• ²History:

  • Primary (unexplained) pulmonary hypertension: a rare lung disorder with significant pulmonary artery pressure elevations above the normal range.

  • By review, the pulmonary artery is the vessel carrying oxygen-depleted blood from the right ventricle to the lung for oxygenation.

  • First reported case: In 1891, Dr. Romberg in Germany published a description of an autopsy case in which significant thickening of the pulmonary artery was noted in the absence of clearly evident cardiac or lung disease.

    • The disease was formally named in 1951 by Dr. D. Dresdale reporting on 39 cases in United States

  • The frequency of primary pulmonary hypertension appears to be abouty 10 to 50 cases per million

    • However, there is evidence that pharmacological agents might influence the frequency of this rare disorder. 

    • For example, there was an order of magnitude increase in the disease frequency in Europe between 1967 in 1973 because ultimately linked to an amphetamine-like drug aminorex funarate promoted to control appetite. 

      • Following removal of this agent from the market, the incidence of pulmonary hypertension in Europe return to previous levels. 

      • In view of this experience, it may not be surprising that some cases of primary pulmonary hypertension have been associated with the appetite suppressants fenfluramine and dexfenfluramine, which have been removed from the market.

  1Thickening of muscular arterial wall in a patient with primary pulmonary hypertension;Division of Lung Diseases and Office of Prevention,  Education, and Control; Primary pulmonary hypertension; National Institutes of Health; National Heart, Lung, and Blood Institute,1996

• ²Possible causes:

  • The general suggestion has been that their use a generalized vascular hyper-reactivity, such that vessels constrict in response to certain factors.  These factors may be external or internal.  Along these lines, patients with pronounced disease appear more likely to develop primary PH.

  • Factors include: diet suppressants, cocaine, HIV, and pregnancy.  These factors promote in susceptible patients pulmonary artery narrowing.

  • Genetics: about 6%-10% of cases exhibit familial linkage.

• ³Patient presentation: 

  • Dyspnea, precordial discomfort, angina

  • Physical examination may reveal cyanosis and cardiomegaly

• ²Disease progression:

  • The initial insult may be in injury to the vascular endothelial cells

  • Subsequent to this injury, the intrinsic interrelationships between the endothelial cells and the underlying vascular smooth muscle may be changed.  The direction of the change is to cause increased smooth muscle contraction.

  • As the disease progresses, vessel wall muscle cell proliferation causes thickening.  Not only do regions possessing muscle cells normally thickening, but also muscle cells appear in regions not typically exhibiting vascular smooth muscle

  • Vascular stiffness with scarring and fibrosis accompanies thickening; vessels may become completely occluded; within smaller arteries, there is an increased likelihood for thromboembolism.

  • A secondary consequence is that the right ventricular myocardial muscle mass increases in order to pump against this increasing vascular resistance.  Ultimately, following cardiac dilatation hypertrophy, right ventricular failure may occur.

• ¹Clinical consequences: significant morbidity/mortality associated with right-sided cardiac failure and sudden death

  • Problematic diagnosis at least initially; however, acute PH is difficult to manage as it is associated with significant mortality.

  • The most successful treatment management is associated with early diagnosis allowing intervention preceding significant damage to the pulmonary vasculature

  • Most common cause of acute pulmonary hypertension:

    • pulmonary thromboembolism [perhaps up to 15% of hospital admitted patients have complications of pulmonary embolism]

• ¹Pathophysiological comments:

  • There are key interrelationships between right ventricular function and pulmonary circulation properties

  • Normal physiology: normally minimal pulmonary vascular bed resistance to blood flow

  • Pathophysiology: Pulmonary hypertension occurs because of either:

    1. pulmonary vascular vasoconstriction

    2. OR increase in pulmonary blood flow

    • These pathophysiological changes may be referable to pulmonary parenchymal abnormalities, myocardial abnormalities, and/or pulmonary vascular pathologies. 

• ¹Normal pulmonary circulation physiology:

  • The pulmonary circulation is a high-volume low pressure system which is in contrast to the systemic circulation.

  • Pulmonary artery mean pressure is about 12 mm Hg.  The left atrial mean pressure ranges from 2 to 6 mm Hg; therefore, the normal pulmonary circulatory pressure gradient is only about 6 mm Hg.  For comparison, the pressure gradient between the left ventricle and right atrium ranges from 80-100 mm Hg [for cardiac output of about 5 liters per minute].  The systemic vascular bed has a resistance to blood flow of about 10 times that observed for the pulmonary circulatory system.

  • For the high flow low pressure pulmonary system, only small differences in either right ventricular volume or pressure load can alter function in an important manner.

  • By definition, pulmonary hypertension occurs if the resting pressure is > 20 mm Hg or the resting pulmonary artery systolic pressure is > 30 mm Hg.

• ¹Factors that influence pulmonary vasomotor tone:

  • Histamine

  • norepinephrine

  • angiotensin II

  • serotonin

  • arachidonic acid metabolites

  • lipoxygenase products

  • acetylcholine will induce a temporary vasodilation in patients with elevated pulmonary  vascular resistance; moreover, this effect is probably mediated by release of endothelial-derived relaxing factor (nitric oxide) from the vascular endothelium.

• ¹Hypoxic pulmonary vasoconstriction:

  • Pulmonary vasoconstriction may be induced as part of a mechanism to balance capillary perfusion with alveolar ventilation.

    • These vascular tone adjustments occur at the level of small pulmonary arteries and arterioles; however, the underlying mechanism remains to be elucidated definitively.  It is possible that local hypoxia causes local histamine release which results in H₁-receptor-mediated vasoconstriction.

  • Although vascular endothelium releases the smooth muscle relaxing chemical nitric oxide (NO), endothelial cells also release a vasoconstricting peptide endothelin.  Probably the balance between nitric oxide and endothelin release is important in setting local pulmonary vasomotor tone.

    5Richard E. Klabunde, Ph.D.,Cardiovascular Physiology Web Resource  used with permission

     

    • ³ET-1 (endothelin-1) is secreted as "big-endothelin-1", which is a 38 amino acid peptide that is converted to ET-1 by the action of a protease [ET-1 converting enzyme-1, ECE-1].

      • There are two subtypes of ECE-1 which exhibit different anatomical distributions.  ECE-1A is an endothelial cell product and ECE-1B is found on smooth muscle cells.

    • ³There are two principal effects of ET-1: vasoconstriction and a mitogenic effect on smooth muscle [i.e. a stimulant of cellular proliferation]. In evaluation of patients with pulmonary hypertension, there appears to be correlation between disease severity and the level of ET-1 molecular expression.  Molecular biological methods demonstrated that the higher levels of ET-1 were associated with higher levels of ET-1 mRNA.

    • ³That ET-1 levels are important in the pathophysiology of pulmonary hypertension is supported by the observation that ECE-1 inhibitors (that is chemicals which inhibits the converting enzyme which creates ET-1 from "big-endothelin-one") reduce pulmonary artery pressure. 

    •  ³Endothelins Receptors: Three endothelin receptor subtypes have been noted (ET-A, ETB-1, ETB-2).  

      • ET-A receptors appear localized mainly on smooth muscle cells; 

      • ETB receptors appear mainly associated with endothelial cells.  A complexity that must be noted is that under some circumstances ET-1 (endothelin-1) has been observed to cause vasodilation-probably by interacting with the ETB receptor subtype, whereas interacting with the ETA subtype causes vasoconstriction.  The prominent effect however is the vasoconstrictive effect.

    •  ^3,4The nitric oxide story:

      • Endothelial cells produce nitric oxide (NO,N=O) which is a vasodilator and vasodilates by activating guanylyl cyclase thus increasing cGMP.

        • cGMP can activate a GMP-dependent protein kinase, activate K+ channels, decrease IP₃, and inhibit calcium entry into the vascular smooth muscle; these actions likely mediate vascular relaxation.⁵

          • NO also in may produce vasodilation by decreasing vasoconstrictor factor expression. 

          • Therefore the amount of nitric oxide synthesis is of interest in view of its center role in potentially modulating pulmonary vasomotor tone in pulmonary hypertension.

      • ⁴NO causes many biological effects including acting as a "bronchodilator, neurotransmitter, anticoagulant, anti-microbial agent, antithrombogenic factor, antiaggregatory factor, inhibitor of smooth muscle mitogenesis and a vasodilator"

        • Nitric oxide is synthesized from L-arginine (oxidative cleavage of the guanidino nitrogen) in a reaction catalyzed by nitric oxide synthase (NOS) and one requiring molecular oxygen and produces nitric oxide and L-citrulline.

        • NOS is a  complex enzyme, depending upon five redox cofactors: NADPH, FAD, FMN, heme and tetrahydrobiopterin.  

          • Furthermore there are three forms of NOS: a neuronal form (nNOS a.k.a.NOS-I),an inducible form (iNOS a.k.a. NOS II) and endothelial NOS or eNOS. 

            • nNOS and eNOS are induced by calcium, whereas iNOS is activated by lipopolysaccharides, other inflammatory agents and cytokines.

          • iNOS catalyzes the production of the most nitric oxide

          • The significance of the level of NOS activity is in part due to the relationship between NOS activity and pulmonary hypertension disease severity.

            • eNOS levels in human disease correlate inversely with total pulmonary vascular resistance than pulmonary arteropathic severity. 

              • By contrast, normal lungs stained intensely for eNOS in both pulmonary vascular endothelium and pulmonary epithelium.

          • A possible therapy for pulmonary hypertension might be therefore increasing the levels of nitric oxide or reducing the levels of ET-1

      • 5Richard E. Klabunde, Ph.D.,Cardiovascular Physiology Web Resource used with permission

         

          

  • Smooth muscle vascular tone ultimately depends on activation of myosin light chain kinase with subsequent phosphorylation of myosin light chains.  This step promotes interaction between actin and myosin.  Myosin light chain kinase activation requires calcium complex with calmodulin.  Therefore it is not surprising the calcium channel blocking drugs reduce the vasoconstrictive pulmonary response to hypoxemia since the reduction in intracellular calcium would limit myosin light chain kinase activation.

⁵Richard E. Klabunde, Ph.D.,Cardiovascular Physiology Web Resource  used with permission

• ¹Development of pulmonary hypertension

  • Right ventricular dysfunction may be caused by factors that also contribute to the development of pulmonary hypertension and include:

    • anatomical structural characteristics of the right ventricle

    • functional relationships between the right and left ventricle

    • factors that influence right ventricular coronary blood flow

  • ¹Primary pathophysiological consequence of PH: progressive attenuation of right ventricular function due to progressive increase in right ventricular afterload

    • Anatomical considerations -- right vs. left ventricle: The right ventricle is relatively thin-walled, compliant and easily distended. 

      • Also compared to the left ventricle, the right ventricle is considerably more sensitive to afterload increases, that is, small increases in ejection resistance leads to marked decreases in right ventricular stroke volume.

  • Yale center for Advanced Instructional Media, Yale Tech University School of Medicine, Medical Editor: C. Carl Jaffe, MD; Site Producer: Patrick J. Lynch; used with permission, copyright 2000,  Yale University School of Medicine

• ¹Note in the image above the relatively thin right ventricular wall compared to the left ventricular wall.  Furthermore, given the compliance of the right ventricle in the sensitivity of the right ventricle to small afterload increases, compensatory right ventricular wall tension increases may readily occur.  

  • Such increases in wall tension are directly linked to increases in myocardial oxygen requirements, which is not met, may cause a deterioration right in right ventricular function.

• ¹Anatomically, the heart must be described as two pumps operating in parallel and synchrony.  Therefore if an output-mismatch occurs for even a short interval, vascular congestion will result -- either on the pulmonary side or systemically.

  • In accord with the difference in right vs. left ventricular muscle mass, the workload of the right ventricle is only about 15 percent of the left ventricle, despite the need to pump about the same cardiac output.  This rough equivalence in cardiac output is only possible given the significantly reduced  right vs. left afterload (resistance).

  • Increases in right ventricular afterload, even small increases, would be sufficient to shift the ventricular septum from right to left and thus impair left ventricular function.  Additionally, septal shift (right to left) which would be associated with increased right ventricular end-diastolic volumes, impair left ventricular diastolic filling (increased filling pressures required to obtain a given diastolic left ventricular volume)

  • The above phenomena connect the increase in pulmonary artery pressure to a reduction left ventricular volume.

    1. increased pulmonary artery pressure leads to increased right ventricular end diastolic volume

    2. increased right end diastolic pressure shifts the intraventricular septum to the right which interferes with left ventricular function

    3. reduce less ventricular function causes reduced cardiac output leading to increase pulmonary capillary wedge pressure

• ¹The general rule is that coronary vascular perfusion occurs during diastole. 

  • This assessment focuses on the coronary vasculature supplying the left side of the heart. 

    • However the right side of the heart supplied by right ventricular coronary flow normally can occur both in systole and diastole, assuming normal, nonhypertrophied muscle and attendant low intracavity pressure.

  • Now consider what happens with right ventricular hypertrophy with higher intracavity pressures: The higher intracavity pressure tends to restrict coronary flow to diastole with its greater pressure gradient.  Accordingly, the right side of the heart is much more sensitive to systemic hypotension in terms of getting adequate oxygen perfusion through coronary flow.  Therefore, reduced coronary flow can further exacerbate right ventricular function secondary to hypotensive states and higher right ventricular intracavity pressures.

• ¹Anatomical causes of pulmonary hypertension:

  1. left ventricular dysfunction

  2. left atrial lesions (e.g. ,mitral valve stenosis, mitral valve endocarditis, myxomas, thrombi)

  3. pulmonary circulation lesions

  4. right ventricular lesions

     • The above conditions promote long-term increases in pulmonary venous pressures which ultimately cause right ventricular hypertrophy, dilatation and ultimately right-sided pump failure.

     • Considering the consequences of left ventricular lesions: with inadequate left ventricular contractility or valvular dysfunction, elevation in left ventricular end diastolic volume will increase pulmonary venous pressure promoting pulmonary hypertension.

       •   Factors responsible for left ventricular dysfunction include valvular dysfunction (mitral valve dysfunction), ischemic coronary vascular disease, as well as idiopathic/infectious cardiomyopathies. Again the effect on right ventricular performance will be indirect since these left ventricular lesions all increase the right-side afterload, i.e. right ventricular ejection resistance.

  5. Obstructive disease:  these lesions cause an increase pulmonary venous an arterial systemic pressure.

• ¹Pulmonary hypertension in the clinical settings: acute vs. chronic presentations and pathologies

  • Pulmonary vascular resistance can be induced by many factors including hypoxia, acidosis, increase sympathetic tone as well as exogenous/endogenous vasoconstrictors such as thromboxane, catecholamines, and serotonin, hypercarbia and acidosis

  •  Patients presenting perioperatively with significant pulmonary hypertension often will have a combination of both the chronic form within acute increase in pulmonary vascular resistance [as noted above, increase circulating catecholamines associated with perioperative stress might be sufficient to exacerbate underlying pulmonary hypertension]

  • Initial management perioperatively, may be centered on reversing at least the acute component.  In considering a specific example, pulmonary vasoconstrictors or reduced endogenous nitric oxide from endothelial injury associated with cardiopulmonary bypass could explain increased right ventricular dysfunction after this procedure.  Possibly inadequate interoperative protection of the right ventricle could be a contributing factor.

  • Chronic settings:

    • In chronic disease there has been long-term significant, fundamental changes in the pulmonary vasculature.  

      • There is a fairly long list of contributing factors including primary PH, thromboembolic disease, vasculitis.  Additionally parenchymal lung damage due to fibrosis  or COPD promotes PH.  

      • Abnormal ventilation such as obesity-hypoventilation syndrome or even sleep apnea may contribute to PH.

  • Early stage and then later stage considerations: 

    • Increased pulmonary vascular resistance detected early can be managed with drugs.  Unfortunately over time fundamental changes in the vasculature reduce pharmacological options.  The vasculature changes include remodeling which is consistent with the mitogenic effects of ET-1.

    • As resistance to right ventricular ejection increases over time, the right ventricle is stressed and responds in a manner limited by limited compensatory reserves.

• ¹Evaluation of right ventricular function

  • Since early identification of increased pulmonary vascular resistance allows effective pharmacological intervention, there is value in understanding initial clinical presentations however difficult to discern.  Early presentations include dyspnea upon exertion, whereas more advanced pulmonary hypertension is associated with more serious clinical concerns including syncope, chest pain, or even sudden death.  Clearly there is a great interest in identifying the disease early in the process begins with the physical examination.

    • ¹Physical examination: Factors consistent with pulmonary hypertension:

      1. increase jugular venous distention

      2. systolic murmur increasing in intensity during inspiration (consistent with tricuspid valve regurgitation)

      3. pronounced second heart sound at the base of a heart -- due to forceful  pulmonic valve closure

      4. diastolic pulmonary valve murmur along less stern border

    • ¹Chest radiography:

      1. Enlarged central, right, and left main pulmonary arteries in the medialstinal hilum.

      2. Enlarged right ventricle may be observed in severe cases

      3. Chest films may correlate with worsening symptoms.

    • ¹Electrocardiography (ECG):

      • Right ventricular enlargement may be sufficient to induce detectable ECG changes.  These changes may not affect the basic cardiac rhythm; however, other changes may be discernible, including:

        1. tall R wave and small S wave: lead V1 (R wave > 7 mm, S wave < 2 mm; R/S > 1)

        2. tall S wave and small R wave and lead V5 or V6 (R/S < 1)

        3. right axes deviation --QRS axis > 90 degrees

        4. ST-segmental depression and T wave inversion in anterior leads (V1 through V4) indicative of significant right-sided heart dysfunction

        5. right atrial enlargement would be indicated by P  waves > 2.5 mm and leads II, III, and aVF

        6. Note that traditional lead placement may make it difficult to detect early right ventricular dysfunctional indications; however, a new specially placement using the V₄R lead in the fourth intercostal space in the mid-clavicular line has been shown to exhibit increased specificity insensitivity to correlations with other diagnostic methods such as radionuclide and echocardiographic standards for detecting right ventricular ischemia.

    • ¹Central venous and pulmonary artery pressures and thermal dilution

      • This method is  now considered an inaccurate predictor of right ventricular end diastolic pressure and volume

      • Appropriate generalizations based on CVP hemodynamic patterns:

        1. Decreased CVP is caused by decrease preload: appropriate therapy is volume administration (of course volume administration must proceed carefully in order to avoid further worsening of right ventricular function through distention)

        2. Increased CVP is caused by decreased contractility which may require inotropic agents.

      • Thermal dilution methodologies may approximate right ventricular ejection fractions, although there are specific limitations that affect the accuracy of this method

    • ¹CT scan measurements:

      1. inner endocardial wall identification

      2. measurements of total ventricular stroke volume

      3. epicardial surface outlines

      4. wall thickness (ultrafast CT)

      5. This technology can demonstrate increased right ventricular muscle mass in patients with PH

    • ¹Nuclear imaging:

      • Right ventricular and systolic pressure-volume relationships may be estimated using radionuclide ventriculogram; furthermore variations of right ventricular volume with varying loads can be determined

    • ¹Echocardiography:

      • Echocardiography has been an important technology in the assessment of right ventricular dimensions as a function of loads.  Movement of the interventricular septum may also be resolved -- as noted earlier with increasing right ventricular pressures septal shift would be expected (right to left)

      • A number of important measurements ranging from the description of right atrial and ventricular dimensions to assessment of valvular regurgitation are available using electrocardiographic technologies.