![ Recent genetic and pathophysiologic studies of PH
have emphasized the relevance of several other
mediators, such as angiopoietins, serotonin, bone
morphogenetic proteins (BMPs), and growth
factors (platelet-derived growth factor [PDGF],
fibroblast growth factor [FGF], epidermal growth factor
[EGF], and the transforming growth factor-beta [TGF-
β] superfamily)
Abnormal proteolysis of the extracellular matrix,
autoimmunity, and inflammation are also likely to
contribute to the pathobiology of PH, and there is a
growing body of literature on the role of cytokines and
chemokines in pulmonary vascular remodeling](https://image.slidesharecdn.com/pah-220125173601/85/Pulmonary-Hypertension-Clinical-diagnosis-hemodynamics-and-approach-Dr-Akif-Baig-7-320.jpg)
Pulmonary Hypertension: Clinical diagnosis, hemodynamics and approach - Dr. Akif Baig
- 1. - Dr. Akif A.B
- 2. Definition PH is defined as an increase in mean pulmonary arterial pressure >25 mmHg at rest as assessed by right heart catheterization (RHC) Normal PAPm at rest is 14±3 mmHg with an upper limit of normal of approximately 20 mmHg
- 4. PH has a multifactorial pathobiology: Imbalance in vasoconstriction and vasodilation Thrombosis, Cell proliferation and Remodeling of the walls of the pulmonary arteries contribute to increased PVR
- 5. Pulmonary vasoconstriction has been regarded as an early component of the PH process Excessive vasoconstriction has been related to abnormal function or expression of potassium channels and to endothelial dysfunction Endothelial dysfunction is characterized by impaired production of vasodilators such as nitric oxide (NO) and prostacyclin, along with overexpression of vasoconstrictors such as endothelin-1
- 6. Pulmonary vascular remodeling involves the intima, media, and adventitia of small pulmonary arteries All cell types (endothelial, smooth muscle, and fibroblastic), as well as inflammatory cells and platelets, may play a significant role in the condition
- 7. Recent genetic and pathophysiologic studies of PH have emphasized the relevance of several other mediators, such as angiopoietins, serotonin, bone morphogenetic proteins (BMPs), and growth factors (platelet-derived growth factor [PDGF], fibroblast growth factor [FGF], epidermal growth factor [EGF], and the transforming growth factor-beta [TGF- β] superfamily) Abnormal proteolysis of the extracellular matrix, autoimmunity, and inflammation are also likely to contribute to the pathobiology of PH, and there is a growing body of literature on the role of cytokines and chemokines in pulmonary vascular remodeling
- 8. Pathophysiology of pulmonary hypertension in left heart disease
- 9. The increased pulmonary venous pressure results in disruption of alveolar-capillary walls termed alveolar-capillary stress failure, resulting in capillary leakage and acute alveolar edema
- 10. This acute stage is reversible However with chronically increased pulmonary venous pressure there is irreversible remodeling of the alveolar-capillary membrane as a compensatory mechanism to decrease the frequency and severity of potentially life-threatening pulmonary edema
- 11. The remodeling affects both pulmonary venous and arterial system with thickening of the capillary endothelial and alveolar epithelial cell basement membranes and pulmonary veins These changes reduce the permeability of the alveolar- capillary membrane to fluids, and prevent development of pulmonary
- 12. The process also results in muscularization of the arterioles and neointima formation along with medial hypertrophy of distal small pulmonary arteries leading to increased pulmonary vascular resistance With long-standing disease, pulmonary edema becomes less frequent and the clinical picture is dominated by development of PH and right heart failure
- 13. The development of pulmonary vascular disease is variable, with some patients developing severe PH while others being spared of PH despite similar rises in PCWP While why this happens is unknown, some factors may be responsible The patients with large compliant left atria may be less prone to development of pulmonary edema and ultimately less severe PH Also development of AF may make them more prone to develop PH
- 14. No pulmonary hypertension (PH) Fluid is continuously cleared from the alveolar surface by the Na+ channels and Na+-glucose co-transport system passively Then the adenosine triphosphate (ATP) dependent Na+-K+ pumps “drain” fluid through the interstitium and the vascular bed In between the alveolar surface and capillary there is the extracellular matrix with cellular attachments composed primarily by collagen type IV
- 16. Isolated post-capillary PH (IpcPH) This hemodynamic condition leads to a pathological increase in left atrial pressure (LAP), pulmonary artery wedge pressure (PAWP) and mean pulmonary artery pressure (mPAP) with pulmonary vascular resistance (PVR) and diastolic pressure gradient (DPG) still in the normal range The increase in capillary hydrostatic pressure promotes some anatomic breaks in the endothelium and vascular wall and fluid swelling in the interstitium and in the alveoli In addition, some initial impairment in the alveolar surface continuous fluid reabsorption (by Na+ Channels) and capillary Na+-K+ pumps may occur Overall, these disruptive processes are resembled under the “alveolar capillary stress failure” definition Small arteries exhibit endothelial dysfunction and vasoconstriction but no defined changes in the composition of small pulmonary arteries are detectable, the pulmonary veins already show some thickness and trend to arteriolarization
- 18. CpcPH This hemodynamic stage is characterized by a further mechanical injury and progressive increase in PVR, DPG and Mpap As protection toward the excessive fluid swelling from capillaries, a progressive thickening and collagen proliferation of the lamina densa occurs This phenomenon protects against fluid swelling but compromise gas exchange diffusion for lengthening the path between air and red blood cell The alveolar surface continuous fluid reabsorption and capillary Na+-K+ pumps activity become fully impaired The venous system becomes fully arteriolarized and the small arteries exhibit a clear muscularization process and remodeling
- 21. Pulmonary function abnormalities The gas diffusion across the alveolar capillary membrane is decreased in HF, the degree of impairment depending on severity of HF Leads to decreased FVC, FEV1 and diffusion capacity of lung for carbon monoxide (DLCO) and increase in residual volume Structural changes in the alveolar-capillary membrane decrease diffusion capacity of the lung with resultant impedance to gas transfer contributing to exercise intolerance
- 24. RV EF predicts exercise tolerance and survival in advanced HF However, RV EF is inversely proportional to PAP; thus, this result could simply reflect the impact of increased PAP PH has been repeatedly shown to be associated with decreased exercise capacity and shorter life expectancy in HF
- 25. Why is RV function a major determinant of outcome in HF?
- 26. A main reason is ventricular interdependence, defined as the forces directly transmitted from one ventricle to the other through the myocardium and pericardium More recent studies pointed also to the importance of systolic interaction, by which contraction of one ventricle supports the contraction of the other It is estimated that 20% to 40% of RV systolic pressure results from LV contraction and that 4% to 10% of LV systolic pressure results from RV contraction
- 27. Pre-capillary and post-capillary pulmonary hypertension Pre-capillary Post-capillary Predominantly in the pulmonary arterioles and small pulmonary arteries Left heart disease
- 28. Isolated Post-Capillary PH The raised PAP is a passive phenomenon There is no intrinsic pathology in pulmonary circulation
- 29. Combined Post and Precapillary PH Chronic passive elevation of PAP leads to pathologic changes in the small pulmonary arteries and arterioles such that the process is no longer passive The raised PAP in such cases has dual cause Elevated left sided filling pressures Intrinsic pulmonary vascular disease Termed combined post-capillary and pre-capillary PH (Cpc-PH)
- 30. Pulmonary capillary wedge pressure (PCWP) Used to assess left ventricular filling, represent left atrial pressure, and assess mitral valve function It is measured by inserting a balloon-tipped, multi- lumen catheter (Swan-Ganz catheter) into a central vein and advancing the catheter into a branch of the pulmonary artery The balloon is then inflated, which occludes the branch of the pulmonary artery and then provides a pressure reading that is equivalent to the pressure of the left atrium
- 32. In most cases, the PCWP is also an estimate of left ventricular end-diastolic pressure (LVEDP) The normal pulmonary capillary wedge pressure is between 4 to 12 mmHg Elevated levels of PCWP might indicate severe left ventricular failure or severe mitral stenosis
- 33. Clinical Significance of PCWP To evaluate and diagnose pulmonary arterial hypertension (PAH), as patients with group 1 PAH will have PCWP ≤ 15 mmHg PCWP is also useful in differentiating cardiogenic shock (PCWP > 15 mmHg) from non-cardiogenic shock (PCWP ≤ 15 mm Hg) To evaluate blood volume status to guide fluid administration during hypotensive shock, where the PCWP goal should be maintained between 12 to 14 mmHg
- 34. In many patients with LHD, PAWP may be reduced to <15 mmHg with diuretics For this reason, the effect of an acute volume challenge on left heart filling pressures has been considered Limited data suggest that a fluid bolus of 500 ml appears to be safe and may discriminate patients with PAH from those with LV diastolic dysfunction
- 36. Pulmonary vascular resistance is the resistance against blood flow from the pulmonary artery to the left atrium. It is most commonly modeled using a modification of Ohm’s law
- 38. Trans-Pulmonary Gradient Defined as the difference between the mean pulmonary arterial pressure and the left atrial pressure, which is usually equal to pulmonary capillary wedge pressure (PCWP) When transpulmonary gradient is >12 mm Hg in left heart disease, it is considered as out of proportion pulmonary hypertension indicating pulmonary vascular disease
- 40. Diastolic pulmonary gradient (DPG) is the difference between the pulmonary artery diastolic pressure and pulmonary capillary wedge pressure Normal DPG is 1-3mmHg A DPG value ≥ 7 mm Hg signals the presence of pulmonary vascular remodeling in patients with combined pre- and post-capillary pulmonary hypertension (CPCPH) A DPG > 30-40 mm Hg is associated with the worst prognosis and may warrant an aggressive
- 46. Idiopathic Pulmonary Arterial Hypertension Formerly referred to as primary pulmonary hypertension (PPH) IPAH is a rare disease of unknown cause Most common type of group 1 PAH IPAH is a sporadic disease for which there is neither a family history of PAH nor an identified risk factor It has a female preponderance (2 : 1 in the NIH registry, 4 : 1 in the current-day REVEAL registry) Even though the mean age at diagnosis was 37 years in the NIH registry and approximately 50 years in the more recent registries, IPAH can affect children and adults into their 70s.
- 48. Pulmonary Arterial Hypertension Associated With Connective Tissue Diseases Scleroderma
- 49. Pulmonary Arterial Hypertension Associated With Human Immunodeficiency Virus Infection Incidence of PAH is approximately 0.5% Independent of the CD4+ cell count or previous opportunistic infections Prevalence of HIV-associated PAH has not changed with the widespread use of highly active antiretroviral therapy Survival rate was 88% at 1 year and 72% at 3 years with a CD4+ lymphocyte count greater
- 51. The symptoms of PH are non-specific and mainly related to progressive right ventricular (RV) dysfunction Initial symptoms are typically induced by exertion They include shortness of breath, fatigue, weakness, angina and syncope
- 52. Abdominal distension and ankle oedema will develop with progressing RV failure
- 53. Mechanical complications of PH Haemoptysis related to rupture of hypertrophied bronchial arteries Pulmonary arterial dilatation leading to : Hoarseness caused by compression of the left recurrent laryngeal nerve Wheeze caused by large airway compression Angina due to myocardial ischaemia caused by compression of the left main coronary artery Significant dilation of the PA may result in its rupture or dissection, leading to signs and symptoms of cardiac tamponade
- 54. Physical Signs Left parasternal lift Accentuated pulmonary component of the second heart sound RV third heart sound Pansystolic murmur of tricuspid regurgitation and a diastolic murmur of pulmonary regurgitation Elevated jugular venous pressure, hepatomegaly, ascites, peripheral oedema
- 56. ECG An electrocardiogram (ECG) may provide supportive evidence of PH, but a normal ECG does not exclude the diagnosis An abnormal ECG is more likely in severe rather than mild PH
- 57. ECG abnormalities may include : P pulmonale Right axis deviation RV hypertrophy RV strain Right bundle branch block
- 58. ECG Criteria of Right Atrial Enlargement Right atrial enlargement produces a peaked P wave (P pulmonale) with amplitude: > 2.5 mm in the inferior leads (II, III and AVF) > 1.5 mm in V1 and V2
- 59. RV Hypertrophy and Strain Dominant R wave in V1 (> 7 mm tall; R/S ratio > 1) Dominant S wave in V6 (> 7 mm deep; R/S ratio < 1
- 61. RV hypertrophy has insufficient sensitivity (55%) and specificity (70%) to be a screening tool, RV strain is more sensitive Prolongation of the QRS complex and QTc suggest severe disease
- 62. ARRHYTMIAS IN PULMONARY HYPERTENSION Supraventricular arrhythmias may occur in advanced disease, in particular atrial flutter, but also atrial fibrillation Incidence in 25% of patients after 5 years Atrial arrhythmias compromise CO and almost invariably lead to further clinical deterioration Ventricular arrhythmias are rare
- 64. In 90% of patients with IPAH the chest radiograph is abnormal at the time of diagnosis Central pulmonary arterial dilatation ‘pruning’ (loss) of the peripheral blood vessels Right atrium (RA) and RV enlargement may be seen in more advanced cases
- 65. A chest radiograph may assist in differential diagnosis of PH by showing signs suggesting lung disease (group 3) or pulmonary venous congestion due to LHD (group 2) Degree of PH in any given patient does not correlate with the extent of radiographic abnormalities
- 66. Criteria for PAH Enlarged RDPA >14mm in females or >16mm in males Peripheral pruning of pulmonary vasculature-will lose more than 50% diameter as they branch Prominent MPA
- 67. How to measure main pulmonary artery If we draw a tangent line from the apex of the left ventricle to the aortic knob(red line) and measure along a perpendicular to that tangent line (yellow line) The distance between the tangent and the main pulmonary artery (between two small green arrows) falls in a range between 0 mm (touching the tangent line) to as much as 15 mm away from the tangent line
- 69. Prominent MPA Main pulmonary artery projects more than the tangent Causes: 1. Increased pressure 2. Increased flow
- 70. Criteria for RA enlargement Vertical height of rt atrium > 50% of right heart border -most specific Rt. Atrial border extends >3 intercostal spaces Measurement from mid vertical line to max. convexity in rt. Border>5 cm in adult & >4cm in children Right atrium extending >1/3 rd of rt hemithorax horizontally
- 72. RV ENLARGEMENT Cardiophrenic angle is acute Clockwise rotation of heart causes RV to form the middle portion of the left heart border
- 75. Pulmonary function tests and arterial blood gases identify the contribution of underlying airway or parenchymal lung disease Patients with PAH have usually mild to moderate reduction of lung volumes related to disease severity Although diffusion capacity can be normal in PAH, most patients have decreased lung diffusion capacity for carbon monoxide (DLCO) An abnormal low DLCO, defined as <45% of predicted, is associated with a poor outcome
- 76. The differential diagnosis of a low DLCO in PAH includes PVOD, PAH associated with scleroderma and parenchymal lung disease Due to alveolar hyperventilation at rest, arterial oxygen pressure (PaO2) remains normal or is only slightly lower than normal and arterial carbon dioxide pressure (PaCO2) is decreased
- 77. The prevalence of nocturnal hypoxaemia and central sleep apnoeas are high in PAH (70– 80%) Overnight oximetry or polysomnography should be performed where obstructive sleep apnoea syndrome or hypoventilation are considered
- 79. Two-dimensional and Doppler echocardiography Echocardiography is used for the diagnosis and quantification of severity of left heart disease like left ventricular systolic/diastolic dysfunction and valvular heart disease Features suggestive of PH like right atrial (RA) enlargement and RV dilatation, hypertrophy or dysfunction
- 81. Doppler echocardiography is used to estimate the right ventricular systolic pressure (RVSP) from tricuspid regurgitation velocity jet by adding estimated RA pressure
- 82. Dilatation of the right cavities, compression of the left cavities, presence of a pericardial effusion (arrow)
- 83. One of the leading theories as to why patients develop a pericardial effusion is an inability to reabsorb subepicardial venous and lymphatic drainage into the right atrium Because the chronically overloaded right atrium is unable to accommodate this drainage, it results in the formation of a pericardial effusion.
- 93. RV Base to Apex Ratio
- 95. CMR imaging is accurate and reproducible in the assessment of RV size, morphology and function and allows non-invasive assessment of blood flow, including stroke volume, CO, pulmonary arterial distensibility and RV mass
- 96. Contrast-enhanced and unenhanced MR angiography have a potential in the study of the pulmonary vasculature in patients with suspected CTEPH, particularly in clinical scenarios such as suspected chronic embolism in pregnant women, young patients or when iodine-based contrast media injection is contraindicated
- 98. Serological testing is required to detect underlying CTD, hepatitis and human immunodeficiency virus (HIV) Up to 40% of patients with IPAH have elevated antinuclear antibodies usually in a low titre (1:80) It is important to look for evidence of SSc since this disease has a relatively high prevalence of PAH Limited scleroderma typically has antinuclear antibodies, including anti-centromere, dsDNA, anti- Ro, U3-RNP, B23, Th/To and U1-RNP
- 99. Diffuse Scleroderma typically associated with a positive U3-RNP Patients with systemic lupus erythematosus may have anticardiolipin antibodies
- 100. Patients with CTEPH should undergo thrombophilia screening, including antiphospholipid antibodies, anticardiolipin antibodies and lupus anticoagulant HIV testing is required in PAH N-terminal pro-brain natriuretic peptide (NT- proBNP) may be elevated in patients with PH and is an independent risk predictor in these patients
- 101. V/Q Scan A ventilation/perfusion (V/Q) lung scan should be performed in patients with PH to look for CTEPH The V/Q scan has been the screening method of choice for CTEPH because of its higher sensitivity compared with CT pulmonary angiogram (CTPA), especially in inexperienced centres A normal- or low-probability V/Q scan effectively excludes CTEPH with a sensitivity of 90–100% and a specificity of 94–100%
- 102. HRCT and CT-PA CT imaging is a widely available tool that can provide important information on vascular, cardiac, parenchymal and mediastinal abnormalities It may suggest the diagnosis of PH (PA or RV enlargement), identify a cause of PH such as CTEPH or lung disease CT may raise a suspicion of PH in symptomatic patients or those examined for unrelated indications by showing an increased PA diameter (≥29 mm) and pulmonary:ascending aorta diameter ratio (≥1.0) A segmental artery:bronchus ratio .1 : 1 in three or four lobes has been reported to have high specificity for PH
- 103. The pulmonary artery (PA) aorta ratio was obtained by measuring the widest transverse diameter of the PA (blue) and the corresponding transverse diameter of aorta (red).
- 104. Grading of tricuspid regurgitation (A)0=There is no reflux into IVC (B)2=reflux into IVC but not hepatic veins (C)3=reflux into IVC and proximal hepatic veins and (D) 4=reflux into IVC and distal hepatic veins.
- 105. Maximum mid-transverse diameters of the RV (right arrow) and LV (left arrow) cavities were measured in the axial plane at their widest points between the inner surfaces of the free wall and the interventricular septum. (B) For assessing the right atrial margin (arrow) on CT, right atrial length was measured from the centre of tricuspid annulus to the superior right atrial margin.
- 108. Pulmonary vasoreactivity testing For identification of patients suitable for high-dose calcium channel blocker (CCB) treatment Recommended only for patients with IPAH, HPAH or drug-induced PAH It should be performed at the time of RHC In all other forms of PAH and PH the results can be misleading and responders are rare
- 109. Inhaled nitric oxide (NO) at 10–20 parts per million (ppm) is the standard of care for vasoreactivity testing I.V. epoprostenol,i.v. adenosine or inhaled iloprost can be used as alternatives Only about 10% of patients with IPAH will meet these criteria The use of CCBs, O2, phosphodiesterase type 5 inhibitors or other vasodilators for acute vasoreactivity testing is discouraged A positive acute response is defined as a reduction of the mean PAP ≥10 mmHg to reach an absolute value of mean PAP ≤40 mmHg with an increased or unchanged CO