Dissertation on
“THE MORPHOLOGICAL CHANGES IN THE RIGHT VENTRICLE IN PULMONARY HYPERTENSION: AN
ECHOCARDIOGRAPHIC ANALYSIS”
Submitted in Partial Fulfillment for the Degree of
M.D GENERAL MEDICINE BRANCH –I
INSTITUTE OF INTERNAL MEDICINE MADRAS MEDICAL COLLEGE
THE TAMIL NADU DR.MGR MEDICAL UNIVERSITY CHENNAI-600 003
MAY-2020
CERTIFICATE
This is to certify that the dissertation entitled “THE MORPHOLOGICAL CHANGES IN THE RIGHT VENTRICLE IN PULMONARY HYPERTENSION: AN ECHOCARDIOGRAPHIC ANALYSIS” is a bonafide original work done by Dr. SUSHEEL MADASAMY KARPENTER, in partial fulfillment of the requirements for M.D GENERAL MEDICINE BRANCH- I Examination of the Tamil Nadu Dr.MGR Medical University to be held in APRIL 2020, under my guidance and supervision in 2019
Prof.Dr.M.ANUSUYA, M.D., Prof. Dr.S. RAGHUNANTHANAN, M.D., Guide and Research Supervisor Director and Professor
Institute of Internal Medicine Institute of Internal Medicine Madras Medical College Madras Medical College
Rajiv Gandhi Govt. General Hospital Rajiv Gandhi Govt. General Hospital
Chennai-600 003 Chennai-600 003
Prof. Dr. R. JAYANTHI, M.D., FRCP(Glasg) DEAN
Madras Medical College &
Rajiv Gandhi Government General Hospital Chennai-600 003
DECLARATION BY THE CANDIDATE
I Dr. SUSHEEL MADASAMY KARPENTER, Registration No:201711021 hereby solemnly declare that the dissertation entitled “THE MORPHOLOGICAL CHANGES IN THE RIGHT VENTRICLE IN PULMONARY HYPERTENSION: AN ECHOCARDIOGRAPHIC ANALYSIS” is done by me at the Institute of Internal Medicine, Madras Medical College and Rajiv Gandhi Government General Hospital, Chennai during 2019 under the guidance and supervision of Prof. Dr. M. ANUSUYA M.D .This dissertation is submitted to the Tamil Nadu Dr.MGR Medical University, Chennai towards the fulfillment of requirements for the award of M.D Degree in General Medicine (Branch -I)
Dr. SUSHEEL MADASAMY KARPENTER Post Graduate Student
M.D.General Medicine Place: Institute of Internal Medicine
Date: Madras Medical College &RGGGH Chennai-600 00
ACKNOWLEDGEMENT
I express my heartful gratitude to the Dean, Prof. Dr. R. JAYANTHI M.D., FRCP (Glasg) Madras Medical College & Rajiv Gandhi Government General Hospital, Chennai-3 for permitting me to do this Study.
I am very grateful to Prof. Dr. M. ANUSUYA M.D., Professor of Medicine, Institute of Internal Medicine, Madras Medical College & Rajiv Gandhi Government General Hospital, Chennai-3 who guided my work throughout the period of my study and for her constant support and encouragement.
I am very grateful to Prof. Dr. S. VENKATESAN, M.D., D.M., Professor of Cardiology, Institute of Cardiology, Madras Medical College & Rajiv Gandhi Government General Hospital, Chennai-3 who guided my work throughout the period of my study and for his constant support for my thesis.
I am very much thankful for the help rendered by my Assistant Professors Dr.P.BALAMANIKANDAN M.D., and Dr. MOHAMMED HASSAN MARICAR M.D., for their constant help and encouragement.
I am indebted to Cardiology Residents Dr. Raghuram and Dr. Rajesh, Institute of Cardiology, Madras Medical College, Chennnai-3, for their immense help in doing echocardiograms of the patients.
I am extremely thankful to all the members of the Institutional Ethical Committee for giving approval for my study
LIST OF ABBREVIATIONS
PH – pulmonary hypertension RA – right atrium
RV – right ventricle
SPAP – systolic pulmonary arterial pressure MPAP – mean pulmonary arterial pressure PAH – pulmonary arterial hypertension
COPD – chronic obstructive pulmonary disease FAC – fractional area change
TAPSE – tricuspid annular plane systolic excursion HFpEF – heart failure with preserved ejection fraction LVDD – left ventricular diastolic dysfunction
RVH – right ventricular hypertrophy LVH – left ventricular hypertrophy
CTEPH – chronic thromboembolic pulmonary hypertension IVC – inferior vena cava
OSA – obstructive sleep apnoea ILD – interstitial lung disease
RVDD – right ventricular diastolic dysfunction RVSD – right ventricular systolic dysfunction A4C – apical four chamber view
LVSD – left ventricular systolic dysfunction
CONTENTS
S. No. TITLE PAGE NO
1 INTRODUCTION 1
2 AIM OF STUDY 3
3 REVIEW OF LITERATURE 4
4 MATERIALS AND METHODS 34
5 OBSERVATION AND RESULTS 48
6 DISCUSSION 70
7 CONCLUSION 77
8 STRENGTH AND LIMITATIONS 79
9 RECOMMENDATIONS 80
10 REFERENCES 81
11 ANNEXURE
• Proforma
• Information Sheet
• Consent Form
• Institutional Ethical Committee Approval
• Plagiarism Digital Receipt
• Plagiarism Certificate
• Master Chart
1
INTRODUCTION
Pulmonary hypertension encompasses a spectrum of diseases involving the pulmonary vasculature. It is a heterogeneous entity. There are five classes of pulmonary hypertension according to the latest classification criteria[1].Untreated pulmonary hypertension results in high mortality rates and is the commonest cause of right heart failure.
Pulmonary hypertension profoundly affects the right ventricle [2].The right ventricle undergoes hypertrophy and dilatation in response to pulmonary hypertension. The nature of the response depends primarily on the duration and severity of pulmonary hypertension [3]. Initially, it is an adaptive response, which later becomes maladaptive [4]. Presence of right ventricular dysfunction is a predictor of morbidity and mortality in patients with pulmonary hypertension [6]. So, in this context the evaluation of the right ventricular morphology and function assumes great importance.
The transthoracic echocardiogram is the currently recommended first line diagnostic modality for assessment of pulmonary hypertension and its effect on the heart [5]. Detailed information on the morphological and functional status of the right ventricle will help in the management, prognostication of pulmonary hypertension and development of novel therapeutic interventions.
2
At present there are no disease modifying therapies to prevent adverse pulmonary vascular and right ventricular remodelling. Knowledge about the exact pathophysiology of the right ventricle in response to pulmonary hypertension, including cellular and molecular mechanisms will help in the future development of disease modifying interventions.
3
AIMS AND OBJECTIVES
• To study the morphological changes of the right ventricle by echocardiography in patients with pulmonary hypertension.
• To assess the systolic and diastolic function of the right ventricle using echocardiography in patients with pulmonary hypertension
4
REVIEW OF LITERATURE
The term pulmonary hypertension encompasses a group of disorders with various aetiologies and clinical course with the common component of elevated pulmonary arterial pressures. Elevated pulmonary arterial pressures may be the primary pathology as in pulmonary arterial hypertension or it may be a complication of several disorders like chronic lung disease or pulmonary thrombo-embolism.
Pulmonary hypertension is defined as mean pulmonary arterial pressures greater than 25 mm Hg [7]. Pulmonary hypertension is classified into five major groups according to the latest clinical classification system [8]. Group 1 pulmonary hypertension also requires an additional criteria of pulmonary arterial wedge pressure less than 15 mm Hg.
The recent clinical classification of pulmonary hypertension is as follows:
Group 1: Pulmonary arterial hypertension
Group 2: Pulmonary hypertension due to left heart disease
Group 3: Pulmonary hypertension due to lung diseases and/or hypoxia Group 4: Chronic thromboembolic pulmonary hypertension
Group 5: Pulmonary hypertension with unclear/ multifactorial mechanisms.
5
Pulmonary hypertension is a rare condition and has been long regarded as an ‘orphan’ disease. But it is no longer so. Tremendous advancements have been achieved in the pathophysiology, diagnosis and treatment of pulmonary hypertension, especially in pulmonary arterial hypertension and chronic thrombo-embolic pulmonary hypertension [9].
But still there are many unanswered questions.
There are no large scale data regarding the prevalence of pulmonary hypertension in India. The largest US registry for pulmonary hypertension is the Registry to Evaluate Early and Long-term PAH disease management (REVEAL) [10]. In India the Pulmonary Hypertension Registry of Kerala (PROKERALA) was started in 2016[11]. Based on the data Harikrishnan S et al published an article in the International Journal of Cardiology. The mean age of the patient in the PROKERALA registry was 56 years. Among the patients, 52% were women. Majority of patients (59%) belonged to group 2 pulmonary hypertension. One fourth of this was due to valvular heart disease[12]. It also revealed low rates of prescription of PH specific therapies.
Pulmonary hypertension is an under diagnosed disease. Despite the advancements in the diagnostic capabilities, there is still a mean delay of approximately 2 years from symptom onset to diagnosis, according to data
6
from the NIH registry[13]. So a majority of patients already have advanced disease when diagnosed, rendering them less responsive to therapeutic interventions [14]. The earliest symptoms of PH are exertional dyspnoea, reduced exercise tolerance and chest pain. Due to the non-specific nature of the symptoms, a high index of suspicion is required to diagnose pulmonary hypertension and right ventricular failure in the early stages, where it might be amenable to therapeutic interventions.
In spite of significant advancements in diagnostic modalities, there is a delay in the diagnosis of pulmonary hypertension in a significant number of patients according to the REVEAL registry data [15]. It is especially so of pulmonary hypertension associated with chronic lung disease, obstructive sleep apnoea and in younger patients with PH. It may be that the symptoms of pulmonary hypertension are attributed to the primary pathology. Pulmonary hypertension should be suspected and screened for in these conditions especially when the severity of symptoms is not explained by the primary disease alone.
The delay to diagnose pulmonary hypertension has been recognised by the international community and the algorithms and guidelines reflect this change. For example, international recommendations advise screening patients with scleroderma annually with echocardiography
7
and pulmonary function testing to diagnose asymptomatic pulmonary hypertension early [16].
The diagnosis of pulmonary hypertension is a challenge. Right heart catheterisation is the gold standard method to diagnose pulmonary hypertension. As it is an invasive procedure and associated with high costs, it cannot be routinely used as a screening procedure. So for screening purposes, we have to resort to other methods.
A careful, comprehensive history and physical examination can give a lot of information. The chest X-ray and ECG can give invaluable diagnostic information. These coupled with a transthroracic echocardiogram is sufficient for screening and diagnosing pulmonary hypertension in most patients, though many patients may eventually require right heart catheterisation.
Physical examination findings can be subtle. But there are some important physical findings suggestive of pulmonary hypertension, which may also indicate the severity of the disease. A loud pulmonic component of the second heart sound, a parasternal heave, tricuspid regurgitation murmur and prominent v waves in the jugular pulse all signify severe pulmonary hypertension.
8
PHYSICAL SIGNS IN PULMONARY HYPERTENSION Physical sign Implication
Loud P2 High pulmonary pressure increases force of valve closure
Pulmonary area early systolic click
Pulmonic valve opening interrupted by high pressure
Pulmonary area mid systolic murmur
Turbulent transvalvular flow
Left parasternal heave Right ventricular hypertrophy Pansystolic murmur in tricuspid
area
Tricuspid regurgitation
Jugular venous distension Right ventricle failure
The physical findings not only give information regarding the presence and severity of pulmonary hypertension but they can also provide invaluable clues regarding the aetiology of pulmonary hypertension. For example presence of cyanosis and clubbing may point to a congenital heart disease. Presence of sclerodactyly may suggest systemic sclerosis as the cause for pulmonary hypertension. Bibasal fine crackles may reveal the presence of pulmonary fibrosis. Thus, history and physical examination form an important initial part of the evaluation of a patient with suspected pulmonary hypertension.
9
The electrocardiogram is a simple, non-invasive and cost effective modality of investigation. Though it is neither specific nor sensitive, it can give important information. The common findings are right atrial enlargement, right axis deviation and right ventricular hypertrophy. It can also give clues for the aetiology, for instance presence of ‘P-mitrale’ may be suggestive of mitral stenosis as the cause for pulmonary hypertension. It can also indicate the presence of coronary artery disease.
ECG IN PULMONARY HYPERTENSION
The chest X-ray classically shows pulmonary artery dilation. It can also show the presence of emphysema and other lung pathologies which can cause pulmonary hypertension.
10
CHEST X-RAY IN PULMONARY HYPERTENSION
The echocardiogram is the most important investigation in the diagnosis of pulmonary hypertension. Echocardiogram helps in the assessment of the morphology of right atrium and ventricle. It also helps in the estimation of atrial, ventricular and pulmonary arterial pressures. It is also important for the assessment of right ventricular function in pulmonary hypertension. In addition, it the diagnostic modality of choice to evaluate for left heart disease.
11
According to a review article by McLaughlin et al the following parameters are to be assessed in the patient suspected to have pulmonary hypertension [17].
1. Estimation of systolic pulmonary artery pressure (SPAP) 2. Evaluation of RV size and function
3. Estimating volume status 4. Pericardial effusion
5. Evaluation for left heart disease.
The European Society of Cardiology has issued guidelines for the diagnosis and treatment of pulmonary hypertension [18].
The American Society of Echocardiography has issued guidelines for the echocardiographic evaluation of the right heart. It has been endorsed by both the European Society of Cardiology and the Canadian Society of Echocardiography. It has been authored by Rudski et al [19]. This also gives normal limits for various parameters and the methods to measure them.
12
The pulmonary arterial pressures are estimated from the tricuspid gradient. Though it may not always be identical with the pressures derived from right heart catheterisation, it is useful during the initial and routine assessment. The systolic function is assessed by fractional area change and TAPSE. Diastolic function of the right ventricle can also be assessed by echocardiography.
Right ventricular function is the most important determinant of the course and prognosis of pulmonary hypertension. It has been proved that right ventricular dysfunction portends a poor prognosis in patients with PH [6]. Both right ventricle morphology and function serve as important prognostic markers.
Raymond and colleagues demonstrated in their study that right atrial area index, eccentricity index and pericardial effusion had significant prognostic value [20]. In this study, 81 patients with severe PPH were prospectively followed. The study had a mean follow-up period of 36.9 months. Pericardial effusion (p=0.003) and indexed right atrial area (p=0.005) predicted mortality. In a multivariable analysis, which incorporated clinical, haemodynamic and echocardiographic variables, both pericardial effusion and enlarged right atrium predicted adverse outcomes.
13
Ghio and colleagues reported that an enlarged RV diameter is associated with worse survival rates [21]. The study included 72 patients with IPAH who were followed for a median period of 38 months. The median RV diameter of the study population was 36.5 mm. The death rate in the group with RV diameter >36.5 mm was more than in those whose RV diameter was <36.5 mm (p=0.0442).
Yeo TC et al in an article published in the American Journal of Cardiology evaluated a Doppler derived right ventricular index to predict outcome in PPH [22]. The Doppler RV index was defined as the sum of the isovolumic contraction time and isovolumic relaxation time divided by the ejection time. This study included 52 patients. The Doppler RV index was associated with adverse outcomes in both univariate (p <0.0001) and multivariate analysis. Several studies by Vonk MC et al., Tei C et al. have validated this index. This led to inclusion of this index in current recommendations.
A study by Tanaka and colleagues examined the usefulness of the Doppler RV index, also known as the Tei index, in patients with COPD [23]. 49 male patients were included in this study. The Tei index showed a significant correlation with the MRC dyspnoea score (p=0.02).Also the index showed a highly significant correlation with both overall survival (p
14
<0.001) and hospital-free survival (p=0.03). The study authors conclude that assessment of RV function has to be included in COPD guidelines.
In pulmonary hypertension the basic pathology is the elevation of the pressures in the pulmonary circulation. But the right ventricular function determines the prognosis and outcome of the patient; and this has been established by D’Alonzo et al and Campo et al [24],[25]. Hence the changes occurring in the right ventricle in response to increased after load assumes a great importance. The right ventricle has inherent differences when compared with the left ventricle.
During intra-uterine life the pulmonary vascular resistance is high, and it is reduced after birth once the lungs start to function. Thus during the postnatal life the right ventricle is part of a low pressure circulation. Normally the right ventricle pumps against an afterload which is only one-fourth that of the left ventricle, though the same quantity of blood passes through both the right and left ventricle. So under normal circumstances the thickness of the right ventricle is less than that of the left ventricle [26].
15
There are subtle differences between the contractile pattern of two ventricles [27]. The main difference is the filling velocity, which is significantly higher in the left ventricle. This reflects the loading conditions of the ventricles. The ejection velocity is lower in the right ventricle when compared to the left. There are also differences in the response of the ventricles to pressure overload. Ventricular enlargement occurs much earlier in the RV than in the LV in response to pressure overload. Fibrosis in the pressure overloaded right ventricle is less when compared with the pressure overloaded left ventricle [28].
The RV remodelling which occurs in response to pulmonary hypertension is a complex process. It depends on several factors like severity of pulmonary hypertension, coronary perfusion and other comorbid conditions [29]. A rapid rise in pulmonary vascular resistance, for example as in acute pulmonary embolism, leads to acute dilatation of the right ventricle and RV failure [30]. But a gradual and sustained increase in pulmonary vascular resistance leads to remodelling of the RV and adaptation without immediate development of RV failure [31].
Two types of ventricular adaptation to increased afterload are described. They are the homeometric adaptation and heterometric adaptation.
16
Beat to beat changes in the preload and afterload of ventricles lead to heterometric adaptation. These are in accordance with Starling’s law of the heart.But sustained changes in loading conditions lead to a homeometric pattern of adaptation as described by von Anrep in an article in 1912 [32].
Studies by Taquini and colleagues demonstrate the homeometric adaptation of the right ventricle. In their study, the authors exposed the right ventricle to pulmonary arterial constriction and evaluated the response of the right ventricle. There was hypertrophy of the ventricle without dilatation of the chamber [33].
The homeometric adaptation is related to systolic function of the ventricle. It can be studied by plotting a pressure-volume curve and obtaining a series of pressure-volume loops [34]. As the impedance in the pulmonary circulation is lower, the normal RV pressure volume-loop has a triangular shape [35].
Ventricular remodelling in pulmonary hypertension is a continuum.
Various experimental studies have been published on this aspect. Several authors have described two patterns of right ventricular remodelling:
adaptive and maladaptive [36]. Adaptive remodelling leads to concentric hypertrophy with preserved systolic and diastolic functions. There is a
17
higher mass to volume ratio. Maladaptive remodelling is characterised by eccentric hypertrophy with systolic and diastolic dysfunction. There is dilatation of the ventricle. Moreover tricuspid regurgitation associated with ventricular dilatation leads to further adverse remodelling leading to progressive RV failure.
There are differences at the cellular and molecular level between adaptive and maladaptive remodelling [37]. There is increased glucose uptake and decreased micro-RNA 133a and Vascular Endothelial Growth Factor (VEGF) in maladaptive remodelling when compared to adaptive remodelling.
CHARACTERISTIC ADAPTIVE REMODELLING
MALADAPTIVE REMODELLING RV size Normal/mild dilation RV enlargement
Mass/volume ratio Higher Lower
RVEF at rest Normal/mild decrease Decreased Functional capacity Better preserved
exercise capacity
Decreased exercise capacity
Metabolism Normal glucose uptake Increased glucose uptake
Micro-RNA 133a Normal Decreased
VEGF Increased Normal/reduced
18
Recent focus has shifted from considering the pulmonary vasculature and the right heart as separate entities to considering them together as a single unit [38].This is more appropriate not only in physiological terms but also in therapeutic aspects. The relationship between the contractility of the RV and afterload is termed ‘ventriculo-arterial coupling’ [39]. Ventriculo- arterial coupling can be objectively measured using the ratio of ventricular to arterial elastance.
In a study by Kuehne et al, the authors demonstrated that chronic RV pressure overload leads to RV failure even in the presence of increased RV contractility. Tedford and colleagues in their article published in 2013 showed RV failure as a result of deranged ventriculo-arterial coupling[40].
In response to pressure overload the RV adapts with increased contractility but only a little increase in the chamber dimensions is noted.
Also the systolic function of the RV is preserved. But as the pulmonary hypertension advances, the RV can no longer compensate and it starts to dilate. In addition myocardial fibrosis also develops leading to diastolic dysfunction. Finally right-sided filling pressures increase and output decreases leading to right heart failure.
19
When the right ventricle is not able to maintain its output in response to demands, right heart failure develops. The World Symposium on Pulmonary Hypertension, which was held in 2013 endorsed the following definition of RV failure[41]:
“RV failure is defined as a dyspnoea fatigue syndrome with eventual systemic venous congestion, caused by inability of the right ventricle to maintain flow output in response to metabolic demand without heterometric adaptation, and consequent increase in right heart filling pressures.”
Though RV-arterial coupling measurements can be used to evaluate RV function, they cannot be used routinely in daily practice. So surrogate measurements have been developed and validated. Doppler echocardiography is one such method. The fractional area change (FAC) of the right ventricle measured in the apical four-chamber view and TAPSE (measured in M-mode) have been validated in studies.
In a study by Ghio S et al, 59 patients with idiopathic pulmonary arterial hypertension were followed up for a median period of 52 months.
FAC and TAPSE were associated with survival. Patients with TAPSE
<16mm had the highest event rate[42].
20
Diastolic function of the RV also contributes significantly to RV failure. Surrogate measurements have also been developed for assessing the diastolic function of the RV. These include the ratio of transtricuspid E and A waves, right atrial pressures estimated by inferior vena caval dimension, presence of pericardial effusion and others [43].
As previously described there are five types of pulmonary hypertension according the 2015 ESC/ERS guidelines.
GROUP 1: PULMONARY ARTERIAL HYPERTENSION
This can be primary/idiopathic or secondary to another condition.
Connective tissue diseases like scleroderma, HIV infection can also cause pulmonary arterial hypertension. Drugs like fenfluramine, methamphetamines and dasatinib can be associated with pulmonary arterial hypertension [44]. Pulmonary arterial hypertension can also develop in the setting of portal hypertension. Epidemiological studies suggest a prevalence of 2 to 6%. Pulmonary arterial hypertension can also be associated with congenital heart diseases like in Eisenmenger syndrome.
A patient with pulmonary arterial hypertension is said to have Idiopathic pulmonary arterial hypertension (Idiopathic PAH) when all other
21
secondary causes have been ruled out. It is the most common form of PAH reported in current day registries. IPAH has a female preponderance.
The histopathological findings include luminal hypertrophy, hypertrophy of the media, adventitial proliferation, occlusion of small arteries and formation of in situ thrombosis. There is also infiltration of the vessel wall with inflammatory and progenitor cells [61].
PLEXIFORM LESIONS IN PAH
22
MEDIAL HYPERTROPHY IN PAH
Diagnosis of pulmonary arterial hypertension is suspected based on symptoms and signs on physical examination. ECG and chest X-ray are also required. The echocardiogram is the most important investigation required for the diagnosis and prognostication of pulmonary arterial hypertension. It is used to assess chamber dimensions and RV function. The pulmonary vascular and right heart chamber pressures can also be estimated by Doppler echocardiography.
23
Treatment:
Treatment of IPAH has considerably advanced in recent years. The European Society of Cardiology has published guidelines for the treatment[45].
Treatment goals are to improve symptoms, exercise tolerance and RV function. General measures include avoidance of heavy physical exertion and isometric exercise since these can evoke exertional syncope. Sodium restricted diet is also advised. Mereles and colleagues showed that exercise rehabilitation training leads to better exercise capacity. It improved the 6- min walk distance by 56-111m (p<0.002)[46]. Expert consensus also recommends long term oxygen therapy in patients with resting hypoxemia [18].
Diuretics can be used to reduce volume overload. Selected patients are subjected to acute vasoreactivity test and a positive result suggests possible effiency of calcium channel blockers in these patients. Calcium channel blockers are recommended in such patients [18]. In a study by Sitbon and colleagues treatment of patients with idiopathic PAH who had a positive vasoreactivity test had 97.4% survival at a mean follow up of 7 years (p<0.001).[47] Long acting nifedipine and amlodipine are the
24
preferred drugs. Since verapamil has a negative inotropic effect, it should be avoided.
Endothelial dysfunction is an important pathogenetic mechanism in PAH. It contributes to disease onset and progression. It is characterised by reduced production of prostacyclin and nitric oxide and increased production of endothelin-1[48]. So these pathways are potential targets for pharmaceutical agents in the treatment of pulmonary arterial hypertension.
Prostacyclin has vasodilator and antiproliferative effects. So they are a therapeutic option in PAH. Their efficiency and safety have been demonstrated in several studies and currently they are a mainstay of therapy in PAH. They are available in intravenous (epoprostenol, trepostinil), subcutaneous (trepostinil) and inhaled (iloprost) forms. Barst et al published one of the first studies which compared intravenous epoprostenol with conventional therapy [49]. The experimental group demonstrated improvements in quality of life and survival. There was also substantial improvement in exercise tolerance. Common side effects are jaw pain, nausea and musculoskeletal pain.
Phophodiesterase-5 inhibitors increase intracellular cGMP leading to increased nitric oxide levels. In a 12 week multicentre, randomized placebo
25
controlled trial sildenafil improved the 6-min walk distance and haemodynamics[50]. Tadalafil has also been tested in clinical trials and found to increase the exercise capacity. PDE-5 inhibitors can cause headache, flushing, dyspepsia and rarely visual disturbance.
Endothelin-1 is a potent vasoconstrictor and it also has smooth muscle mitogenic properties. Three endothelin receptor blockers are available at present namely bosentan, ambrisentan and macitentan. In the multicentre, randomised placebo-controlled BREATHE-1 trial, 213 patients who were randomised to the bosentan arm showed a significant improvement in exercise capacity and time to clinical worsening [51]. Side effects include elevated liver function tests, headache, anaemia and oedema.
Riociguat is a recently developed guanylate cyclase stimulator. In a open-labelled uncontrolled trial it improved 6MW distance and haemodynamics [52].Even though newer agents are under development, using available agents in combination therapy has also been evaluated and found to be efficient. The AMBITION trial enrolled 500 treatment-naive PAH patients. They were randomised either to tadalafil monotherapy or combination therapy with tadalafil and ambrisentan. There was a 50%
reduction in a composite end point consisting of death, hospitalisation and PAH progession in the combination therapy group [53].
26
TREATMENT OF PAH
Prognosis:
Despite advancements in the understanding of the pathophysiology and therapeutics, the survival rate for PAH remains suboptimal. As per the NIH registry, the 1-,2- and 3-year survival rates are 85.7%, 69.5% and 54.9% respectively.
27
GROUP 2: PULMONARY HYPERTENSION CAUSED BY LEFT- SIDED HEART DISEASE
This is probably the most frequent cause of pulmonary hypertension.
The important difference from other groups of PH is presence of elevated pulmonary capillary wedge pressures. It can be caused by left ventricular dysfunction, valvular heart disease or cardiomyopathy. HFpEF is a common cause in the current scenario.
Pulmonary venous hypertension develops as result of left heart disease and this leads to capillary and arterial remodelling due to transmission of high pressures. The pathological changes include thickened and dilated pulmonary veins, interstitial oedema and lymphatic vessel hypertrophy. Pulmonary arteries show medial hypertrophy and intimal fibrosis.
The diagnosis is usually confirmed by echocardiography which also reveals the exact left sided heart disease. Recognition of HFpEF is more difficult. It can be misdiagnosed as idiopathic PAH. Presence of orthopnoea and paroxysmal nocturnal dyspnoea are in favour of HFpEF.
Echocardiography reveals left atrial enlargement, left ventricular hypertrophy and LV diastolic dysfunction.
28
DIFFERENCE BETWEEN IPAH AND HFpEF
CHARACTERISTIC IPAH HFpEF
Age Younger Older
DM/SHTN/CAD Usually absent Often present
PND Often absent Often present
Cardiac exam RV heave, loud P2, TR murmur
Sustained LV impulse, LVS4
ECG RAD, RVH LAE, LVH, LAD
LVDD Grade 1 can be present Often grade 2 or 3 LVDD
CXR Clear lung fields Pulmonary vascular congestion, pleural effusion, pulmonary oedema
Treatment:
Treatment involves management of the underlying cause. Blood pressure control, volume management and sodium restriction have to be emphasised. Comorbid conditions including diabetes and atrial fibrillation if present, should be managed optimally.
Though PDE-5 inhibitors have been evaluated in two clinical trials, they did not show any benefit when compared to standard therapy [54][55].
29
GROUP 3: PULMONARY HYPERTENSION CAUSED BY CHRONIC RESPIRATORY DISEASES
PH is frequent complication of chronic lung disorders like COPD and interstitial pulmonary fibrosis. The PH is commonly not severe but still it impacts the functional capacity and survival.
Chronic respiratory disease
Alveolar hypoxia
Pulmonary vasoconstriction
Vascular remodelling
Pulmonary hypertension
The diagnosis of PH in patients with COPD is difficult and challenging. Symptoms are non-specific. Though echocardiography is useful to diagnose pulmonary hypertension, it is suboptimal in patients with COPD.
30
Treatment:
Smoking cessation and long term oxygen therapy are key interventions for the prevention and management of PH in COPD. Optimal pharmacological management of COPD is also vital. Trials evaluating vasodilators have proved disappointing with failure to reach endpoints.
Blanco and other authors compared sildenafil with placebo in 60 patients[56]. The primary end point of gain in cycle endurance time and the secondary end points were not achieved in the treatment arm. Since vasodilator therapy does not improve outcomes, they are not recommended by current guidelines. But future research is warranted in this area.
GROUP 4: CHRONIC THROMBOMBOLIC PULMONARY HYPERTENSION (CTEPH)
CTEPH is a common cause of PH. It is amenable to surgery.[57] It should be diagnosed based on clinical findings at least after 3 months of effective anticoagulation. This is to differentiate CTEPH from acute disease.
CTEPH is caused by chronic obstruction of the major pulmonary arteries as a consequence of pulmonary embolism. It occurs equally in males and females. The median age is 63 years. Clinically the symptoms are similar to idiopathic PAH.
31
The ventilation-perfusion scan is the main imaging modality for diagnosing CTEPH. At least one defect encompassing at least half of a pulmonary segment should be present.
Treatment:
The median 2-3 year survival in patients with untreated severe CTEPH is 10-20%[58].In all eligible patients with CTEPH, surgical pulmonary endarterctomy is the recommended treatment of choice. Madani et al from the CTEPH centre in San Diego reported cumulative 5- and 10- year survival rates of 82% and 75% respectively [59]. However, about one- third of patients are not eligible candidates for surgery due to advanced age and other associated comorbities.
In those patients, who are not candidates for surgery, optimal medical management is recommended. It consists of anticoagulants and in the presence of heart failure or hypoxemia, diuretics and oxygen can be added.
Anticoagulants have to be continued life-long. Presence of pulmonary microvascular disease has provided a rationale for the use of other PH- targeted medications. Riociguat was tested by Ghofrani et al and it showed an improvement in NYHA functional class and 6-minute walk distance (p<0.001) [60]. There is not enough evidence to justify the routine use of inferior vena caval filters.
32
TREATMENT OF CTEPH
GROUP 5: PULMONARY HYPERTENSION WITH UNCLEAR OR MULTIFACTORIAL CAUSES
Haematological disorders like polycythemia vera, essential thrombocythemia and chronic myeloid leukaemia can be complicated by pulmonary hypertension. Several mechanisms have been suggested including congestive heart failure, CTEPH, pulmonary artery obstruction by intrapulmonary haematopoiesis, drugs and splenectomy. Chronic
33
haemolytic anaemia, sickle cell disease and beta-thalassaemia can also cause pulmonary hypertension by several mechanisms.
Sarcoidosis can lead to pulmonary hypertension. It is because of destruction of the capillary bed by fibrotic changes. Chronic hypoxia also contributes to the development of pulmonary hypertension in sarcoidosis.
Pulmonary hypertension has also been reported in pulmonary histiocytosis, fibrosing mediastinitis and renal failure patients maintained on long term haemodialysis.
Treatment:
Treatment of group 5 pulmonary hypertension patients consists of treating the primary disease.
34
MATERIALS AND METHODS
Source of data:
Patients treated at Rajiv Gandhi Government General Hospital, Chennai, who had been previously diagnosed as having pulmonary hypertension and those who were diagnosed to have pulmonary hypertension during their hospitalisation. They had to fulfill the inclusion and exclusion criteria to be included in this study.
SAMPLE SIZE: 50
STUDY DESIGN: Observational study
STUDY DURATION: 6 months
INCLUSION CRITERIA:
• Patients with known pulmonary hypertension
• Patients diagnosed to have pulmonary hypertension during hospitalisation.
35
EXCLUSION CRITERIA:
• Patients with history of cardiac surgery
• Patients with congenital heart disease
• Patients with history of right ventricular myocardial infarction
• Patients with acute myocardial infarction
• Patients with acute pulmonary embolism
• Patients with acute valvular lesions
• Patients with pulmonary valvular disease
METHODOLOGY :
The study was approved by the Institutional Ethics Committee.
Informed written consent was obtained from all study participants. Patients with pulmonary hypertension who fulfilled the inclusion and exclusion criteria were selected for the study.
A thorough history and physical examination was done. Patients also underwent routine investigations. Chest X-ray and electrocardiogram was also done for all patients. The aetiology for pulmonary hypertension was determined by use of other additional investigations as needed.
36
The functional class of the patient was assessed by the WHO functional classification for pulmonary hypertension.
All patients underwent a complete transthoracic echocardiogram including 2-D, M-mode and Doppler echocardiography in the Institute of Cardiology, Rajiv Gandhi Government General Hospital, Chennai-3 using Phillips Aloka Echo machine. Echocardiography was performed in the standard left lateral decubitus position.
The echocardiographic parameters were measured using the methods described in the ASE’s Comprehensive Echocardiography by Lang RM et al. 2nd edition and Guidelines for the echocardiographic assessment of the right heart in adults.
RIGHT ATRIUM:
The right atrium was studied in the apical four chamber view at end- diastole. The major and minor dimensions were measured as follows:
¾ Major dimension: measured between the centre of the tricuspid annular plane to the centre of the superior RA wall parallel to the interatrial septum
¾ Minor dimension: measured between the middle of the RA free wall to the interatrial septum perpendicular to the major dimension
37
RIGHT ATRIAL DIMENSIONS – A4C VIEW
RIGHT VENTRICLE:
The right ventricle dimensions were measured in the RV focused apical four chamber view at end-diastole. The dimensions measured are RV basal dimension (RVD1)and RV midcavity dimension (RVD2).
¾ RVD1 is the maximal transverse dimension in the basal one third of RV inflow part
¾ RVD2 is the transverse RV diameter in the middle third of RV inflow, approximately halfway between the maximal basal diameter and the apex, measured at the level of papillary muscles
38
RV DIMENSIONS – A4C VIEW
RV thickness: RV free wall thickness was measured in the subcostal view, below the tricuspid annulus at a distance approximately the length of the anterior tricuspid leaflet, when fully open and parallel to RV free wall.
Measurement was done at end-diastole.
RA PRESSURE:
RA pressures were estimated using the IVC dimension and collapsibility. It was measured using the subcostal view. IVC dimension is measured in end expiration 0.5 – 3cm proximal to RA ostium. Collapsibility was measured using M-mode.
39
IVC DIMENSION – SUBCOSTAL VIEW
Specific RA pressures were used. They were calculated as given below.
IVC diameter (cm) Collapsibility Estimated RA pressure (mm Hg)
<2.2 >50% 3
<2.2
>2.1
<50%
>50%
8
>2.1 <50% 15
40
FRACTIONAL AREA CHANGE(FAC):
FAC was measured in the apical four chamber view. The RV endocardial border was traced during both end-systole and end-diastole.
Area was calculated by planimetry. FAC was calculated by the following formula:
FAC = ( EDA – ESA)/EDA x 100 EDA – End diastolic area.
ESA – End systolic area It is expressed as a percentage
41
TAPSE:
TAPSE is the abbreviation for tricuspid annular plane systolic excursion. It is the measure of the longitudinal displacement of the RV annular segment during ventricular systole. It was measured in the apical four chamber view using M-mode. The cursor was placed over the tricuspid annulus and the excursion measured during peak systole.
42
TAPSE – M-MODE
DIASTOLIC FUNCTION OF RV:
The parameters measured to assess the diastolic function of the RV are :
• Peak tricuspid valve filling velocity (E wave)
• Peak atrial filling velocity (A wave)
• E/A ratio
• Tricuspid lateral annular velocity (e’)
• E/e’
These parameters were measured using tissue Doppler methods in the apical four chamber view.
43
E/A E/E’ RVDD grade
<0.8 - 1 Impaired relaxation
0.8-2.1 >6 2
Pseudonormalisation
>2.1 >6 3 Restrictive filling
SYSTOLIC PULMONARY ARTERIAL PRESSURE (SPAP):
The SPAP was estimated using the modified Bernoulli equation. First the estimated pressure difference between the right ventricle and atrium was calculated by the peak TR jet velocity using continuous wave Doppler. The estimated right atrial pressure was added to this. This gave the value of the right ventricle systolic pressure, which is equal to the SPAP in the absence of pulmonic stenosis.
SPAP = 4 (TRv)^2 + RAP
Where TRv = peak tricuspid regurgitant jet velocity, RAP = estimated right atrial pressure.
44
MEASUREMENT OF TRv
MEAN PULMONARY ARTERIAL PRESSURE (MPAP):
The MPAP was estimated from the SPAP using the following formula:
MPAP = SPAP x 0.61 + 2 PERICARDIAL EFFUSION:
The presence of pericardial effusion was assessed by visualisation of an echolucent space surrounding the cardiac chambers. It was assessed both in the parasternal long and short axis views.
The reference limits were obtained from the Guidelines for echocardiographic assessment of the right heart published by the American Society of Echocardiography and the ASE’s Comprehensive Echocardiography textbook.
45
PARAMETER ABNORMAL VALUE
RA major dimension >53mm RA minor dimension >44 mm RV basal dimension >42 mm RV mid-cavity dimension >35 mm RV longitudinal dimension >83 mm RV thickness >5 mm
FAC < 35%
TAPSE <1.6 cm
E/A ratio <0.8 or >2.1
E/E’ ratio >6
Grading of severity of pulmonary hypertension:
Grade Value of MPAP(mm Hg)
Mild 25-40 Moderate 41-55
Severe >55
Grading of RV diastolic dysfunction
Grade E/A E/E’
Impaired relaxation 1 <0.8 <6
Pseudo- normalisation
2 0.8-2.1 >6
Restrictive filling 3 >2.1 >6
46
WHO functional class for pulmonary hypertension:
Class I: No limitation of physical activity, ordinary physical activity does not cause dyspnoea, fatigue, chest pain or pre-syncope
Class II: Mild limitation of physical activity; no discomfort at rest; but normal activity causes increased dyspnoea, fatigue, chest pain or pre- syncope
Class III: Marked limitation of physical activity; no discomfort at rest but less than normal physical activity causes dyspnoea, fatigue, chest pain or pre-syncope.
Class IV: Unable to perform physical activity at rest; may have signs of RV failure; symptoms increased by almost any physical activity.
In this study, the age and sex distribution of the patients, aetiologies of pulmonary hypertension and the various echocardiographic parameters of the heart were studied. The functional classification of the patients was also assessed.
47
Correlation between the severity of pulmonary hypertension and the following variables was assessed:
• RA dimensions
• RV dimensions
• WHO functional class
• RV systolic dysfunction
• RV diastolic dysfunction
• Presence of pericardial effusion
STATISTICAL METHODS:
The data was analysed using SPSS software. Mean and standard deviations were calculated for linear dimensions and correlation was calculated using Chi square test and p values calculated. Variables were considered significant if p value was less than 0.05.
AG
the
bet yea
GE AND Total e study pa T Age g
<20 y 21-30 31-40 41-50 51-60
>60 Y To
In this tween 41a ars. This s
OBS
SEX DIS number o tients was TABLE-1 group
years years years Years Years Years
tal
s study 34 and 50 yea study inclu
7%
SERVAT
TRIBUT of participa
s 48.2 year 1: AGE D
N
4% of the p ars, 14% w uded parti
0%
32%
20%
48
TION A
ION:
ants in thi rs (range 2
ISTRIBU No of pati
- 3 14 16 7 10 50
patients w were 51-60
icipants fr
% 6%
Age
ND RES
s study wa 29-68year UTION O
ients
were less th 0 years an
om all age
28%
e Group
SULTS:
as fifty. Th rs).
F PATIE
han forty y nd 20% we e groups.
p
he mean a
ENTS Percent
- 6%
28%
32%
14%
20%
100%
years, 32%
ere above
<20 year 21-30 ye 31-40 ye 41-50 ye 51-60 Ye
>60 year
age of
% were sixty
rs ears ears ears ears
rs
we
Amon ere female T Se Ma Fem To
ng the stud e.
TABLE-2 ex
ale male otal
42%
dy particip
2: SEX DI N
49
pants twen
ISTRIBU No of pati 29 21 50
Sex
nty-nine w
UTION OF ients
x
were male
F PATIE
58%
and twent
NTS Percent
58%
42%
100%
Male Fema
ty-one
le
50
DISTRIBUTION OF AETIOLOGIES:
The aetiologies for pulmonary hypertension in this study population was due to various causes like
9 Pulmonary arterial hypertension both primary and secondary (Sjögren, Scleroderma etc)
9 Chronic Obstructive Pulmonary Disease 9 Interstitial Lung Disease
9 Left heart failure (RHD, CAD etc) 9 Obstructive sleep Apnoea
9 Chronic thrombo-embolic pulmonary hypertension TABLE-3: AETIOLOGICAL DISTRIBUTION Aetiology No of males No of
females
Total no Percentage (total)
PAH 1 5 6 12%
COPD 13 2 15 30%
ILD 2 3 5 10%
Left heart disease
6 5 11 12%
OSA 3 3 6 12%
CTEPH 4 3 7 14%
In this study the most common aetiology was COPD (30%) and the frequencies of other aetiologies are as follows: Pulmonary arterial hypertension (12%), ILD (10%), left heart disease (12), Obstructive sleep apnoea (12%) and chronic thrombo-embolic pulmonary hypertension (14%).
51
The distribution of various aetiologies between males and females showed marked differences.
TABLE-4: AETIOLOGIES IN MALES
Aetiology No of males Percentage
PAH 1 3.4%
COPD 13 44.8%
ILD 2 6.9%
Left heart disease 6 20.7%
OSA 3 10.3%
CTEPH 4 13.8%
TABLE-5: AETIOLOGIES IN FEMALES
Aetiology No of females Percentage
PAH 5 23.8%
COPD 2 9.5%
ILD 3 14.3%
Left heart disease 5 23.8%
OSA 3 14.3%
CTEPH 3 14.3%
The commonest cause of pulmonary hypertension among males in this study was COPD (44.8%) but for females it was PAH (23.8%) and left heart disease (23.8%). PAH was the least common aetiology in males(3.4%). In females COPD (9.5%) was the least common aetiology.
52
Left heart disease contributing to pulmonary hypertension was a common cause among both males (20.7%) and females (23.8%). ILD was more common among female participants (14.3%) than male participants (6.9%).
SEVERITY AND FUNCTIONAL STATUS OF PATIENTS:
The distribution of mild, moderate and severe pulmonary hypertension in various aetiologies are given in the following table:
TABLE-6: PULMONARY HYPERTENSION GRADES Pulmonary hypertension grade
Mild Moderate Severe PAH 0 3 3
COPD 6 9 0
ILD 1 1 3
Left heart disease 3 5 3
OSA 0 4 2
CTEPH 2 3 2
53
PULMONARY HYPERTENSION SEVERITY IN EACH AETIOLOGY
All COPD patients had either mild or moderate pulmonary hypertension.
TABLE-6: FUNCTIONAL CLASS DISTRIBUTION WHO_class No of patients Percent
1 2 4%
2 24 48%
3 21 42%
4 3 6%
Total 50 100%
0 2 4 6 8 10 12 14 16
PAH COPD ILD LEFT HEART DISEASE
OSA CTEPH
SEVERE MODERATE MILD
(48
eac yea
Of the 8%) and 3
The m ch WHO f ars.
T
e fifty pati 3(42%).
mean age o functional
TABLE-7
WHO f
42%
ients majo
of the stud l class was
: MEAN
functiona 1 2 3 4
6
54
ority belon
dy patients s the simil
AGE OF
al class
6% 4%
WHO
nged to W
s was 48.2 lar except
FUNCTI
Mean a
O FUNCT
WHO functi
2 years. Th class 4 w
IONAL G
age (year 49 49.4 48.1 39.3
48%
TIONAL
ional class
he mean ag where it wa
GROUPS
rs)
L CLASS
s 2
ge in as 39
1 2 3 4
55
MORPHOLOGICAL PARAMETERS OF RA AND RV:
The following echocardiographic parameters were assessed. The mean, standard deviation are as follows:
TABLE-8: MEAN AND SD OF ECHO PARAMETERS
Parameter Mean SD
RA major dimension (mm) 49.7 6.6
RA minor dimension (mm) 41.1 6.4
RV basal dimension (mm) 46.7 6.6
RV midlevel dimension (mm) 38.3 4.8
RV thickness (mm) 5.8 0.49
RAP (mm Hg) 10.1 4
SPAP (mm Hg) 74.5 15.2
MPAP (mm Hg) 47.5 9.3
TAPSE(mm) 14.6 2.6
FAC(%) 31.3 5.5
The severity of pulmonary hypertension was graded based on the mean pulmonary arterial pressure (MPAP) as mild, moderate and severe.
• Mild – 25 to 40 mm Hg
• Moderate — 41 to 55 mm Hg
• Severe— more than 55 mm Hg
T
Se
cal
TABLE-9
everity of
The c lculated.
9: DISTR
Pulmona
Mild Modera
Sever
correlation
RIBUTION
ry hypert
d ate
e
n between
26%
M
56
N OF PUL SEVERI tension
n MPAP
24%
50%
PAP GR
LMONAR ITY
No of patients
12 25 13
and WH
OUPS
RY HYPE
F
HO functi
ERTENS
Frequency
24%
50%
26%
ional clas
Mild Moderate Severe
SION
y
ss was
57
TABLE-10: PULMONARY HYPERTENSION SEVERITY AMONG FUNCTIONAL GROPS
MPAP GROUP Total Mild Moderate Severe
WHOclass 1
%
2 0 0 2
(16.7%) (0%) (0%) (4%) 2
%
10 12 2 24
(83.3%) (48%) (15.4%) (48%) 3
%
0 13 8 21
(0%) (52%) (61.5%) (42%) 4
%
0 0 3 3
(0%) (0%) (23.1%) (6%) Total Count 12 25 13 50 Pearson Chi-square = 27.691, p<0.001 (significant)
17%
0% 0%
83%
48%
15%
0%
52%
62%
0% 0%
23%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Mild Moderate Severe
I II III IV
58
All patients with mild pulmonary hypertension belonged either to WHO functional class 1 or 2, with majority in class 2 (83.3%). In patients with moderate pulmonary hypertension 48% (12) belonged to WHO class 2 and 52% (13) to WHO class 3. None of the patients were in class 1 or 4. In the severe pulmonary hypertension group also no patient belonged to WHO class 1. Majority belonged to WHO class 3 (61.5%). Significant numbers belonged to class 4 (23.1%) and class 2 (15.4%). The more severe the pulmonary hypertension, higher was the functional class. This correlation had a p value of <0.001, which is significant.
The correlation between the RA and RV dimensions and the severity of pulmonary hypertension was estimated.
TABLE-11: MEAN RA/RV DIMENSIONS IN PULMONARY HYPERTENSION GRADES
Pulmonary hypertension
Parameters Mild Moderate Severe
RA major (mm) 42.5 50.3 55.2
RA minor (mm) 33.9 42 45.6
RV basal (mm) 40.4 45.6 54.6
RV mid level (mm)
33.8 37.7 43.5
RV thickness (mm)
5.4 5.9 6.1
59
As the severity of pulmonary hypertension increases, the right atrial and ventricular also increased. The mean RA major and minor dimensions in mild pulmonary hypertension were 42.5 mm and 33.9 mm. In moderate pulmonary hypertension they were 50.3 and 42 mm. In the severe pulmonary hypertension group the mean RA dimensions are 55.2 and 45.6 mm.
The mean RV basal and midlevel dimensions in mild pulmonary hypertension are 40.4 and 33.8 mm. For moderate pulmonary hypertension the values are 45.6 and 37.7 mm. In severe pulmonary hypertension group the mean values are 54.6 and 43.5 mm. The mean thickness of the RV in mild, moderate and severe pulmonary hypertension are 5.4, 5.9 and 6.1 mm respectively.
0 10 20 30 40 50 60
RA major RA minor RV basal RV midlevel RV thickness
Mild Moderate Severe
60
When comparing to standard reference values the mean values for RA dimensions in mild and moderate pulmonary hypertension are within normal limits. For severe pulmonary hypertension the dimensions of RA are above the normal limits.
The RV the mean chamber dimensions are within normal limits for mild pulmonary hypertension. For both moderate and severe pulmonary hypertension group they are abnormal. The values for severe pulmonary hypertension are higher than the values for moderate pulmonary hypertension.
Increasing pulmonary arterial pressures increase the size of the right heart chambers.
The thickness of the right ventricle is increased in all groups of pulmonary hypertension and as the pulmonary arterial pressures increase the thickness also increases.
61
The correlation between RA and RV dimensions and WHO functional class was also assessed.
TABLE-12: MEAN RA/RV DIMENSIONS AMONG FUNCTIONAL CLASSES
WHO functional class Parameters
(mm)
1 2 3 4
RA major 37 47 53 56.7
RA minor 28.5 38.5 44.2 48.7
RV basal 37.5 43.8 49.5 56.3
RV mid level 30.5 36.4 40 46
RV thickness 5 5.8 6 5.6
P<0.001
0 10 20 30 40 50 60
RA major RA minor RV basal RV midlevel RV thickness
I II III IV
62
The mean linear dimensions of both RA and RV were within normal limits in WHO class 1. In Class 2 only ventricular dimensions were above normal limits. In class 3 and 4 both right ventricular and right atrial mean dimensions were above normal limits. The mean thickness of the RV was maximum in WHO functional class 3. Also the mean RV thickness in class 2 was more than that of class 4.
SYSTOLIC FUNCTION OF RV:
Among the study group 33 (66%) had systolic dysfunction of the right ventricle. The proportion of systolic dysfunction within the different severity groups of pulmonary hypertension differed significantly.
TABLE-13: RVSD AMONG PULMONARY HYPERTENSION GRADES
MPAP Total Mild Moderate Severe
RVSD absent
10 (83.3%)
6 (24%)
1 (7.7%)
17 (34%) RVSD
present
2 (16.7%)
19 (76%)
12 (92.3%)
33 (66%)
Total no 12 25 13
Pearson Chi-square = 18.138, P<0.001
ven tho rig pu ven
eac giv
Only ntricular s ose with s ght ventri ulmonary
ntricle. Th
The p ch WHO ven in the
0%
20%
40%
60%
80%
100%
16.7% of systolic dy severe pul icle. So hypertens his correla
presence o functiona table belo
Mild 8 1
f patients w ysfunction lmonary h majority sion grou ation was s
f right ven al class an
ow.
d 83%
17%
63
with mild n. 76% of hypertensi of patien ups had
significan
ntricular s nd correlat
Moderat 24%
76%
No Y
d pulmona f those wit ion had sy
nts in th systolic d t with a p
systolic dy tion was c
e
%
%
Yes
ary hypert th modera ystolic dy he moder dysfunctio
value of <
ysfunction calculated
Severe 8%
92%
tension ha ate and 92 ysfunction
rate and on of the
<0.001.
n was asse d. The valu
ad right 2.3% of of the severe e right
essed in ues are
64
TABLE-14: RVSD AMONG FUNCTIONAL CLASSES WHO_class Total
1 2 3 4
RVSD
No Count 1 13 2 1 17
% (50.0%) (54.2%) (9.5%) (33.3%) (34.0%)
Yes Count 1 11 19 2 33
% (50.0%) (45.8%) (90.5%) (66.7%) (66.0%)
Total Count 2 24 21 3 50
Pearson Chi-square= 10.185, p = 0.017
In WHO class 1 patients with and without RVSD were equal. In class 2 patients with normal RV systolic function were al little higher (54.2% vs 45.8%)In class 3 (90.5%) and class 4 (66.7%) a majority of patients had RV systolic dysfunction. This correlation had a significant p value of 0.017.
TABLE-15: MEAN RV SYSTOLIC PARAMETERS
MPAP group Mean FAC (%) Mean TAPSE (mm)
Mild 36.7 17.4
Moderate 31 14.2
Severe 27 12.8 P<0.001
As the pulmonary arterial pressure became higher the FAC decreased and TAPSE decreased which is consistent with the trend as the systolic dysfunction. This correlation was also significant with a p value <0.001.
65
TABLE-16: MEAN RV SYSTOLIC PARAMETERS AMONG FUNCTIONAL CLASSES
WHO class Mean FAC (%) Mean TAPSE (mm)
1 34 16.5
2 34.4 16
3 29 13.7
4 21.3 9.7
The mean FAC and mean TAPSE decreased down the WHO functional classes.
DIASTOLIC FUNCTION OF RV:
The presence of RV diastolic dysfunction and severity of pulmonary hypertension was compared.
TABLE-17: RVDD AMONG PULMONARY HYPERTENSION GRADES PUL. HTN. GROUP Total Mild Moderate Severe
RVDD Grade
1 Count 11 4 1 16
91.7% 16.0% 7.7% 32.0%
2 Count 1 16 7 24
% 8.3% 64.0% 53.8% 48.0%
3 Count 0 5 5 10
% 0.0% 20.0% 38.5% 20.0%
Total 12 25 13 50
Pearson Chi-square = 27.726, p<0.001
ven dy dy
RV hy pat pu wa 38 sev pu (p<
All th ntricle. O ysfunction ysfunction.
91.7%
VDD, whi ypertension
tients wit ulmonary h
as found .5% of pa vere grade ulmonary
<0.001)
0%
20%
40%
60%
80%
100%
he particip Out of the of RV, .
% of patien ich was 1 n groups th modera
hypertens in 20% p atients wi es of RVD
hypertens
Mild 92
80
pants had e total stu
48% had
nts with m 6% and 7 respective ate pulmo ion. Grad patients w
th severe DD was fo sion group
2%
%%
1
66
some for udy popu d grade 2
mild pulmo 7.7% in th ely. Grade onary hyp de 3 diast with mode
pulmonar ound to be ps. This
Moderate 16%
64%
20%
1.00 2.00
rm of dias ulation 32
2 and 20%
onary hype he modera e 2 RVDD pertension tolic dysfu
erate pulm ry hyperte e higher in correlatio
3.00
stolic dysf
% had gr
% had gr
ertension h ate and se D was pre n and 53.
function o monary h ension. Th n the mod on was hi
Severe 8%
54%
38%
function o rade 1 di rade 3 di
had only g evere pulm
esent in 6 8% with f right ve hypertensio he propor derate and
ighly sign
of right iastolic iastolic
grade 1 monary 64% of
severe entricle on and rtion of
severe nificant
