lead to a decrease in the volume of the left ventricle because of a leftward shift of the interventricular septum.[29] In fact, systolic overload of the right ventricle results in the most severe geometric configurational changes of the left ventricle at end-systole. This systolic overload leads to a maximal leftward displacement of the interventricular septum, or flattening or reversal of septal curvature and compression of the left ventricle at end-systole. This result was shown in a dog model in which the tricuspid valve was excised, the pulmonary artery was constricted, and right ventricular preload was increased, leading to an increase in right ventricular diastolic volume and pressure and decreased left ventricular compliance and function (Fig. 5).[24]
Figure 5.

(Enlarge

The illustration demonstrates the left ventricular diastolic volume pressure curve in three groups of dogs: normal dogs, dogs with right ventricle pressure stress in which right ventricular end diastolic pressure (RVEDP) is maintained at low levels similar to normal humans, and dogs with right ventricle pressure stress in which the RVEDP

Image)

is allowed to increase to higher levels. This demonstrates a form of "ventricular interdependence" in which the right ventricle stress decreases left ventricular compliance. (From Wiedemann and Matthay[24] with permission.)

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Figure 5. The illustration demonstrates the left ventricular diastolic volume pressure curve in three groups of dogs: normal dogs, dogs with right ventricle pressure stress in which right ventricular end diastolic pressure (RVEDP) is maintained at low levels similar to normal humans, and dogs with right ventricle pressure stress in which the RVEDP is allowed to increase to higher levels. This demonstrates a form of "ventricular interdependence" in which the right ventricle stress decreases left ventricular compliance. (From Wiedemann and Matthay[24] with permission.)

When negative intrathoracic pressure increases, the pressure difference across the ventricular wall may increase, resulting in an increase in left ventricular afterload.[25] This effect may be more pronounced in patients with restrictive lung diseases in whom greater negative intrathoracic pressure is needed to assist expansion of poorly compliant lungs. The demand to generate greater negative intrathoracic pressure increases afterload and may lead to worsening left ventricular performance in patients with even mild systolic impairment. Hypoxia, acidosis, and systemic hypertension have all been proposed as possible contributing factors to worsening left ventricular function.[1] Hypoxia is known to impair relaxation of both ventricles in normal humans. Disruption of intracellular calcium transport due to myocyte hypoxia may be responsible for impaired ventricular relaxation. Therefore the effects of chronic

hypoxemia (e.g., in COPD) may significantly affect the energy production of the myocardium and lead to abnormal relaxation of the ventricles. This theory was postulated by Tutar and colleagues[30] in an echocardiographic study assessing left ventricular diastolic function in patients with chronic cor pulmonale.
Respiratory Diseases Associated with Cor Pulmonale Chronic Obstructive Pulmonary Disease

COPD is the most common cause of chronic cor pulmonale in North America.[31] (Also see the article by Lee-Chiong and Matthay in this issue of Seminars.) COPD affects more than 14 million people yearly in the United States and is the fourth leading cause of death. Pulmonary artery hypertension is the primary cardiovascular complication encountered in COPD. The actual prevalence of cor pulmonale in patients with COPD is difficult to establish; however, it is estimated that between 10 and 30% of all hospital admissions for heart failure in the United States yearly are due to cor pulmonale.[1] Autopsy studies in patients with chronic lung disease found that more than 40% had evidence of cor pulmonale.[20,32] The prevalence of cor pulmonale was also increased in patients with hypoxemia, hypercapnia, or evidence of severe airflow obstruction [measured as forced expiratory volume in 1 second (FEV1)] . Pulmonary artery hypertension has been estimated to be present in almost 40% of patients with an FEV1 < 1 L.[33] The presence of right ventricular dysfunction in patients with COPD is a poor prognostic indicator.[34] In a 1966 Veterans Administration trial, patients with COPD and cor pulmonale had a 4-year mortality rate of 73%.[35] Changes in the pulmonary vessels due to arterial hypoxemia in COPD include thickening of the intimal smooth muscle cells, and medial layer hypertrophy.[1,5] These structural changes cause a rise in the pulmonary artery pressure rather than hypoxic vasoconstriction alone. The elevation in pulmonary artery pressure tends to be rather mild in patients with COPD; severe pulmonary artery hypertension is uncommon in this disease. Stevens and colleagues[36] reviewed a cohort of 500 patients with COPD and cor pulmonale, and only six patients had severe elevations of mean pulmonary artery pressure, defined as > 50 mmHg. The authors concluded that the severity of pulmonary artery pressure was not related to the severity of the underlying lung disease in these patients. Therefore, patients with COPD who present with severe pulmonary artery hypertension should be evaluated for other causes of increased pulmonary artery pressure.[32] Although pulmonary artery hypertension develops slowly in patients with COPD, its presence is a poor prognostic indicator. Weitzenblum and colleagues[37] showed a 72% 4-year survival rate in patients with normal pulmonary pressure and a 49% survival rate in patients with elevated pulmonary artery pressure (mean > 20 mmHg). Blood viscosity may be increased in patients with COPD as a result of chronic hypoxemia.[38] Blood viscosity and possible sheer stress due to erythrocythemia can lead to pulmonary artery hypertension. The reduction of blood volume may only lead to a small reduction in pulmonary artery pressure and vascular resistance. But in a small study of seven patients with severe COPD and cor pulmonale, Borst and colleagues[39] found that reducing blood viscosity by phlebotomy over a 3-month period improved pulmonary gas exchange, central circulatory hemodynamics, and exercise tolerance. Polycythemia may also exert a sheer stress on the pulmonary vessel

endothelium, leading to an increase in vascular resistance through inactivation of endotheliumderived NO.

Interstitial Lung Disease

Pulmonary diseases that involve changes in the alveolar walls, perialveolar tissue, and other supporting structures are known collectively as interstitial lung disease. (Also see article by Tanoue in this issue of Seminars.) Cor pulmonale in these disorders is often caused by destruction and obliteration of the pulmonary vascular bed as a result of fibrosis and loss of lung parenchyma.[40] The mechanism for pulmonary artery hypertension is directly related to fibrosis, leading to entrapment of segments of the pulmonary vasculature. The resulting compression of the pulmonary vessels leads to thrombosis and fibrous organization of vessels, with obliteration of areas of the vasculature.[41] Hypoxia ensues from vasculature obliteration. Patients with these disorders initially hyperventilate at rest to compensate and subsequently desaturate with exercise. As the disease progresses, arterial hypoxemia worsens at rest. Moderate pulmonary hypertension develops because of hypoxia and also usually worsens with disease progression. Like patients with COPD, patients with interstitial lung disease and elevated pulmonary artery pressure have a poorer prognosis.[11] Cardiovascular function in interstitial diseases may be additionally complicated by multiorgan abnormalities, depending on the underlying cause of the lung disease.[11] Pulmonary histiocytosis X is a smoking-related interstitial lung disease leading to hyperinflation or obstructive lung disease. A minority of patients develop pulmonary fibrosis and honeycomb lung. In advanced cases of histiocytosis X, exercise capacity may be diminished because of pulmonary vascular dysfunction rather than ventilatory limitation. Histopathologic analysis suggests that pulmonary hypertension in pulmonary histiocytosis X might be related to intrinsic pulmonary vascular disease in which the pulmonary circulation is involved independent of small airway and lung parenchyma injury.[42]
Sleep Apnea and Alveolar Hypoventilation Disorders

Sleep apnea may lead to the development of pulmonary artery hypertension and right ventricular failure.[43] (Also see the articles by Judd et al and Krachman et al in this issue of Seminars.) The prevalence of pulmonary artery hypertension in patients with obstructive sleep apnea without lung disease ranges from 17 to 41%, with most indicating approximately 20%.[44] In most cases, pulmonary artery hypertension is mild, similar to the degree of severity in COPD. In patients with no evidence of daytime arterial hypoxemia, pulmonary artery hypertension is rare. The severity of nocturnal events does not appear to influence pulmonary hypertension.[45] Pulmonary artery hypertension and cor pulmonale are relatively common in patients with severe chest wall deformities, including kyphoscoliosis. Pulmonary artery hypertension is related to a reduction in the pulmonary vascular bed due to hypoventilation and hypoxia. Hypoxia is due to ventilation-perfusion mismatch and underlying atelectasis. When hypoxia is severe, cor pulmonale and right ventricular hypertrophy ensue.[11]

Neuromuscular diseases such as muscular dystrophy, amyotrophic lateral sclerosis, and postpolio syndrome can lead to pulmonary hypertension.[46] But the development of right-sided heart failure is an unusual manifestation of respiratory muscle weakness and respiratory failure. Cor pulmonale and pulmonary artery hypertension usually develop because of underlying hypoxia and hypercapnia due to respiratory muscle weakness.[47] Bilateral diaphragmatic paralysis is also an uncommon and rarely recognized cause of cor pulmonale. This disorder may not be recognized until patients develop respiratory failure and cor pulmonale.[5]
Primary Pulmonary Hypertension

Primary pulmonary hypertension is a rare disorder of unknown cause, although a number of conditions have been associated with it. In autopsy studies, it accounts for approximately 1% of all causes of cor pulmonale. The clinical diagnosis is based on (1) chest radiography, electrocardiography, and echocardiography; (2) elevated pulmonary artery pressure demonstrated by right-sided heart catheterization with normal pulmonary capillary wedge pressure; and (3) no evidence of another cause of elevated pulmonary artery pressure.[17] The vascular lesions responsible for primary pulmonary hypertension occur in the small pulmonary arteries (small muscular arteries and arterioles) in which there is an intrinsic imbalance between factors favoring vasoconstriction over vasodilation that leads to resistance in the pulmonary circulation. For example, the level of endothelin 1 is increased leading to an increase in pulmonary vascular resistance. Endothelial dysfunction may also cause a reduction in vasodilating factors. Most patients present with dyspnea, but as right ventricular failure ensues fatigue, edema, and syncope may occur. Syncope occurs because the increased pulmonary artery pressure prevents the right ventricle from augmenting cardiac output through an increase in stroke volume. The right ventricle in turn attempts to overcome the limitations in cardiac output through an increase in heart rate (especially during exercise). When increases in the heart rate can no longer augment cardiac output syncope occurs. The development of cor pulmonale and the decreased cardiac output correlate with a poorer prognosis in primary pulmonary hypertension.[17] In patients with endstage disease and progression of pulmonary artery resistance, right ventricular failure with hemodynamic collapse is the leading cause of death.[6] In some patients with primary pulmonary hypertension, lung transplantation leads to right ventricular recovery. Improvements have been noted in right atrial and ventricular size and function following the reduction of pulmonary vascular resistance during the postoperative period.[4
Evaluation of the Patient with Chronic Cor Pulmonale Symptoms and Signs

The development of pulmonary hypertension and right ventricular failure in a patient with chronic pulmonary disease has significant prognostic implications; accordingly, careful attention to early physical symptoms and signs is critical.[23] The symptoms of chronic cor pulmonale develop gradually over years. In patients with COPD, clinical signs may be masked by lung

hyperinflation. Most patients initially have dyspnea, which becomes more severe as right ventricular failure occurs. Chest pain may occur and be difficult to differentiate from angina pectoris. In patients with severe COPD, orthopnea is common and is thought to be related to the effect of lung hyperinflation on venous return to the right side of the heart. With worsening right ventricular function, bloating and early satiety occur because of hepatic venous congestion and lower extremity edema.[49] Patients with COPD who develop peripheral edema have a 5-year survival rate of only 27 to 33%.[28] Peripheral edema may be due to other causes, such as hypoalbuminemia, and is not always present in patients with pulmonary hypertension. Edema is rarely present if the pCO2 is normal, and is not always present if the pCO2 is elevated.[50] A systolic left parasternal heave may indicate the presence of right ventricular hypertrophy, and tricuspid regurgitation murmur may indicate the presence of right ventricular dilation. Although the presence of a prominent jugular V wave may indicate tricuspid valvular regurgitation, jugular venous pressure may be difficult to assess in patients with marked lung hyperinflation because of variations in intrathoracic pressures. Accentuation of the second heart sound pulmonic component is an insensitive indication of pulmonary hypertension.[11]
Diagnostic Studies

The chest radiograph may show the presence of pulmonary hypertension or cor pulmonale and provide evidence regarding the etiology. (Also see the article by Kosiborod and Wackers in this issue of Seminars.) Parenchymal lung abnormalities such as hyperinflation may indicate the presence of emphysema or obstructive disease. Skeletal abnormalities such as kyphoscoliosis can be identified as well. The width of the right descending pulmonary artery on the chest radiograph may indicate the presence of pulmonary hypertension (Fig. 6). A width of > 16 mm has been shown to correlate with the presence of pulmonary hypertension in patients with COPD.[9] A width of > 18 mm of the left descending pulmonary artery is also associated with elevated pulmonary artery pressures.[9] In patients with COPD, a high cardiothoracic ratio is highly sensitive and 100% specific for the presence of pulmonary hypertension.[51] Although the chest radiograph may provide evidence for the presence of pulmonary hypertension, it cannot measure the degree of pulmonary artery pressure elevation. A globular heart may indicate right ventricular dilation or hypertrophy, which would be further supported by the presence of a decrease in the retrosternal air space on a corresponding lateral view.[11]
Figure 6.

(Enlarge Image)

Chest radiograph showing the increased width of the right descending pulmonary artery indicating the presence of pulmonary hypertension. (Courtesy of Dr. RA Matthay, New Haven, CT.)

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Figure 6. Chest radiograph showing the increased width of the right descending pulmonary artery indicating the presence of pulmonary hypertension. (Courtesy of Dr. RA Matthay, New Haven, CT.)

Electrocardiographic evaluation for right ventricular hypertrophy is highly specific but not sensitive.[11] Echocardiography can show structural changes due to cor pulmonale or the presence of pulmonary hypertension (Fig. 7.) Gross examination of the right ventricle shows a decrease in its volume relative to its mass in cor pulmonale. The right ventricle becomes less crescent shaped and more concentric overall, similar to the changes that occur in the left ventricle.[52] Early echocardiographic evaluation of the right ventricle was limited by its crescent shape, its substernal location, and the presence of a large amount of artifact. With the advent of twodimensional echocardiography with Doppler and color Doppler imaging, the right ventricle was better visualized.[53] Echocardiography is sensitive in detecting severe elevation in pulmonary artery pressure but may be of limited value in the detection of mild to moderate elevations. Measurement of the peak velocity of the tricuspid valve regurgitation jet using Bernoulli's equation in the absence of tight ventricular outflow tract obstruction can provide an estimate of the pulmonary artery systolic pressure.[54] This technique is limited in patients with COPD because a satisfactory signal cannot be obtained. Pulmonary artery hypertension can also be detected by the measurement of the flow characteristics of the inferior vena cava, although this method has not been studied prospectively. Diastolic flattening of the interventricular

septum occurs with progressive pulmonary hypertension and can be visualized by echocardiography, which may also indicate evidence of right ventricular overload.[5] The detection of right ventricular dimensions and wall thickening is limited by the inability to differentiate the right ventricular wall from its surrounding structures. Correlations between right ventricular wall thickness and right ventricular weight are poor even when measured at autopsy.[28] The measurement of the right ventricular diameter during diastole may indicate evidence of right ventricular enlargement. Transesophageal echocardiography does not seem to provide additional information in assessing the right ventricle. Three-dimensional echocardiography is being investigated in the assessment of pulmonary artery hypertension and right ventricular dimensions.[11]
Figure 7.

(Enlarge Image)

Echocardiogram indicating the evidence of structural changes secondary to cor pulmonale including diastolic flattening of the interventricular septum indicating volume overload of the right ventricle. (Courtesy of Dr. RA Matthay, New Haven, CT.)

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Figure 7. Echocardiogram indicating the evidence of structural changes secondary to cor pulmonale including diastolic flattening of the interventricular septum indicating volume overload of the right ventricle. (Courtesy of Dr. RA Matthay, New Haven, CT.)

The gold standard for the measurement of cardiac volumes and ejection fractions is contrast ventriculography as long as adequate separation of the cardiac chambers can be seen. Although pulmonary artery pressure cannot be calculated directly with this technique, there is an inverse relationship between the pressure measured at right-heart catheterization and right ventricular ejection fraction in patients with COPD.[5] Computed tomography (CT) can be used to determine the pulmonary artery cross-section diameter, which correlates well with pulmonary artery pressure.[55] High-resolution CT scans (HRCT) can provide evidence of parenchymal disease. Magnetic resonance imaging (MRI) is becoming the reference standard for measuring ventricular dimensions because it provides the best image of the right ventricle.[56] MRI can also be used to identify regional right ventricular function to determine the impact of chronic pulmonary hypertension on global cardiac function. The gold standard for the diagnosis of pulmonary hypertension remains right-heart catheterization. A thermodilution balloon catheter is inserted, and right atrial, right ventricular, pulmonary artery, and pulmonary artery occlusion pressures are measured. With pulmonary hypertension the pulmonary artery occlusion pressure should be normal; otherwise, left-heart catheterization may be needed.