NON INVASIVE CARDIAC WORK UP OF HIV POSITIVE PATIENTS

Ponangi Udaya Prashant Consultant, GLOBAL Hospitals, Hyderabad Email: udayaprashant_p@yahoo.co.in

J.J GROUP OF HOSPITALS

DISSERTATION SUBITTED FOR THE DEGREE OF D.M. CARDIOLOGY EXAMINATION (BRANCH II), UNIVERSITY OF MUMBAI May 2008,

INTRODUCTION
HIV aptly called plague of modern era has spread throughout the world in matter of few decades and is now a global pandemic, with cases reported from virtually every country. According to the Centres for Disease Control and Prevention (CDC), the case definition of AIDS is (1) HIV-infected individuals who have <200 CD4 T lymphocytes/L or (2) HIV-infected individuals who have the presence of specific opportunistic infections like Pneumocystis carinii pneumonia, Kaposis sarcoma Cytomegalovirus disease, and pulmonary tuberculosis1. Around 42 million people are now living with HIV/ AIDS worldwide2. In 2003 alone, there were 5 million new cases of the infection worldwide and 3 million deaths from AIDS, making it the 4th leading cause of mortality3, 4. An estimated 5.7 million people lived with HIV infection in India in 2005, which is more than in any other country in the world. Out of these, total 1.2 million patients were suffering from severe form of the disease, AIDS, giving an adult prevalence rate of 0.91%5. There are certain peculiarities of HIV infection. Besides being the most dreaded infectious disease at present, it differs a lot from other viral diseases. With the exception of few viruses, most viral infections usually last from several days to weeks during which development of specific adaptive immunity along with innate immunity clears virus from the body. However HIV infection is unique in that once the virus establishes in the body it succeeds in escaping the immune mediated clearance and hence it is virtually never eliminated from the body completely. Rather a chronic or persistent infection

develops that persists with varying degrees of viral replication, which is a hallmark of this disease. 2 Some of the HIV-infected adults are known to have cardiac involvement in the form of diseases of the pericardium, myocardium and the endocardium. Although pathogenesis of cardiac involvement in HIV infection is uncertain; autoimmunity, autonomic dysfunction and abnormal ventricular growth have been proposed as the possible mechanisms3, The 2 to 5 yr prevalence of symptomatic heart failure ranges from 4 to 28 percent suggesting prevalence of 5 million cases of symptomatic HIV related heart failure6. Before the advent of antiretroviral therapy (ART), clinically significant cardiac disease was unusual in the HIV-infected population and was detected in most cases only at autopsy. After the introduction of HAART in 1996, the death rate from AIDS has decreased dramatically7. Use of new anti retroviral therapies has provided these patients an opportunity to live longer and healthier life. However, increasing the longevity of life in HIV patients has uncovered many late manifestations of the disease. Cardiovascular complication is one of these late manifestations of HIV and is therefore becoming more prevalent. Infection with HIV is one of the leading causes of acquired heart disease and specifically of symptomatic heart failure. In 1996, the estimated prevalences of a significant cardiac morbidity and mortality among HIV-positive patients was 6%7% and 1%5%, respectively8 When HIV-infected patients were examined by

echocardiography in the late 1980s, cardiac abnormalities were detected more often than would be expected from clinical symptoms and physical examination.9 Echocardiography studies showed pericardial effusion as the commonest cardiac manifestation40,41,42, but other studies showed

asymptomatic cardiac dysfunction to be more prevalent

34,35,36

. The effect of

various HAART regimes on long term cardiovascular complications like dyslipidemia, accelerated atherosclerosis is still not known. Few studies were carried out using exercise stress testing to evaluate silent myocardial ischaemia (SMI) in asymptomatic HIV patients treated with HAART and the prevalence was found to be 11%14 Although most conditions are clinically quiescent, most often masked by superimposed secondary infections, some may have fatal outcomes. For example Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study, showed that patients receiving HAART had somewhat higher risk of myocardial infarction than would be predicted by the Framingham risk equation10. Furthermore, the risk of cardiac events also appears to be higher in patients with uncontrolled viremia and worse immunosuppresion. As patients with HIV infection are living longer, they are also at risk of developing coronary atherosclerosis. Cardiac complications are often overshadowed by associated more sinister opportunistic infections and malignancies in HIV patients. Therefore there is paucity of data regarding cardiac manifestations in HIV, AIDS patients and influence of long term HAART . History and clinical examination of HIV patients with cardiac disease is often unrevealing. Even X-ray and ECG are less sensitive in identifying all cardiac diseases in such patients and they are also non-specific3. Hence other tests like Echocardiography, stress test and serum lipid profiles have emerged as convenient, cost effective, sensitive and non-invasive methods for studying cardiac affection in patients of HIV/AIDS. From an

epidemiological standpoint, well-designed longitudinal studies are warranted

to properly assess the natural history of cardiovascular and metabolic abnormalities in the HIV-infected population.

AIMS AND OBJECTIVES

1) Find out various echocardiography, stress test and lipid abnormalities in clinically stable patients with HIV infection/ AIDS.

2) Demonstrate the use of echocardiography, stress test and serum lipid levels in detecting asymptomatic cardiac diseases in HIV/AIDS patients.

3) Effect of HAART on cardiovascular complications in HIV patients.

MATERIALS AND METHODS

This study was carried out on 96 HIV patients, selected randomly from those attending ART Centre, JJ Hospital Mumbai, and satisfied the selection criteria of our study. The study was conducted over a period of 1 year from November 2006 to October 2007 Inclusion criteria 1. Patients of HIV infection diagnosed by at least two positive HIV ELISA tests or one HIV ELISA and one Western Blot test. 2. Age 15 years and above. 3. Those attending JJ ART centre as out patients. Exclusion criteria 1. Patients with known structural cardiac disease. 2. Patients suffering from life threatening opportunistic infections, malignancies and those who are morbidly ill, debilitated and bedridden due to severe AIDS condition. The nature of the study was explained to the patients and an informed consent was taken. A detailed history was taken including that of the risk factors for HIV infection and the history relevant for the cardiovascular diseases. Patients were specifically asked for cardiovascular risk factors like history of diabetes, hypertension, smoking, family history of early ischaemic heart disease.

Cardiac symptoms were sought regarding angina on exertion or at rest, dyspnoea at exertion, orthopnoea, PND, palpitations, giddiness, syncope and symptoms of congestive heart failure. Patients were divided into 3 groups depending upon duration of HIV illness < 1 year 1 5 years 5 years. A thorough clinical examination performed on each patient and findings recorded as per proforma. Antibodies against HIV 1 & 2 were tested using ELISA method. Subjects with single positive HIV ELISA were subjected to either repeat ELISA or Western blot analysis, for confirmation, depending on patients affordability. Patients with at least 2 positive HIV ELISA or one positive HIV ELISA and one positive western blot were considered to be having HIV infection. Routine haematological and biochemical investigations were performed on each patient. Patients were also investigated for particular diseases as directed by their clinical presentation other than those of cardiovascular system. CD4 count testing was performed on all HIV positive patients by flow cytometry.

Clinically classified into A, B or C according to 1993 CDC Atlanta revised classification system for HIV infection and expanded AIDS surveillance for adults1. A: Asymptomatic, Acute HIV or PGL B: Symptomatic not `A` or `C` conditions C: AIDS indicator conditions.

CLINICAL STAING ACCORDING TO CD4 COUNTS1: Stage 1 Stage 2 Stage 3 = CD4 count >500. = CD4 count 200-499. = CD4 count <200.

CLINICAL CATEGORIES: CD4 T CELL CATEGORIES A ASYMPTOMATIC, ACUTE HIV or PGL > 500/L 200-499/L < 200/L A1 A2 A3 B SYMPTOMATIC, NOT A or C CONDITIONS B1 B2 B3 C AIDSINDICATOR CONDITIONS C1 C2 C3

Chest X ray in PA view and standard 12 lead electrocardiograms were obtained for all the patients. Chest roentgenogram was interpreted as normal, cardiac abnormality, pulmonary abnormality or both. Cardiothoracic ratio of more than 50% was taken as criteria for diagnosing cardiomegaly on X ray. ECG was studied for abnormalities in rate, rhythm, P wave, QRS complex, T

wave and U wave. PR interval, QT & RR interval abnormalities and ST segment deviations were looked for. ECHOCARDIOGRAPHY: We used SEIMENS ACCUSON Sequoia C 520 Ehocardiography machine with 3.5 and 5.0 MHz transducers. Transthoracic echocardiography done with subjects in left lateral decubitus position. Detailed echocardiography was done as per convention using standard 2D imaging, M mode, Colour, Pulse and Continuous Doppler. The patients were evaluated for left and right ventricular systolic function in the form of fractional shortening and ejection fraction. Left and right ventricular dimensions recorded and compared with normal values for age and sex21. Other abnormalities like diastolic dysfunction, valvular abnormalities, PAH, vegetations, effusions are specifically looked for

ECHOCARDIOGRAPHIC CRITERIA21 Following Echocardiographic Criteria were used for diagnosis of respective cardiac conditions Dilated cardiomyopathy

Global LV hypokinesia with LV end systolic diameter >55mm and fractional shortening <28% or ejection fraction <55 Mild: 54 - 45% Moderate: 44 30% Severe: < 30%

Borderline LV systolic dysfunction LV end systolic diameter <55mm and fractional shortening <28% or

ejection fraction <55% Isolated RV dysfunction -RV larger than LV on standard echo views or RV mean basal diameter >2.8 cm and RV fractional change <30% then RV dysfunction present. Mild: 31 25% Moderate : 24 18% Severe : < 17%

LV diastolic dysfunction On M mode, motion of the anterior mitral leaflet showing diminished excursion and reduced E/A ratio

Pericardial effusion Diagnosed as echo free space between visceral and parietal pericardium. 1. Small effusion- max. pericardial space < 10mm 2. Moderate effusion- max. pericardial space 10 to 20mm 3. Large effusion- max. pericardial space >20mm

Pulmonary hypertension

Pulmonary artery systolic pressure by TR jet more than 30 mmHg. Mild : 30 50 mmHg

Moderate : 50 70 mmHg Severe : > 70 mmHg

COMPUTERISED STRESS TEST: The computerised cardiac stress test was done on Schiller CS 200 Tread mill machine using Bruce protocol. The test is terminated when

Absolute indications :
o

Drop in SBP of greater than 10 mm Hg from baseline blood pressure, despite an increase in workload, when accompanied by other evidence of ischemia

o o

Moderate-to-severe angina Increasing nervous system symptoms (eg, ataxia, dizziness, near-syncope)

o o o

Subject's desire to stop Sustained ventricular tachycardia ST elevation (>1 mm) in leads without diagnostic Q waves (other than V1 or aVR)

The classic criteria for visual interpretation of positive stress test findings are J-point (defined as the junction of the point of onset of the ST-T wave and normally at or near the isoelectric baseline of the ECG) and ST80 (defined as the point that is 80 ms from the J point) depression (flattening or downsloping) of 0.1 mV (1 mm) in 3 consecutive beats.

LIPIDS:

After 12 hours of overnight fasting blood was collected for lipid profile and analysis was done in standard laboratory using liquid chromatography method According to NCEP ATP III69 lipid goals, present studied population based on age sex distribution and o clinical evaluation of cardiovascular risk profile they were considered to be in low risk group with 0 1 risk factors and dyslipidemia defined when following lipid abnormalities were detected. Total cholesterol >240 mg/dl LDL Cholesterol >160 mg/dl HDL Cholesterol <40 mg/dl VLDL Cholesterol >35 mg/dl Triglycerides >200 mg/dl LDL/HDL ratio 2.5 to 3.5 Statistical analysis were done using SPSS software.

REVIEW OF LITERATURE
Newly discovered infecting organisms are brought in contact with humans either through animals or through changing environment. Human Immunodeficiency Virus (HIV) is one of such recently discovered viruses, which pose threat to whole mankind. First identified in March 1981 when several rare cases of aggressive Kaposi sarcoma and Pneumocystis carinii pneumonia reported in young homosexual men in US, disease was called Gay related immuno deficiency (GRID) or acquired immunodeficiency disease (AID),
12.

The cause of AIDS is a virus that scientists isolated in 198313. The

virus was at first named HTLV-III/LAV (human T-cell lymphotropic virus-type III/lymphadenopathyassociated virus) by an international scientific

committee. This name was later changed to HIV (human immunodeficiency virus). Two types of HIV are currently recognized: HIV-1 and HIV-2. Worldwide, the predominant virus is HIV-1. Both types of virus are transmitted by sexual contact, through blood, and from mother to child, and they appear to cause clinically indistinguishable AIDS. However, HIV-2 is less easily transmitted, and the period between initial infection and illness is longer in the case of HIV2. Currently at least 10 genetically distinct subtypes of HIV-1 are identified within the major group (group M) containing subtypes A to J. In addition, group O (Outliers) contains a distinct group of very heterogeneous viruses. These subtypes are unevenly distributed throughout the world. For instance, subtype B is mostly found in the America, Japan, Australia, the Caribbean and Europe; subtypes A and D predominate in sub-Saharan Africa; subtype C in South Africa and India; and subtype E in Central African

Republic, Thailand and other countries of southeast Asia. Subtypes F (Brazil and Romania), G and H (Russia and Central Africa), I (Cyprus), and group O (Cameroon) are of very low prevalence. In Africa, most subtypes are found, although subtype B is less prevalent2. The History of HIV/AIDS in India

In 1986, Indias first cases of HIV were diagnosed among sex workers in Chennai, Tamil Nadu. In 1987 a National AIDS Control Programme was launched to co-ordinate national responses. Its activities covered surveillance, blood screening, and health education.16. By the end of 1987, out of 52,907 who had been tested, around 135 people were found to be HIV positive and 14 had AIDS. Most of these initial cases had occurred through heterosexual sex, but at the end of the 1980s a rapid spread of HIV was observed among injecting drug users in Manipur, Mizoram and Nagaland - three north-eastern states of India bordering Myanmar (Burma). 16

By this stage, cases of HIV infection had been reported in every state of the country.15 Throughout the 1990s, it was clear that although individual states and cities had separate epidemics, HIV had spread to the general population. Increasingly, cases of infection were observed among people that had previously been seen as low-risk, such as housewives and richer members of society. In 1992 the government set up NACO (the National AIDS Control Organization), to oversee the formulation of policies, prevention work and control programmes relating to HIV and AIDS.

Since the detection of first case of HIV in 1986 in India, epidemic of the disease has led to a sharp increase in the number of cases. An estimated 5.7 million people lived with HIV infection in India in 2005,
16

this gives an adult

prevalence rate of 0.91% for AIDS in India. As of July 2005, 92% of all nationally reported AIDS cases have been found in 10 of the 38 States Union Territories. The greatest numbers were in Maharashtra and Gujarat in the west; Tamil Nadu and Andhra Pradesh in the south; and Manipur and West Bengal in the northeast. A 2006 NACO report revealed 124995 people

suffering from AIDS syndrome with 88245 males and 36750 females16. Of which 5,500 cases are below 15 years age. According to UNAIDS/WHO, between 270,000 and 680,000 Indians died of AIDS in 2005.The statistics for AIDS cases may be a poor guide to the severity of the epidemic, as in many situations a patient will die without HIV having been diagnosed, and with the cause of death attributed to an opportunistic infection, such as tuberculosis HIV Virus HIV1 and HIV2 are RNA viruses of family Retroviridae belonging to subfamily Lentiviridae. HIV1 is the commonest among these and contains several subtypes. Electron microscopy reveals that HIV is an eicosahedral structure containing numerous spikes formed by 2 major proteins Gp120 and Gp41.

REPLICATION: Retroviruses have unique replication cycle whereby their genetic information is encoded by RNA rather than DNA. They contain RNA dependent DNA polymerase (a reverse transcriptase) that directs synthesis of DNA from viral genome. Hence named retroviruses.2, 17 The replication cycle of retroviruses proceeds in 2 phases: First phase: Viral entry into cytoplasm after binding to specific cell surface receptorCD4 and co-receptors CXCR4 and CCR5. Once the virus is internalised its RNA is released from nucleocapsid and is reverse transcribed into proviral DNA. This proviral DNA integrates randomly into host DNA. Second phase: includes synthesis and processing of viral genomes, m-RNAs and proteins using host cell machinery. The virions are assembled and extruded from cell surface by budding. Important coding regions of viral genome are gag, pol and env 2.

PATHOGENESIS The hallmark of HIV disease is a profound immunodeficiency resulting primarily from progressive deficiency of helper T cells. This subset of T cells has a surface molecule CD4, which serves as a primary cellular receptor for HIV. HIV infected CD4+ T cells undergo destruction and/ or immunologically dysfunctioned by a number of mechanisms. When the number of T cells declines below a certain level, the patient is at high risk of developing a variety of opportunistic diseases.17

DIAGNOSIS AND MONITORING HIV: Earliest method developed for screening of HIV antibodies was HIV Elisa in 1985. Today several direct and indirect tests are being used for the diagnosis of HIV infection.2 1. HIV Elisa- standard screening test can be used for detection of both HIV1 and 2 antibodies. Extremely sensitive test. (Sensitivity >99.5%) 2. HIV Western blot- most commonly used confirmatory test. Has high specificity. 3. P24 antigen capture assay- detects viral protein p24 in HIV infected patients. Most useful during window period (before development of HIV sp. Antibodies) and acute HIV syndrome. 4. HIV RNA assay- determines number of copies of HIV RNA per milliliter of Serum. Used for screening and establishing diagnosis. Also in determining need for therapy and monitoring

helpful

efficacy of therapy. CD4+ T cell count- correlates with disease severity. Used for determining need for therapy and monitoring efficacy of therapy. CLINICAL MANIFESTATIONS The clinical features of HIV infection range from acute HIV syndrome to asymptomatic stage to full blown AIDS. Acute HIV syndrome: Within 3 to 6 weeks of primary HIV infection, many patients develop a clinical syndrome of varying severity called acute HIV syndrome. Features

may include fever, pharyngitis, lymphadenopathy, rash etc. it correlates with burst of plasma viremia. Symptoms may persist from one to several weeks 2 Asymptomatic stage: Represents the duration between initial infection to the stage of clinical disease. Although the duration of this stage may have lot of variation it averages about 10 yrs. Even though the patient is asymptomatic the disease is constantly progressing as evidenced by fall in CD4 count and rise in plasma viremia. Symptomatic stage: Symptoms of HIV disease can appear at anytime during the course of HIV infection. Generally, the spectrum of disease that one observes changes as the CD4 counts declines. The more severe and life threatening complications of HIV infection occur in patients with very low CD4 counts. A diagnosis of AIDS is made in anyone with HIV infection and a CD4 count less than 200/l. The causative agents of secondary infections in HIV/AIDS are characteristically mycobacteria opportunistic However organisms such as P.carinii, atypical and

etc.

non-opportunistic

common

bacterial

mycobacteria pathogens frequently affect HIV patients. Approximately 60% of deaths among AIDS patients are as a direct result of an infection other than HIV. Multiple organ system involvement is observed in patients with symptomatic HIV. Respiratory, hepatobiliary, renal cardiovascular, and neurological, gastrointestinal and

genitourinary,

endocrine,

rheumatologic,

hematopoietic, dermatologic diseases are common presenting illnesses in these patients. Defining AIDS The case definition of AIDS has undergone several revisions over years. The current CDC (Centre for Disease Control and prevention) classification system for HIV infected adolescents and adults categorizes persons on the basis of clinical conditions associated with HIV infection and CD4+ T lymphocyte counts. The system is based on three ranges of CD4+ T lymphocyte counts and three clinical categories. Using this system, any HIV infected individual with CD4 count <200/l has AIDS by definition. 1993 REVISED CLASSIFICATION SYSTEM FOR HIV INFECTION AND EXPANDED AIDS SURVEILLANCE CASE DEFINITION FOR ADULTS 1 CLINICAL CATEGORIES : CD4 T CELL CATEGORIES A ASYMPTOMATIC, ACUTE HIV or PGL A1 A2 A3 B SUMPTOMATIC NOT A or C CONDITIONS B1 B2 B3 C AIDSINDICATOR CONDITIONS C1 C2 C3

> 500/L 200-499/L < 200/L

HIV infected patients under classifications A3,B3, C1, C2, C3 are defined as AIDS cases CD4 count <200/microlitre is defined as AIDS regardless of presence pf symptoms or opportunistic infections .

1993 AIDS surveillance case definition CDC Atlanta:

Category A 1 or more of following Category B Category C (AIDS indicator conditions) 1. Candidiasis of the bronchi, trachea or lungs. 2. Esophageal candidosis 3. Coccodiomycosis disseminated or extra pulmonary 4. Cryptococcosis Extra pulmonary 5. Cryptosporidiosis chronic intestinal (> one month) 6. Cytomegalovirus disease (other than lung spleen and nodes) 7. Cervical cancer invasive 8. CMV retinitis 9. HIV related encephalopathy 10. Herpes simplex chronic ulcer, bronchitis, pneumonia or esophagitis 11. Histoplasmosis disseminated or extra pulmonary 12. Isosporiasis disseminated or extra pulmonary 13. Kaposi `s sarcoma 14. Burkits lymphoma 15. Immunoblastic lymphoma 16. Primary brain lymphoma 17. MAIC, M. kansasi infection (disseminated or extra pulmonary) 18. M . tuberculosis 19. Mycobacterium other species or unidentified species (disseminated or extra pulmonary) 20. Recurrent pneumonia 21. Progressive multifocal leukoencephalopathy 22. Salmonella septicemia recurrent

1. 2. 3.

Asymptomatic HIV infection. Progressive Generalised Lymphadenopathy Acute primary HIV infection

1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Bacillary angiomatosis Vulvovaginal candidiasis, oral candidiasis Cervical dysplasia, cervical carcinoma insitu. Constitutional symptoms > 1 month Oral hairy leukoplakia Herpes zoster- 2 distinct episodes more than one dermatome Idiopathic thrombocytopenic purpura Listerosis Pelvic inflammatory disease Peripheral neuropathy

Indications for starting Anti Retroviral Therapy1, 26 1. Acute HIV syndrome 2. Chronic HIV infection A) Symptomatic disease B) Asymptomatic disease i. CD4+ T cell count < 350/L or decreasing ii. HIV RNA > 50,000 copies/ml or increasing 3. Post exposure prophylaxis PRINCIPLES OF THERAPY OF HIV INFECTION: 18 1. Ongoing HIV replication leads to immune system damage and progression to AIDS. 2. Plasma HIV RNA levels indicate magnitude of HIV replication. CD4+ T cell counts indicate current level of immune system competence. 3. Maximum suppression of viral replication is the goal of therapy. 4. Effective therapeutic strategies involve simultaneous initiation of antiretroviral drugs in combination according to optimum schedule and dosages. Compliance is an important part of maximal efficacy of a treatment regimen. ANTIRETROVIRAL DRUGS: 2, 19

ANTIRETROVIRAL DRUGS AND REGIMENS Current antiretroviral drugs comprise four classes I) Nucleoside/nucleotide reverse transcriptase inhibitors: zidovudine,

lamivudine, emtricitabine, stavudine, didanosine, zalcitabine, abacavir, tenofovir II) Non-nucleoside reverse transcriptase inhibitors: efavirenz, nevirapine,

delavirdine III) Protease inhibitors: amprenavir/fosamprenavir, atazanavir, indinavir,

lopinavir/ritonavir, nelfinavir, saquinavir, tipranavir, ritonavir (not commonly used as the sole protease inhibitor in an antiretroviral regimen, but often used in low doses to boost the levels of other protease inhibitors). IV) Fusion inhibitors, of which only enfuvirtide is approved by the US Food

and Drug Administration (FDA). Commonly used abbreviations for antiretroviral drugs S = stavudine A = zidovudine N = nevarapine L = lamivudine E = efavirenze

HAART regimes commonly used SLN ALN SLE

ALE Highly active antiretroviral therapy Highly active antiretroviral therapy (HAART) is a term used to distinguish aggressive multidrug regimens from earlier, less potent ones. Currently, antiretroviral therapy (ART) and HAART both refer to any potent combination of agents that can reduce the plasma HIV level to less than can be detected by polymerase chain reaction or b-DNA assay. These regimens most often consist of a protease inhibitor or nonnucleoside reverse transcriptase inhibitor in addition to a backbone of two nucleoside reverse transcriptase inhibitors. ECHOCARDIOGRAPHY : Echocardiography is the use of ultrasound to examine the heart. It is a safe, non invasive and painless technique.20

ECHOCARDIOGRAPHY: Two-dimensional echocardiography was first demonstrated in the late 1950s, with real-time mechanical systems and, in the early 1960s, with intracardiac probes. Transesophageal echocardiography followed, in the late 1960s. Stop-action two-dimensional echocardiography enjoyed a brief vogue in the early 1970s. It was, however, the demonstration by Bom in Rotterdam of real-time two-dimensional echocardiography using a linear transducer array that revolutionized and popularized the subject. Then, the phased array sector scanner, which had been demonstrated in the late 1960s by Somer in Utrecht, was applied to cardiac studies from the mid-1970s onwards. Satomura had demonstrated the use of the ultrasonic Doppler effect to detect tissue motion in Osaka in the mid-1950s and the technique was soon afterwards applied in

the heart, often in combination with M-mode recording. The development of the pulsed Doppler method in the late 1960s opened up new opportunities for clinical innovation20. NORMAL VALUES FOR AN ADULT:20, 21 Left ventricular internal diameter (end systolic) LVIDsLeft ventricular internal diameter (end diastolic) LVIDd Left ventricular wall thickness Diastolic-septum Diastolic-posterior wall Systolic-septum Systolic-posterior wall 0.6- 1.0 cms 0.6- 1.0 cms 0.9- 1.8 cms 0.9- 1.8 cms 2.0- 4.0 cms 3.5- 5.6 cms

Left ventricular fractional shortening,FS Left ventricular ejection fraction, LVEF Left atrial diameter Aortic root diameter Right ventricular diameter (systolic-diastolic) ECHOCARDIOGRAPHIC FINDINGS21, 22

28- 45% 55- 80% 2.7- 3.8 cms 2.0-4.0 cms 0.7-2.3 cms

In some common heart conditions associated with HIV/ AIDS 1) Dilated cardiomyopathy and systolic dysfunction Characterized by A) dilatation of cardiac chambers, specially LV B) reduced wall thickness C) reduced wall motion, global hypokinesia

D) intra cardiac thrombus M-mode and 2D echo show, increased LVIDs &LVIDd;

decreased LVEF&FS; reduced motion of IVS & LVPW. Doppler studies may show functional mitral or tricuspid regurgitation.

REFERENCE LIMITS AND PARTITION VALUES OF LEFT VENTRICULAR SIZE21

Women Variable Refere nce Range 3.9-5.3 Mildly Abnomal 5.4-5.7 Moderately Abnormal 5.8-6.1 Severly Abnormal >6.2 Reference Range Men Mildly Abnormal 6.0-6.3 Moder ately Abnormal 6.4-6.8 Severly Abnormal >6.9

LV diastolic diameter cm LVIDD/BS A Cm/m2 LVIDD/ height Cm/m

4.2-5.9

2.4-3.2

3.3-3.4

3.5-3.6

>3.7

2.4-3.3

3.2-3.4

3.5-3.6

>3.7

2.5-3.2

3.3-3.4

3.5-3.6

>3.7

2.4-3.3

3.4-3.5

3.6-3.7

>3.8

REFERENCE LIMITS AND VALUES PARTITION VALUES OF LEFT VENTRICULAR FUNCTION21

Women

Men

Variable

Refere nce Range

Mildly Ab-nmal

Moderat ely Abnormal

Severly Abnormal

Reference Range

Mildly Ab-normal

Moderately Abnormal

Severly Abnorm al

Endocardial fractiona shortening % Ejection fraction %

27-45

22-26

17-21

<16

25-43

20-24

15-19

<14

>55

45-54

30-44

<30

>55

45-54

30-44

<30

2) Myocarditis have similar features as dilated cardiomyopathy 3) Right ventricular dysfunction Characterized by dilated or hypokinetic RV. If RV is of the same size as or larger than LV in all views, it is abnormal.

REFERENCE LIMITS AND PARTITION VALES OF RIGHT VENTRICLAR SIZE AND FUNCTION AS MEASURED IN THE APICAL FOUR-CHAMBER VIEW21 Variable RV basal diameter cm RV fractional change % Reference Range 2.0-2.8 32-60 Mildly Abnormal 2.9-3.3 25-31 Moderately Abnormal 3.4-3.8 18-24 Severely Abnormal >3.9 <17

4) Pulmonary hypertension Characterized by abnormal increase in pulmonary artery pressure above 30/20 mmHg. Doppler study showing PASP by TR jet of mean>20mmHg at rest and>30mmHg during exercise. 2D echo features-dilated Pulmonary artery (pulmonary artery

diameter>aortic Diameter), RV dilatation/ hypertrophy, RA enlargement, abnormal IVS motion. M-mode shows abnormal M- mode of pulmonary valve leaflets with absent A waves, dilated RV with normal LV and abnormal IVS motion.

5) Pericardial effusion- abnormal collection of excessive fluid in pericardial space. M-mode reveals an echo free space seen below posterior wall of LV or above the anterior wall of RV. In 2Decho, effusion is seen as an echo free space surrounding heart. It can be diffuse or locculated Minimal pericardial effusion : <10 mm Moderate pericardial effusion : 10 - 20 Large pericardial effusion: >20 mm 6) Cardiac tamponade is seen as large volume of pericardial effusion with Diastolic collapse of RA&/or RV. Patient will also have hemodynamic compromise like resting tachycardia, feeble pulses with pulses paradoxus 7) Constrictive Pericarditis: Echocardiographic features are i) ii) thickened pericardium calcified pericardium

iii) iv) v) vi) vii) STRESS TEST: HISTORY :

abnormal septal motion, especially end diastolic abnormal LV filling pattern LV expands only in early diastole Mid and late diastolic flattening of LVPW motion Restrictive pattern on Doppler study20,22

Feil and Seigel23 first noticed the significance of cardiovascular exercise stress testing in 1928; they reported ST and T changes following exercise in 3 patients with chronic stable angina. Hellerstein et al introduced stress testing as a method of evaluating work capacity of cardiac patients. The following year, Master and Oppenheimer introduced a standardized exercise protocol to assess functional capacity and hemodynamic response24. Bruce in 1956 reported a work test performed on a treadmill and established guidelines that would group patients into NYHA I IV.

Exercise stress testing, which is now widely available at a relatively low cost, is currently used most frequently to estimate prognosis and determine functional capacity, to assess the probability and extent of coronary disease, and to assess the effects of therapy. Ancillary techniques, such as metabolic gas analysis, radionuclide imaging, and echocardiography, can provide further information that may be needed in selected patients, such as those with moderate or prior risk26.

Exercise physiology

The initiation of dynamic exercise results in increases in the ventricular heart rate, stroke volume, and cardiac output due to vagal withdrawal and sympathetic stimulation. Also, alveolar ventilation and venous return increase as a result of sympathetic vasoconstriction. The overall hemodynamic response depends on the amount of muscle mass involved, exercise efficiency, conditioning, and exercise intensity. In the initial phases of exercise in the upright position, cardiac output is increased by an augmentation in stroke volume mediated through the use of the Frank-Starling mechanism and heart rate. The increase in cardiac output in the later phases of exercise is due primarily to an increase in ventricular rate.

During

strenuous

exertion,

sympathetic

discharge

is

maximal

and

parasympathetic stimulation is withdrawn, resulting in autoregulation with generalized vasoconstriction, except in the vital organs (cerebral and coronary circulations). Venous and arterial norepinephrine release from sympathetic postganglionic nerve endings is increased, and epinephrine levels are increased at peak exertion, resulting in an increase in ventricular contractility. As exercise progresses, skeletal muscle blood flow increases; oxygen extraction increases as much as 3-fold; peripheral resistance decreases; and systolic blood pressure (SBP), mean arterial pressure, and pulse pressure usually increase. Diastolic blood pressure (DBP) remains unchanged or may increase

or decrease by approximately 10 mm Hg. The pulmonary vascular bed can accommodate as much as a 6-fold increase in cardiac output, with only modest increases in pulmonary arterial pressure, pulmonary capillary wedge pressure, and right atrial pressure; this is not a limiting determinant of peak exercise capacity in healthy subjects.

The maximum heart rate and cardiac output are decreased in older individuals, related in part to decreased beta-adrenergic responsiveness. Maximum heart rate can be calculated by subtracting the patient's age (y) from 220 (has a standard deviation of 10-12 beats per minute [bpm]). The age-predicted maximum heart rate is a useful measurement for safety reasons and as an estimate of the adequacy of the stress to evoke inducible ischemia. A patient who reaches 80% of the age-predicted maximum is considered to have a good test result, and an age-predicted maximum of 90% or better is considered excellent27.

In the postexercise phase, hemodynamics returns to baseline within minutes of discontinuing exercise. The return of vagal stimulation is an important cardiac deceleration mechanism after exercise and is more pronounced in well-trained athletes but blunted in patients with chronic congestive heart failure. Intense physical work or important cardiorespiratory impairment may interfere with achievement of a steady state, and an oxygen deficit occurs during exercise. The oxygen debt is the total oxygen uptake in excess of the resting oxygen uptake during the recovery period26

STRESS TESTING PROTOCOL REQUIREMENTS23 The test is conducted using standard Bruce Protocol27 STAGE 1 2 3 4 5 6 7 SPEED mph 1.7 2.5 3.4 4.2 5.0 5.5 6.0 METS 4.6 7.0 10.1 10.3 14.9 GRADE 10 12 14 17 18 20 22 CUMULATIVE TIME in min 3 6 9 12 15 18 21

The test is conducted in three minute stages; The Bruce protocol starts at a Functional Class 2 workload (4.6 METS of work, a speed of 1.7 mph and a grade of 10 degrees). Each 3 minutes the workload is increased by a combination of increasing the speed and the grade of the treadmill. Stage 2 reaches a FC1 activity with a speed of 2.5 mph and a grade of 12 degrees. The protocol continues until one of several endpoints is reached. These include a true positive or negative test, hypo or hypertension, fatigue, dyspnoea, certain arrhythmias, or gait problems

Contraindications to exercise stress testing23,27 The following contraindications are from the AHA/ACC guidelines published in 1997.

Absolute contraindications
o o

Acute myocardial infarction (within 2 d) Unstable angina not previously stabilized by medical therapy: Appropriate timing of tests depends on the level of risk of

unstable angina as defined by the Agency for Health Care Policy and Research Unstable Angina Guidelines.
o

Uncontrolled

cardiac

arrhythmias

causing

symptoms

or

hemodynamic compromise
o o o o o

Symptomatic severe aortic stenosis Uncontrolled symptomatic heart failure Acute pulmonary embolus or pulmonary infarction Acute myocarditis or pericarditis Acute aortic dissection contraindications: Relative contraindications can be

Relative

superseded if the benefits of exercise outweigh the risks.

o o o o

Left main coronary stenosis Moderate stenotic valvular heart disease Electrolyte abnormalities Severe arterial hypertension: In the absence of definite evidence, the committee suggests an SBP of greater than 200 mm Hg and/or a DBP of greater than 110 mm Hg.

o o

Tachyarrhythmias or bradyarrhythmias Hypertrophic cardiomyopathy and any other forms of outflow tract obstruction

Mental or physical impairment leading to an inability to exercise adequately

High-degree atrioventricular (AV) block

Acutely ill patients such as those with infections, hyperthyroidism or severe anaemia.

Patients with locomotor problems. Severe symptomatic aortic stenosis.

The test is reported in metabolic equivalents (METs) of exercise. A MET refers to the resting volume oxygen consumption per minute (VO2) for a 70kg, 40-year-old man. One MET is equivalent to 3.5 mL/min/kg of body weight. The standard Bruce protocol, starts at 1.7 mph and 10% grade (5 METs). The Bruce protocol has 3-minute periods to allow achievement of a steady state before workload is increased. Stage 1 is 1.7 mph at 10% grade (5 METs). Stage 2 is 2.5 mph at 12% grade (7 METs). Stage 3 is 3.4 mph at 14% grade (9 METs)27.

Interpretation

Interpretation

should

include

exercise

capacity

and

clinical,

hemodynamic, and ECG response. The occurrence of ischemic chest pain consistent with angina is important, particularly if it forces termination of the test. The classic criteria for visual interpretation of positive stress test findings are J-point (defined as the junction of the point of onset of the ST-T wave and normally at or near the isoelectric baseline of the ECG) and ST80 (defined as the point that is 80 ms from the J point) depression of 0.1 mV (1 mm) or more and/or an ST-segment slope within the range of 1 mV/s in 3 consecutive beats25.

HEART DISEASE IN HIV BACKGROUND: Cardiac involvement in AIDS was first reported in 1983 in a postmortem description of a 24 year old woman of Haitian origin with multiple complications of AIDS, including Kaposis sarcoma involving the entire anterior cardiac wall without pericardial effusion.28 Subsequently, cardiac involvement in patients with HIV infection has been described in multiple necropsy, clinical, and echocardiographic series. Almost any agent that can cause disseminated infection in patients with AIDS may involve the myocardium, but clinical evidence of cardiac disease is usually overshadowed by manifestations in other organs, primarily the brain and lungs. Thus, the number of patients with AIDS and cardiac involvement at necropsy greatly exceeds the number with significant cardiac disease during life. Estimates of prevalence vary widely from 2873%38 according to the screening methods selected. Although exact data are unavailable, conservative estimates derived from European and US series indicate cardiac morbidity and mortality in HIV patients of 610% and 19%39, respectively. INCIDENCE: The 2-5 year incidence of symptomatic heart failure in HIV infected patients ranges from 4%- 28% in various studies.4,5 It suggests that there are 4- 5 million cases of HIV related symptomatic heart failure worldwide.6

Among HIV infected children up to 10 years of age, 25% die due to chronic cardiac disease and 28% develop serious cardiac events after an AIDS defining illness.31 LEFT VENTRICULAR SYSTOLIC DYSFUNCTION AND DILATED

CARDIOMYOPATHY INCIDENCE: The incidence of left ventricular systolic dysfunction in HIV population is different in different studies. It ranges from none to seventy percent among various studies and the difference depends on the echocardiographic criteria.45 The first evidence that HIV can be associated with cardiomyopathy was reported by Cohen and colleagues in 1986.32 Himelman and colleagues reported 71 patients with HIV infection out of which 8(11%) had LV dilatation and poor contraction; 4 had evidence of congestive heart failure.33 In 1988, a study conducted by Corello and colleagues, 41% patients had LV hypokinesia which was the commonest abnoemality found in HIV patients echocardiograpically and this is associated with left ventricular wall thinning, dilatation and failure.34 In a prospective study conducted by Herskowitz and colleagues35, 69 AIDS patients were randomly selected to be followed up for a mean period of 11 months by serial 2D Echo. At the entry into the study, 10 out of 69(14.5%) already had global LV hypokinesia. Of the remaining 59, 11 subsequently developed global LV dysfunction with incidence of 1.5 persons / 100 person months.

Among 21 patients, 20 were clinically silent and 1 had congestive heart failure. In another 4 yr observational study of 296 HIV patients by Curie PF et al, 44(15%) were found to have dilated cardiomyopathy; 13(4%) with isolated RV dysfunction and 12(4%) with borderline LV dysfunction. Dilated cardiomyopathy was strongly associated with CD4 count <100/l.36 LV dysfunction is a common consequence of HIV infection in children. In a study of 205 children infected with HIV by maternal fetal transmission, the prevalence of decreased LV function was 5.7%. 2 year cumulative incidence was 15.3%.4 PATHOGENESIS: Wide variety of possible etiologic agents has been postulated in HIV related cardiomyopathy. These are HIV myocardial infection, opportunistic infections, viral infections, autoimmune response to viral infection, cardio toxicity from therapeutic/ illicit drugs, nutritional deficiencies, cytokine over expression and many others. MyocarditisDilated cardiomyopathy can be related to a direct action of HIV on myocardial tissue or to proteolytic enzymes or cytokine mediators induced by HIV.39, 40 Autopsy and biopsy results have revealed only scant/ patchy inflammatory cell infiltrates. Toxoplasma gondi, coxackie B virus, EBV, CMV, adenovirus and HIV have been found in myocytes of biopsy specimens.41

Cytokine Alterations42, 41HIV infection increases production of TNF which 1. alters intra cellular calcium homeostasis 2. increases nitric oxide production 3. increases TGF 4. causes endothelin 1 upregulation COURSE OF DISEASE: Patients with asymptomatic LV dysfunction (fractional shortening<28%; global hypokinesia) may have transient disease. In one study, 3 out of 6 patients of global LV hypokinesia had normal reading after a mean of 9 months. The three with persistently depressed LV function died within 1 year.43 PROGNOSIS: Mortality in HIV patients with dilated cardiomyopathy is high independent of CD4 count, age, sex and risk groups. Median survival to AIDS related death was 101 days in patients with LV dysfunction whereas it was 472 days in patients with normal heart at a similar stage of infection.36 Isolated RV dysfunction or borderline LV dysfunction did not place patients at any increased risk36. Rapid onset congestive heart failure has a grim prognosis in HIV

infected adults and children. More than 50% of patients died within 6-12 months of presentation. Chronic onset heart failure may respond well to medical therapy.37

THEARAPY: Treatment is same as for non ischemic cardiomyopathy with diuretics, digitalis, ACE inhibitors, aldosterone antagonists and beta blockers. As medical therapy is begun, serial echo studies are to be done at 4 monthly interval.38 Patients not responding or worsening within 2 weeks of initiation of nts medical therapy should be considered for biopsy. Endomyocardial biopsy may reveal lymphocytic infiltrates suggesting Myocarditis or treatable opportunistic infections, permitting aggressive therapy of underlying pathogen.38 therapy

PERICARDIAL EFFUSION Pericardial effusion is the most common cardiovascular complication of HIV infection. Prior to the introduction of highly active antiretroviral therapy (HAART), the frequency of this complication was estimated to be between 5% and 46% , with an incidence of 11%17% per year3 Pericarditis in HIV-infected patients may present with large effusions or cardiac tamponade.39. Although spontaneous resolution of pericardial effusion has occurred in as many as 42% of those affected, the 6-month mortality rate among HIV positive patients with pericardial effusion (62%) is higher than that among HIV-positive patients without that complication (7%).
39

HIV infected

patients with pericardial effusion generally have a lower CD4 counts than those without an effusion marking more advanced disease. It is one of the most common clinical cardiac involvement in AIDS patients. In HIV-positive patients in whom cardiac tamponade develops, mycobacterial infection is the most common cause worldwide (44%) followed by malignancy (16%) and other bacterial infection (11%)39 INCIDENCE: In autopsy series, it has been reported in as few as 3% of autopsies by Wilkins et al to as much as 36.9% of autopsies as reported by Lewis and colleagues.40 In echocardiographic series, variable no of HIV patients had pericardial involvements in various studies. In Corallo and associates series41, 39 out of 102 HIV patients (38%) had pericardial effusion. In Monsurez and colleagues series42, 21% had pericardial effusion.

Steffen and colleagues43 did a prospective study of 151 patients with echocardiography out of which 29(19%) had pericardial effusion.

The 5 yr PRECIA study (prospective evaluation of cardiac involvement in AIDS) 44 selected 231 patients of HIV (59 subjects with asymptomatic HIV, 62 with AIDS related complex, 74 with AIDS) 16 of whom developed pericardial effusion. 3 already had effusion on enrolment, 13 developed subsequently; 12 of these 13 had AIDS.44 80% of them had small pericardial effusion (max pericardial space<10 mm at the end diastole) and 87% were asymptomatic. Incidence of pericardial effusion was 11% per year in patients with AIDS.

CAUSES: Causes of pericardial effusion in HIV individuals are37, i) Infections Viral a) HIV b) Ebstein-Barr virus c) Herpes virus d) Coxsackie virus e) Cytomegalovirus Parasitic : Toxoplasma gondii Mycobacterial : a) M tuberculosis b )M kanassi c) M avium-intracellulare d) M fortuitum Fungal

a) Asperillosis b) Candida c) Histoplasmosis d) Cryptococcus Bacterial a) Salmonella b) Staphylococcus c) Enterococcus d) Chlamydia e) Nocordia f) Listerosis g) Pseudomonas h) Klebsiella i) Streptococcus Tumours a) Lymphoma b) Kaposi sarcoma c) Adenosarcoma

COURSE OF DISEASE AND PROGNOSIS: Effusion markedly increases mortality e.g. in PRECIA study, pericardial effusion nearly tripled the risk of death among AIDS patients.44 2 out of 16 patients developed cardiac tamponade. Effusion spontaneously resolved in 42% of the patients.44

MONITORING AND THERAPY: Screening echocardiography is recommended in HIV infected

individuals regardless of the stage of the disease.38 Patients should undergo pericardiocentesis if they have pericardial effusion with signs of tamponade. Patients with pericardial effusion should be evaluated for possible treatable conditions like tuberculosis and malignancy. HAART should be considered if therapy has not been started. Repeat echocardiography is recommended after 1 month of initial diagnosis.3,38 INFECTIVE ENDOCARDITIS Injection drug users are at a greater risk than general population for infective endocarditis, chiefly of the right sided heart valves. Surprisingly HIV patients may not have higher incidence of endocarditis than people with similar risk behaviors. However HIV patients may have difference in the clinical picture than general population.45 HIV patients are more prone to salmonella endocarditis than immunocompetent persons because they are more likely to have salmonella bacteremia. HIV patients respond better to IV antibiotics. HIV patients are less likely to have damaged heart valves due to lack of immunity.

CAUSATIVE ORGANISMS: Common organisms associated with endocarditis in HIV patients include staphylococcus aureus, salmonella sp. Fungal endocarditis due to aspergillus fumigatus, candida species and Cryptococcus neoformans are more common in IV drug abusers. Fulminant causes of infective endocarditis with high mortality can occur in late stages of AIDS.46 PROGNOSIS AND THERAPY: Fulminant courses of infective endocarditis with high mortality can occur in late stages of AIDS patients with poor nutritional status and severely compromised ability to fight infection, but several cases have been successfully treated with antibiotic therapy. Operative indications for HIV infected patients with infective

endocarditis include Hemodynamic instability Failure to sterilize cultures after appropriate intravenous

antibiotics Severe valvular destruction in patients with reasonable life expectancy2 NON BACTERIAL THROMBOTIC ENDOCARDITIS Non-bacterial thrombotic endocarditis (or marantic endocarditis) involves large friable, sterile vegetations that form on cardiac valves. These lesions are associated with DIC and systemic embolization. Lesions are

rarely diagnosed ante mortem. Clinically relevant emboli occur in about 42% of cases.3 However no cases found in prospective series. Marantic endocarditis should be suspected in any patient with systemic embolization. Yet it should be considered rare in AIDS patients. ISOLATED RV DISEASE Isolated RV hypertrophy with or without RV dilatation is relatively uncommon in HIV infected individuals. It is generally related to pulmonary diseases that increase pulmonary vascular resistance. Possible causes include multiple bronchopulmonary infections, pulmonary arteritis due to HIV disease, microvascular pulmonary emboli caused by thrombus or

contaminants in injected drugs3,48. PULMONARY HYPERTENSION Primary pulmonary hypertension has been described in

disproportionate number of HIV infected individuals. It is estimated to occur in 0.5% of hospitalized AIDS patients.47 Plexogenic pulmonary arteriopathy characterized by remodeling of pulmonary vasculature with intimal fibrosis and replacement of normal endothelial structure was frequently demonstrated in lung histology. All these patients had clear lung fields on examination, chest radiographs and normal perfusion scans. Pulmonary hypertension is often explained by lung infections, venous thromboembolism or LV dysfunction. In a study conducted by Hilario Nunro et al., of 82 patients with HIV associated pulmonary arterial hypertension, pulmonary hypertension was the

direct cause of death in 72% of cases48. Survival rates of overall population, at 1,2 and 3 yrs were 73, 60 and 47% respectively. Survival was significantly lower in patients with NYHA functional class III and IV at presentation. The results of the study suggest that patients with severe HIV infection, associated pulmonary hypertension should be considered for long term epoprostenol therapy.49 VASCULITIS Vasculitis is being reported more often in HIV infected patients.50 It should be suspected in patients with Fever of unknown origin Unexplained multisystem disease Unexplained arteritis/ myositis Glomerulonephritis Peripheral neuropathy Unexplained gastrointestinal, cardiac or CNS ischemia Successful immunomodulatory therapy, chiefly with steroids has been described. ACCELERATED ATHEROSCLEROSIS Accelerated atherosclerosis has been observed in young HIV infected individuals without traditional coronary risk factors.51-52 Significant coronary lesions were discovered at autopsy in HIV positive patients who died unexpectedly. Cytomegalovirus was present in 2 of 8 patients and hepatitis B in 2 of 8 patients. Premature cerebrovascular disease is common in AIDS

patients. An estimated 8% prevalence of stroke was observed in HIV infected patients.52 Coronary artery disease and ischemic heart disease have been reported in patients with HIV infection. Both the prevalence of ischemic heart disease and the mortality associated with apparently are increased among HIV-positive patients54. The increased prevalence could be, at least in part, related to an improvement in the overall survival of HIV-positive patients, especially since the introduction of HAART. The origins of the disease appear to be multifactorial and related to the higher incidence of infection with herpesvirus, cytomegalovirus, or HIV-1, as well as to the inclusion in HAART of protease inhibitors, which have been reported to produce lipodystrophy, hyperlipidemia, and hyperglycemia55. In a retrospective analysis of data from the Frankfurt HIV cohort, which included almost 5000 patients, a fourfold increase in the annual incidence of myocardial infarction among HIV-infected patients was found after the establishment of HAART with protease inhibitors, compared with the incidence among patients who underwent treatment before the institution of56. Histopathologic examination of coronary arteries generally reveals eccentric atheromatous and fibrous plaques, with variable degrees of chronic inflammation and accelerated arteriosclerosis. Unusual proliferation of smooth muscle cells with abundant elastic fibres, as well as diffuse and circumferential involvement of the coronary arteries without any intervening healthy segments, also have been reported57. To assess these manifestations by non invasive methods the present study is performed

Silent Ischaemia in AIDS patients : Numerous studies have shown that a silent ischemic

electrocardiographic response to an exercise test is a powerful predictor of major coronary events, including sudden cardiac death, in clinically healthy populations. In asymptomatic men in their fourth and fifth decades, prevalences of SMI of 5% have already been documented. However, SMI is more frequent in populations at high risk for coronary disease such as patients with diabetes, in whom the prevalence of SMI ranges from 10% to 15%, and in patients with familial hypercholesterolemia58. In their study on exercise testing for detecting Silent Myocardial Iscahemia in HIV patients Duong et al found that central fat accumulation, age and cholestrol levels were the factors most strongly associated with a positive exercise test result, whereas duration of HIV illness, duration of HAART therapy or use protease inhibitors did not influence positive stress test result14. AUTONOMIC DYSFUNCTION Clinical signs of autonomic dysfunction in HIV infected patients include syncope, presyncope, diminished sweating, diarrhoea, bladder dysfunction and impotence. In one study, it was shown that autonomic dysfunction was more pronounced in AIDS patients. Patients with HIV associated nervous system disease had the greatest abnormalities in autonomic dysfunction.60 CARDIOVASCULAR MALIGNANCY Malignancy affects many AIDS patients, generally in the later stages of disease. Cardiac malignancy is usually metastatic disease. Kaposis sarcoma

is associated with human herpes virus 8 and affects up to 35 percent of AIDS patients particularly homosexuals. Autopsy studies found that 28 percent of HIV infected patients with widespread Kaposi sarcoma had cardiac involvement60. Kaposi sarcoma has not been found invading the coronaries but is often an endothelial cell neoplasm with predilection for subpericardial fat around the coronaries. Pericardial fluid found in patients with Kaposi sarcoma is typically serosanguinous without malignant cells or infection.60 Primary cardiac malignancy associated with HIV infection is generally due to cardiac lymphoma. Non-Hodgkin lymphomas are 25 to 60 times more common in HIV infected individuals. They are the first manifestation of AIDS in up to 4 percent of cases.61 Patients with primary cardiac lymphoma can present with dyspnoea, right heart failure, biventricular failure, chest pain or arrhythmias.61 Cardiac lymphoma is associated with rapid progression to cardiac tamponade, symptoms of congestive heart failure, myocardial infarction, tachyarrhythmias, conduction abnormalities or superior vena cava syndrome. Pericardial fluid typically reveals malignant cells. Leiomyosarcoma associated with Epstein-Barr virus, is a rare malignant tumour of smooth muscle origin. Protease inhibitor use has significantly decreased the incidence of Kaposi sarcoma.60

EFFECT OF LIPIDS BY HIV AND ANTIRETROVIRAL DRUGS In a recent review of the effect of HAART associated dyslipidemia on cardiovascular risk and life expectancy, a HAART regimen associated with a 24% increase in total cholesterol (28% increase in LDL cholesterol) compared with one with only a 4% increase in total cholesterol (1% increase in LDL cholesterol) was associated with a 50% increase in cardiovascular risk over 10 years70. Absence of dyslipidemia was estimated to preserve life

expectancy by 0.15- 1.53 additional years, with the greatest effect of dyslipidemia on life expectancy seen among younger patients and those at high or very high risk62. HIV has been associated with dyslipidemia independent of

antiretroviral therapy. Grunfeld et al found that HIV infection was associated with elevated triglyceride levels that worsened with progression of HIV-related disease63. Antiretroviral therapy can also contribute to dyslipidemia. Dyslipidemia has been described as being more common and more severe in HIV patients receiving antiretroviral therapy than in patients not on therapy64. The severity of the dyslipidemia and the typical pattern of the lipid profile differ among and within the classes of antiretroviral agents55. Also, dyslipidemia does not develop in everyone who takes these medications, suggesting that host factors play a major role in its development64

Reverse transcriptase inhibitors Non-nucleoside reverse transcriptase inhibitors have been associated with elevated levels of high-density lipoprotein cholesterol (HDL-C). Nucleoside reverse transcriptase inhibitors, on the other hand, are heterogeneous in their lipid effects, which may depend somewhat on interactions with other antiretroviral drugs in the regimen. For example, stavudine is often associated with elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels. Protease inhibitors Protease inhibitors are generally associated with elevated levels of total cholesterol and triglycerides. Triglyceride levels of greater than 1,000 mg/dL have been reported in association with protease inhibitors. Carr et al reported elevated total cholesterol levels, defined as greater than 5.5 mmol/L, in 58% of patients receiving protease inhibitors vs 11% of those not receiving them; elevated triglycerides, defined as greater than 2.0 mmol/L, were seen in 50% of patients receiving these drugs vs 22% of those not receiving them55. Segerer et al, in another study, reported a 15% increase in total cholesterol and a 25% increase in triglycerides after 3 to 6 months of protease inhibitor therapy64. Protease inhibitor therapy increased lipoprotein (a) by 48 percent in patients with elevated pretreatment values(>20mg/dl).57 All protease inhibitors are not the same in regard to dyslipidemia, however, and lipid abnormalities may vary. Ritonavir has been most associated with triglyceride elevations, whereas indinavir is more associated with elevations of LDL-C.

Although HIV and its treatment have been associated with dyslipidemia in some studies, no one has definitively established that this association translates to an increased risk of cardiovascular events. Recent reports of myocardial infarction in young patients receiving protease inhibitors have focused interest on the association between HIV infection, antiretroviral therapy, and coronary artery disease. For example, in a small French study, patients treated with protease inhibitors had an almost threefold increase in risk of myocardial infarction compared with untreated controls, suggesting that rapidly forming drug induced plaques are unstable and prone to rupture. The most compelling evidence that dyslipidemia in HIV patients may increase the risk of myocardial infarction comes from the Data Collection of Adverse Events of Anti-HIV Drugs study65. In this prospective, observational study, the relative risk of myocardial infarction attributed to antiretroviral therapy increased by 26% per year. Measurement of lipid values58. Evaluation of serum lipid levels should be performed after fasting for a minimum of 8 h, and preferably for 12 h, and the levels should be determined before initiation of antiretroviral therapy (B-III). The standard screening lipid profile should include measurement of total cholesterol, HDL-C, and triglyceride levels . Using these measured values, LDL-C and nonHDL-C levels are calculated. This should be repeated within 36 months after the initiation of HAART, then yearly, unless abnormalities are detected or therapeutic interventions are initiated. For individuals with an elevated triglyceride level (1200 mg/dL) at baseline, it may be preferable to repeat a lipid profile sooner (e.g., within 12 months after initiating HAART)

Lipodystrophy in patients on HAART. Fat redistribution was first described with PIs but has also been described in patients not on PI therapies66. Characteristic clinical findings include dorsocervical fat pad (buffalo hump), increased abdominal girth and breast size, lipoatrophy of subcutaneous fat of the face, buttocks, and limbs, and prominence of veins on the limbs (pseudovenomegaly). Despite the intensive investigations, a case definition for its general term lipodystrophy still does not exist, and well-controlled studies and long-term followup data are lacking. An increased incidence of abdominal fat accumulation in HIV-positive women suggests that gender differences may be affecting the presentation of this syndrome55. The mechanisms for this phenomenon are not well defined; however, several intriguing findings have suggested decreased lipolytic activity (4), stoichiometric similarity between the binding site of PIs with retinoic-acid binding protein type 1 (RBAP-1), and LDL-receptor-related protein (LRP) causing impaired adipocyte differentiation and apoptosis as well as chylomicron uptake and triglyceride clearance67 Unfortunately for the sufferers of these side effects, there are no consistent data showing reversal of fat redistribution after removal of the suspected offending antiretroviral((s) from the treatment regimen; however, lipid profiles tend to improve68. Expanded study of the effects of HIV infection and its treatment on cardiovascular disease and metabolic abnormalities is warranted for several reasons. Additionally studies specifically designed to assess the relative risk of metabolic and cardiovascular diseases in HIVinfected women are lacking, From the perspective of basic science, the causes of many syndromes do not appear to be manifesting as single entities

but rather a complex interaction among HIV-, drug-, and immune-related factors, especially in the study of metabolic complications of HIV66. TREATMENT Targeting LDL cholesterol Recommendations for managing dyslipidemia in HIV patients are based on the NCEPs third Adult Treatment Panel guidelines for the general population69. The first step is to assess the patients cardiovascular risk, which affects the decision whether to start treatment and the goals of treatment. The main factor is the LDL-C concentration, but the assessment also takes into account other risk factors such as confirmed cardiovascular disease, age older than 45 years in men and 55 in women, cigarette smoking, hypertension, low HDL-C (< 40 mg/dL), and diabetes. The level of cardiovascular risk is traditionally classified as low, intermediate, or high, and each category entails a different LDL-C treatment goal: Lowest risk means no risk factors or one risk factor; the goal LDL-C concentration is less than 160 mg/dL. Intermediate risk means one or two risk factors; the goal LDL-C is less than 130 mg/dL. High risk means confirmed coronary heart disease or coronary heart disease equivalents, or two or more cardiovascular risk factors and a Framingham 10-year risk score of 20%; the goal LDL-C is less than 100 mg/dL. In view of several recent studies, 2226 the NCEP recently modified these guidelines to include an LDL-C goal of less than 70 mg/dL as an option in patients at very high risk, ie, those with established cardiovascular disease and multiple major risk factors (especially diabetes), severe and poorly

controlled risk factors, multiple risk factors of the metabolic syndrome, and acute coronary syndromes68-69. Although lower LDL-C levels are the primary goal of lipid-lowering therapy, the triglyceride level and the non-HDL cholesterol level (ie, total cholesterol minus HDL-C) are often significant factors in patients with antiretroviral therapy-related dyslipidemia, who commonly have triglyceride elevations. When triglyceride levels are borderline high (150199 mg/dL), dietary and exercise interventions are emphasized. When triglyceride levels are high (200499 mg/dL), non-HDL cholesterol becomes a secondary target of therapy. When triglyceride levels are 500 mg/dL or higher, triglycerides are the primary target of therapy68. The NCEP guidelines recommend non-HDL cholesterol as a secondary target of therapy in people with high triglyceride levels (200 mg/dL). The goals for non- HDL cholesterol are defined as 30 mg/dL higher than those for LDL-C.69

Preliminary guidelines for the evaluation and management of dyslipidaemia in HIV positive patients receiving HAART have recently been published. Statins which are independent of the cytochrome P450 system (for example, pravastatin, atorvastatin) are recommended to avoid interaction with protease inhibitors, and use of fibrates and gemfibrozil has been described in patients with isolated hypertriglyceridaemia.

OBSERVATIONS

TABLE 1: SEX DISTRIBUTION N = 96 SEX MALE FEMALE NO. OF PATIENTS 70 26 PERCENT % 73 27

During the study total of 96 clinically stable patients attending JJ ART Center OPD were randomly selected and enrolled into the study. 73% of total patients were male (70) and 27% of patients were female (26) [Table 1, Fig 1]. TABLE 2 : AGE SEX DISTRIBUTION . N=96 AGE GROUP 20- 29 30- 39 40- 49 50- 60 MALE 8 35 19 5 FEMALE 8 11 6 2 TOTAL 16 46 25 7 Percentage % 17 43 27 7

The youngest patient in our study was 18 years and oldest was 60 years. The age sex distribution is shown in above Table ( Fig 2). The mean age of the patients is 36.5 8 years and majority (43%) belonged to 3rd 4th decade age group.

TABLE 3: DURATION OF ILLNESS N=96 Duration of illness in years <1 15 >5 Total No Patients 24 59 12 Percentage % 25 62 13

The average duration of known HIV illness is 3 years with 25% of patients belonging to < 1 year duration of illness and majority, 62% belonging to 1 5 years group and 13% to >5 years age group. (Table 3) (Fig 3). The shortest duration of known HIV illness recorded was 1 month and the longest was 14 years. TABLE 4: CARDIAC SYMPTOMS N= 96 Cardiac symptoms Angina Dyspneoa Palpitations Giddiness, Syncope Total No 22 27 11 5 Percentage % 34 41 17 8

Out of 96 patients examined 36 (37%) patients had some cardiac complaints and rest of 60 (63%) patients had no cardiac symptoms. Among the reported symptoms dyspnoea was the commonest (41%), followed by angina (34%), palpitations (17%) and least common reported was giddiness

or presyncope (8%) and none complained of frank syncope. All the symptoms were of minor nature, NYHA class I to II except 2 patients, one with depressed LV function and other had severe mitral stenosis due to rheumatic heart disease.

TABLE 5: CARDIAC RISK FACTORS N=96 Cardiac Risk Factors Hypertension Diabetes Mellitus Smoking Family H/O IHD No Patients 2 0 12 1 Percentage of Total Patients % 2 0 12.5 1.04

In the study 84.3% of patients had no cardiac risk factors, and 15 patients had some cardiac risk factors, smoking being the commonest among them (12 patients) and 2 patients had history of hypertension and 1 patient had family history of IHD.

TABLE 7: Clinical staging and HAART N=96 HAART regime Clinical Stage A 3 0 0 1 5 9 (9%) Clinical stage B 6 0 3 0 7 16 (17%) Clinical Stage C 21 5 17 1 26 71 (74%) Total No in Various HAART regimes 30 (32%) 5 (5%) 20 (21%) 2 (2%) 38 (40 %) 96 (100%)

SLN SLE ALN ALE none Total no in Clinical Stages

According to CDC Atlanta criteria patients were assessed and clinically classified into 3 groups A, B & C. 74% of patients belonged to group C, while 17% belonged to group B and 9 % to group A. This is depicted in chart (Fig. 5). 58(60%) patients were on some HAART regime. 38 (40%) patients were from pre ART group not taking any anti retroviral drug. Maximum patients were receiving SLN regime around 30 patients, 20 patients were on ALN, 6 patients were on SLE regime and 2 patients were on ALE drugs.

TABLE 8: HIV patients in different Categories based on CD4 count N = 95 CD4 COUNT Total No of Patients Category 1 (CD4>500) Category 2 (CD4 = 499- 200) Category 3 (CD4<200) 28 29 25 42 26 45 Percentage %

25 (26%) our patients belonged to category 1 with CD4 count >500, 42 (45%) belonged to category 2 with CD4 count between 499 200 and 28 (29%) patients had CD4 counts less than 200. The mean CD4 count of the patients was 384 In specific general examination findings, clubbing was the commonest finding observed in total of 11 patients followed by minor degree of pallor but all the patients had Hb > 12 gm. 12 patients had minor auscultable physical findings and majority were normal clinically.

TABLE 9: DISTRIBUTION OF PATIENTS IN DIFFERENT BMI GROUPS: N=96 BMI <18 18 -25 25 - 30 >30 No of Patients 24 67 3 2 Percentage % 25 70 3 2

Most of patients (70%) were in normal BMI range group between 18-25, 24% were underweight i.e. BMI < 18, 3% belonged to overweight and 2% obese group.

TABLE 10: ABNORMAL X RAY FINDINGS N=96 X RAY ABNORMALITY NORMAL X RAY CARDIOMEGALY OTHER CARDIAC FINDINGS PULMONARY PATHOLOGY BOTH CARDIOPULMONARY PATHOLGY NO. OF PATIENTS 78 4 3 9 2 PERCENTAGE 82 4 4 9 2

64 (66%) patients had normal ECG findings and rest had minor ECG changes. 8 patients had right axis deviation and non specific T inversions, 2 had VPC`S, 4 had bundle branch blocks and 5 had early repolarisation abnormalities. 82% had normal x-ray findings and 4 patients had cardiomegaly out of which 2 patients were found to have dilated cardiomyopathy ( Table 10:, Figure: 7)

ECHOCARDIOGRAPHY
TABLE 11: ECHOCARDIOGRAPHY FINDINGS OF HIV PATIENTS AND INFLUENCE OF HAART N=45 CARDIAC DISEASE DILATED CARDIOMYPATHY PERICARDIAL DISEASE LV SYSTOLIC DYSFUNCTION LV DIASTOLIC DYSFUNCTION PULMONARY HYPERTENSION RV DYSFUNCTION TOTAL patients 4 (6%) 14 (21%) 15 (23%) 16 (24%) 9 (14%) 8 (12%) No patients on HAART 2 8 9 10 4 5 p value 0.634 0.748 0.66 0.9252 0.303 0.747

Out of 96 patients examined 45 (46.8%) patients had positive ECHO findings. The commonest echocardiography finding in our study was diastolic dysfunction, which was present in 16 (24%) patients. Next common abnormality was LV systolic dysfunction not associated with much dilatation or regional wall motion abnormality. Some of them had increased myocardial thickness with poor contractility. Only one patient had very poor left ventricular function (20%) and others had mild to moderate impaired LV function Pericardial effusion was detected in 14 (21%) patients. 3 patients had moderate effusion and rest had mild pericardial effusion. Frank dilated cardiomyopathy occurred in only 4 (6%) patients, which was less common than idiopathic pulmonary hypertension 9 (14%) patients, or isolated RV dysfunction 8 (12%) patients. The pulmonary hypertension and RV

dysfunction could not be attributed to pulmonary or left heart abnormality. One patient had severe mitral stenosis due rheumatic heart disease. 57% of patients with positive ECHO findings were on HAART regimes and others were not. There was no statistical difference between those patients on HAART and those who were not with respect to any of the echocardiography findings. Table 12: Influence of Duration of HIV illness and ECHO findings N=96 CARDIAC DISEASE < 1 year n = 24 2 3 7 6 6 4 1-5 years n =59 1 8 6 8 4 4 >5y ears n=12 1 3 3 2 0 0 Total P value 0.35 0.727 0.102 0.484 0.02 0.18

DILATED CARDIOMYPATHY PERICARDIAL DISEASE LV SYSTOLIC DYSFUNCTION LV DIASTOLIC DYSFUNCTION PULMONARY HYPERTENSION RV DYSFUNCTION

4 14 16 16 9 8

Patients were categorised into 3 groups depending upon known HIV illness duration. The incidence of abnormal cardiac findings were more frequently detected in those with symptom duration < 1 year (n=30) than when compared to other groups, second group with symptom duration between 1 5 years (n=53) and last one with illness duration >5 years (n=13). However the numbers did not achieve statistical significance. Only PAH was significantly association with duration of illness (p = 0.02) occurs more commonly in those with lesser duration of illness.

TABLE 13: RELATIONSHIP OFECHOCARDIOGRAPHY FINDINGS AND CD4 COUNTS N=45

CARDIAC DISEASE Category 1 CD4 Category N= 42 Category 3 N =28 Total P value

DILATED CARDIOMYPATHY PERICARDIAL DISEASE LV SYSTOLIC DYSFUNCTION LV DIASTOLIC DYSFUNCTION PULMONARY HYPERTENSION RV DYSFUNCTION RHD MS

0.006

4 1

5 10

5 5

14 16

0.8 0.08

16

0.31

0.424

8 1

0.09

On subgroup analysis of various echocardiography findings with CD4 count, only dilated cardiomyopathy was associated with low CD4 count (p = 0.006) whereas other ECHO findings did not achieve statistical significance.

TABLE 14: STRESS TEST RESULTS N=96 STRESS TEST RESULT Negative Not done Positive Terminated early No of Pateints 68 14 8 6 Percentage % 71 15 8 6

Eight patients had positive stress test among, 15 patients not done and 6 patients terminated early because of poor effort tolerance. 67 patients had negative test. The positive yield of the stress test was approximately 10%. Average METS achieved by HIV patients was 10.13 (SD 2.32). Average work duration of exercise of HIV patients was 10.57(SD 2.23) minutes. The average heart rate of the subjects was 153 bpm. 92 % of patients achieved target heart rate. Average BP recorded of the subjects during stress test was 140/88 mm Hg. Out of 8 patients 3 had history of angina and 5 patients had no symptoms of angina. There were no significant differences between stress test positive and those with negative groups, with respect to age group, BMI, duration of illness, CD4 count or lipid profile status.

TABLE 15: LIPID LEVELS IN HIV PATIENTS N=85 Type of cholestrol Mean value of patients on HAART Total cholestrol Total triglycerides LDL cholestrol HDL cholestrol VLDL cholestrol 170 147 102 40 27 184 142 120 39 25 0.146 0.824 0.018 0.958 0.61 Mean value of not on HAART p value

85 HIV patients had complete lipid profile. 52 patients were found to have dyslipidemia i.e. 61% of our HIV patients were found to be dyslipidemic. 57% of the dyslipidemic patients were receiving HAART, whereas rest were not on any antiretroviral drugs. None pf the patients were found to have lipodystrophy. The mean values of various lipids in two groups, those who were on ART drugs and those who were not, are similar except LDL cholesterol which was lower in HAART group (mean 102 vs 120; p = 0.018)

TABLE 16: INCIDENCE OF DYSLIPIDEMIA IN HIV PATIENTS N=85 Cholesterol Levels Total no of patients Hypercholestremia Low HDL High LDL Hypertriglyceridemia High VLDL 6 (8%) 45 (62%) 7 (10%) 9 (12%) 6 (8%) No on HAART 2 27 2 6 4 0.13 0.419 .06 .417 0.7 p value

. The commonest lipid abnormality found was low HDL (62%) followed by hypertriglceridemia (12%), high LDL cholesterol (10%), high VLDL cholesterol (8%) and hypercholestremia (8%). There were no statistically significant differences in numbers between those who were on HAART and those who were not on antiretroviral drugs.

DISCUSSION
The heart is an organ frequently affected in patients with AIDS. Researchers have demonstrated cardiac involvement in as many as 28% 73% of patients infected with HIV3,8,9,11 Cardiac involvement generally occurs in the latter stages of the disease but can occur at any point. Although it can be clinically silent or masked by other comorbid diseases and demonstrated only by echocardiography or at autopsy, cardiac involvement can result in significant cardiac morbidity and mortality. In 1996, the estimated

prevalences of a significant cardiac morbidity or cardiac mortality among HIVpositive patients were 6%7% and 1%5%, respectively34. During the period of one year total of 96 clinically stable patients attending JJ ART Centre OPD were randomly selected and enrolled into the study. The total no of male patients were 70 (73%) and females were 26 (27%). Patients belonged to age group between 18 years to 60 years with average age of being 36.5 years. The mean duration of illness is 2 years and majority belonged to Category 2 with CD4 count in range of 200- 499. 60% of patients were on HAART and the commonest regime is SLN. 47% of our study patients had positive ECHO findings. Himelman33 and colleagues showed echocardiographic abnormality in 64% of admitted HIV patients. De Casto8 et al in 1992 studied 72 AIDS patients and found that 47 (65.2%) presented with cardiac involvement. However some studies showed a lower prevalence of heart disease. Steffen43 and colleagues reported 21% prevalence of heart disease in HIV infected patients. Among

those patients with positive ECHO findings, many of them had non specific complaints of minor degree and even ECG, Chest X-ray were not suggestive of significant cardiac disease in these cases Electrocardiographic changes were of little clinical relevance. In one multicenter trial, 57 percent of asymptomatic HIV infected individuals had baseline abnormalities on ECG including supraventricular and ventricular ectopic beats. The chest radiogram has low sensitivity and specificity for congestive heart failure72. Our study showed 44% of patients had minor ECG changes and 6 percent had cardiac findings on chest X-ray. So we conclude that Echocardiography was very useful in detecting cardiac abnormalities in HIV patients even when clinical pointers for cardiac disease are not very significant SYSTOLIC DSFUNCTION ECHO 5.5% 7% 16% 16.4% 21% 23% 64% 24% 6%

STUDY DE Casto8 Himelman33 Cuire36 et al Barbaro73 et al Cardoso75 JS Present study

PE 18% 10%

DD

DCM 12% 11% 15% 8%

PAH 1%

RVD

4%

2% 9% 8%

The incidence of pericardial effusion in patients with asymptomatic AIDS (defined as patients with CD4 count <200 cells/L) was 11% per year before the introduction of effective ART37. In a review of 15 autopsy and echocardiography studies involving 1139 patients with HIV disease, incidence of pericardial disease was 21%39. Some studies showed lower incidence of

pericardial involvement. Himelman33 et al reported 10% prevalence of pericardial involvement, whereas Corallo and Multinelli9 reported 38% incidence of pericardial involvement but the study included only patients in advanced stage of the disease i.e. AIDS. Our study findings are in accordance general prevalence of pericardial effusion in HIV patients39 i.e. 21%. Himelman46 and colleagues showed that 11% of HIV patients in their study had dilated cardiomyopathy and systolic LV dysfunction. Currie36 et al showed 7% incidence of borderline LV systolic dysfunction, 4.3% dilated cardiomyopathy and 4% RV dysfunction. Our study shows mild to moderate degree of impaired LV dysfunction without LV dilatation and regional wall motion abnormality, as one of the commonest echocardiography finding (23%), more than that of pericardial effusion (21%). Our study showed that diastolic dysfunction to be the commonest finding during echocardiography (24%). These findings are similar to Indian studies carried out which have demonstrated the presence of diastolic dysfunction as commonest finding on echocardiography in HIV infected adults70. Diastolic dysfunction was the commonest (63%) cardiac finding in a prospective study by Cordoso J.S74 et al. and also studies by Paula Moyer75 et al which showed that 50% of HIV positive patients have diastolic dysfunction. The other findings in were 9 patients (14%) had PAH, and 8 patients (12%) had RVD and one patient had incidental RHD with severe mitral stenosis and no patient was found to have infective endocarditis unlike previous studies6,8,11.

Prospective echocardiography studies reported increase frequency of cardiac diseases as duration of HIV illness increases7,8,9,11. But our study after categorising patients into 3 groups based on duration of HIV illness failed to establish statistical significance between illness duration and cardiac abnormality, except for pulmonary hypertension which seemed to occur commonly in those with duration of illness less than 1 year (p = 0.02) (Table: 12 ). Currie36 et al reported high incidence of dilated cardiomyopathy in HIV patients with low CD4 counts. In their study DCM was strongly associated with CD4 count less than 100/. In our study DCM is strongly associated with low CD4 count < 200 (p =0.006) but other cardiac abnormalities had no relation to CD4 count (Table: 13) After introduction of HAART both the mortality and morbidity of AIDS patients is reduced and also the incidence of severe cardiac

complications35,44,46. In our study there were no statistical difference between those who are on HAART and those not on any antiretroviral drugs, probably due to relatively small sample size analysed. (Table: 15) Numerous studies have shown that a silent ischemic

electrocardiography response to an exercise test is a powerful predictor of major coronary events, including sudden cardiac death, in clinically healthy populations14. In asymptomatic men in their fourth and fifth decades, prevalences of SMI of 5% have already been documented58. However, SMI is more frequent in populations at high risk for coronary disease, such as patients with diabetes, in whom the prevalence of SMI ranges from 10% to 15%, and in patients with familial hypercholesterolemia14,58. In our study, a

higher than normal expected prevalence of positive stress test (10%) for the age group indicating HIV patients constitute a high risk group for coronary ischaemia Duong et a in their study on Silent Myocardial Iscahemia in HIV patients found that central fat accumulation, age and cholestrol levels were the factors most strongly associated with a positive exercise test result, whereas duration of HIV illness, duration of HAART therapy or use of protease inhibitors did not influence positive stress test result14. In present study patients with positive stress test had no association with HAART intake (Table: 15), which could be explained on basis that none of our patients were on protease inhibitors, the main drugs implicated in drug induced metabolic syndrome, and also HIV infection itself constituted higher prevalence of ischaemia irrespective of HAART intake. The increased prevalence of accelerated atherosclerosis in HIV patients could be, at least in part, related to an improvement in the overall survival of HIV-positive patients and inclusion in HAART of protease inhibitors, which have been reported to produce lipodystrophy, hyperlipidemia, and hyperglycemia52,55. In our study there were 13 (14%) HIV patients having > 5 year duration of illness, but none of our patients were on protease inhibitors. Therefore these patients are likely to have abnormal cardiovascular risk status. Results from D:A:D Study indicate that incidence of MI increases 26% per year of exposure to HAART10 but none of our patients had history, ECG or ECHO evidence of myocardial infarction.

Out of 85 patients who had complete lipid profile and 61% had dyslipedemia which is similar to several other several studies55-59 indicating that incidence of dyslipidemia is very common in HIV patients (44%-66%). The commonest lipid abnormality observed was low HDL cholesterol (62%) followed by hypertriglceridemia (12%). Carr et al reported elevated total cholesterol levels, defined as greater than 5.5 mmol/L, in 58% of patients receiving protease inhibitors vs 11% of those not receiving them; elevated triglycerides, defined as greater than 2.0 mmol/L, were seen in 50% of patients receiving these drugs vs 22% of those not receiving them55. Segerer et al, in another study, reported a 15% increase in total cholesterol and a 25% increase in triglycerides after 3 to 6 months of protease inhibitor therapy64 . Our study showed (Table 15; Fig 11) that mean total cholesterol level is lower in HAART group than non drug group (170 vs 184). Mean triglycerides and LDL cholesterol were also low in HAART group whereas mean HDL and VLDL levels are higher. Only LDL cholesterol was significantly lower in HAART group than non drug group (p = 0.018) Dyslipidemia has been seen in patients with HIV infection, even prior to use of protease inhibitors and has been linked both to HIV infection and to ART. In untreated HIV infected patients, lower CD4 counts are associated with lower total blood cholesterol, lower HDL cholesterol, and higher triglyceride levels67. Total and LDL cholesterol decreased after the onset of HIV disease, but rose to preinfection levels or higher with ART, while HDL cholesterol levels decreased markedly after the onset of HIV and did not recover. Furthermore, an early placebo-controlled study of zidovudine monotherapy reported declines in both IFN- and triglycerides in patients

taking zidovudine56. This may be the likely reason why no significant elevation of lipids is seen in HAART group. Dyslipidemia is an important risk factor for atherosclerotic coronary heart disease and the high prevalence of dyslipidemia (61% in our study) and improved survival of AIDS patients, indicates these patients must be investigated more often and treated early to prevent adverse cardiovascular events in future.

LIMITATIONS This is an observational study and there are no matched controls of normal population to compare.

There is no follow up to determine the long term effects on mortality and morbidity in HIV patients of the cardiac abnormalities detected.

Sample size is relatively small especially for the individual cardiac abnormalities detected.

ART regimes used in JJ Hospital do not contain protease inhibitors and therefore

SUMMARY
Total of 96 clinically stable HIV patients not known to have any prior cardiac illness were studied, which included 70 male patients and 26 female patients. The average age of patients was 36.78 years.

37 % of patients had insignificant cardiac complaints often nonspecific involving other systems also.

60 % of patients were on some HAART regime, the commonest being SLN regime. Routine 12 lead ECG and chest X ray were not very sensitive in detecting cardiac abnormalities in HIV patients.

47% had some cardiac abnormality detected echocardiographically, commonest being diastolic dysfunction followed by impaired LV function, pericardial effusion, PAH, isolated RV dysfunction and least dilated cardiomyopathy. The positive echocardiographic findings were not significantly

influenced by duration of illness or CD4 counts except for dilated cardiomyopathy, which was strongly associated with CD4, count < 200.

HAART regimes used in JJ hospital had no influence on any of the echocardiographic abnormalities detected.

Exercise testing was positive in 10 % of HIV patients tested, which is higher than general population prevalence constituting high risk group for coronary artery disease. Dyslipidemia is widely prevalent in HIV patients (61%) even when patients are not on any protease inhibitors.

The commonest lipid abnormality detected was low HDL cholesterol (62%) followed by hypertrigliceredemia (12%).

HAART regimes used in JJ Hospital did not significantly influence the lipid levels in except for LDL cholesterol.

CONCLUSIONS
Cardiovascular complications are very common in HIV patients, especially after introduction of HAART. ECHO, exercise testing and lipid profiles are useful to detect cardiac complications early and should be performed routinely when indicated.

FIGURE 1:

SEX RATIO

FEMALE 27%
MALE FEMALE

MALE 73%

AGE SEX DISTRIBUTION

40 35 35 30 NO OF PATIENTS 25 20 15 11 10 5 0 20- 29 3030 39 40- 49 AGE GROUPS 50- 60 8 8 6 5 2 19
MALE FEMALE

FIGURE 2:

FIGURE 3:

DURATION OF HIV ILLNESS

>5
in years

18

15

53
Total No Patients

<1

24

20

40
No of patients

60

FIGURE 4:

CARDIAC SYMPTOMS REPORTED BY PATIENTS

Giddiness, Sync ope 8% Palpitations 17% Angina 34%

Dyspneoa 41%

FIGURE 5:

DISTRIBUTION OF HIV PATIENTS IN VARIOUS HAART REGIMES

30 26 25 21 20 No of patients15 10 6 5 0 SLN SLE ALN ALE none HAART Category 3 0 0 5 3 1 1 5 17

Clinical Stage A Clinical stage B

7

Clinical Stage C

FIGURE 6:
DISTRIBUTION OF PATIENTS BASED ON CD4 COUNT

Category 3 (CD4<200) 30%

Category 1 (CD4>500) 26%

Category 1 (CD4>500) Category 2 (CD4 = 499 200) 499Category 3 (CD4<200)

Category 2 (CD4 = 499 200) 49944%

FIGURE 7:

X RAY FINDINGS IN HIV PATIENTS

NORMAL X RAY

10% 3% 4%

2%

0%
CARDIOMEGALY OTHER CARDIAC FINDINGS

81%
PULMONARY PATHOLOGY BOTH CARDIAC AND PULMONARY

FIGURE 8:

FREQUENCY OF ECHOCARDIOGRAPHY FINDINGS

30% 25% 21% 20% 15% 10% 6% 5% 0% 14% 12%
ECHO observation

23%

24%

FIGURE 9:

INCIDENCE OF CARDIAC DISEASE AND DURATION OF HIV ILLNESS

8 8 7 6 5 NO OF PATIENTS4 3 2 1 0
LV SYSTOLIC DYSFUNCTION LV DIASTOLIC DYSFUNCTION DILATED CARDIOMYPATHY PULMONARY HYPERTENSION PERICARDIAL DISEASE RV DYSFUNCTION

8 7 6 6 6

4 3 2 1 1 0 3 3 2

4 4

< 1 year 1-5 years > 5 y ears n=13

CARDIAC DISEASE

FIGURE 10:

INCIDENCE OF CARDIAC DISEASES BASED ON CD4 COUNT 10 10 9 8 7 6 No fo patients 5 4 3 2 1 0 DILATED CARDIOMYPATHY PULMONARY HYPERTENSION LV SYSTOLIC DYSFUNCTION LV DIASTOLIC DYSFUNCTION PERICARDIAL DISEASE RV DYSFUNCTION 0 0
CD4 COUNT 500-200 CD4 COUNT <200

5 5 4 4

5 4 4

2 1 1 1

2
CD4 COUNT >500

Cardiac disease

FIGURE 11: MEAN LIPID LEVELS IN HIV PATIENTS

184 170 147 142 120 102

200 180 160 140 120 100 80 60 40 20 0

40 39

27 25

Total cholestrol

Total triglycerides

LDL cholestrol

HDL cholestrol

VLDL cholestrol

FIGURE 12:

DYSLIPEDEMIA IN HIV PATIENTS

4 High VLDL Hypertriglyceredemi a High LDL Low HDL Hypercholestremia 0 2 6 10 20 30 40 50 6 6 9 2 7 27 45

No on HAART Total no of patients

No of patients

BIBLIOGRAPHY

1. 1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents and Adults. Website of the Centres for Disease Control. Available at:

http://www.dvd.gov/mmwr/preview/mmwrhtml/00018871.htm. ) 2. Lane CF, Fauci AS. Human Immunodeficiency Virus disease: AIDS

and related disorders. In: Kasper DL, Fauci AS et al Editors. Harrisons Principles of Internal Medicine. 16th Ed: New medical publishers, 2005:1076 1140. 3. Fisher SD, Lipshultz SE. Cardiovascular abnormalities in HIV infected individuals. In: Zipes DP Ed. Braunwalds Heart Disease, Textbook of cardiovascular medicine, 7th Ed, Elsevier Saunders, Philadelphia. 2005; 61: 1719 1731. 4. AIDS epidemic update. In: Joint United Nations Programme on HIV/AIDS (UNAIDS). Geneva, Switzerland: World Health Organization, 2006;. 5. NACO (April 2006), HIV/AIDS epidemiological Surveillance & York; Mc graw Hill

Estimation report for the year 2005. 6. Rerkpattanapipat P, Wongpraparut N, Jacobs LE, et al. Cardiac manifestations of acquired immunodeficiency syndrome. Arch Intern Med 2000; 160:6028. 7. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. Declining morbidity and

mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998; 338:853860. 8. De Castro S et al. Heart involvement in AIDS; a prospective study during various stages of the disease. Eur Heart J 1992;13(11):14521459. 9. Corallo S, Multinelli MR et al. Echocardiography detects myocardial damage in AIDS; prospective study in 102 patients. Eur Heart J 1988; 9:887- 892. 10. Law MG, Friis-Moller N, El Sadr WM, et al. The use of the Framingham equation to predict myocardial infarctions in HIV-infected patients: comparison with observed events in the D:A:D Study. HIV Med. 2006;7:218-230. 11. Barbaro G, Di Lorenzo G, Grisorio B, et al. Cardiac involvement in the acquired immunodeficiency syndrome. A multicenter clinical-

pathological study. AIDS Res Hum Retroviruses 1998;14:1071. 12. Brennan RO, Durack DT. 'Gay compromise syndrome', the Lancet, 1981; 2: 1338-1339. 13. Barre-Sinoussi F , Chermann JC, Montagnier L et al. 'Isolation of a TLymphotropic retrovirus from a patient at risk for Acquired Immune Deficiency Syndrome (AIDS)', Science,1983 May 20. 14. M. Duong,1 Y. Cottin,2 L. Piroth et al Exercise Stress Testing for Detection of Silent Myocardial Ischemia in Human Immunodeficiency VirusInfected Patients Receiving Antiretroviral Therapy: Clinical Infectious Diseases 2002; 34:5238

15. Panda S. The HIV/AIDS epidemic in India: an overview, in Panda S., Chatterjee A, Abdul-Quader AS. Eds. The epidemic and the response in India, 2002:20. 16. NACO (April 2006), HIV/AIDS epidemiological Surveillance &

estimation report for the year 2006. 17. Fauci AS. Host factors and the pathogenesis of Human

Imunodeficiency virus induced disease. Nature. 1996; 384: 529. 18. Dybul M. et al: Guidelines for using antiretroviral agents among human immunodeficiency virus infected adults and adolescents,

Recommendations of the panel on clinical practices for treatment of HIV, 2002. 19. Gulick RM et al. New antiretroviral drugs. Clin Microbiol Infect. 2003; 9: 186. 20. Feigenbaum Febiger,1994 21. Lang RM, Bierig M, Devereaux RB et al, American Society of H. Echocardiography, 5th ed. Philadelphia:Lea &

Echocardiography`s Guidelines and Standards Committee: A report from the American Society of Echocardiography`s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of

Echocardiography, a branch of the European Society of Cardiology. Journal. of the American Society of Echocardiography, 2005;18: 14401463. 22. Jae K. OH, A. Jamil Tajik. The ECHO Manual. Third edition. Philadelphia: Lippincott Williams & Wilkins, 2006.

23. Gibbons RJ, Balady GJ, Beasley JW, et al: ACC/AHA Guidelines for Exercise Testing. A report of the American College of

Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). J Am Coll Cardiol 1997 Jul; 30(1): 260-311. 24. Master AM, Oppenheimer ET: A simple exercise tolerance test for circulatory efficiency with standard tables for normal individuals. Am J Med Sci 1929; 177: 223 25. Fletcher GF, Flipse TR, Kligfield P, Malouf JR: Current status of ECG stress testing. Curr Probl Cardiol 1998 Jul; 23(7): 353-423 26. Stein RA, Chaitman BR, Balady GJ, et al: Safety and utility of exercise testing in emergency room chest pain centers: An advisory from the Committee on Exercise, Rehabilitation, and Prevention, Council on Clinical Cardiology, American Heart Association. Circulation 2000 Sep 19; 102(12): 1463-7. 27. Ellstead MH: Stress Testing: Principles and Practice. 4th ed. Philadelphia, Pa: FA Davis; 1995. 28. Autran BR, Gorin I, Leibowitch M et al. AIDS in a Haitian woman with cardiac Kaposis sarcoma and Whipples disease. Lancet 1983; i: 7678. 29. Lewis W. Cardiomyopathy in AIDS: a pathophysiological perspective. Prog Cardiovasc Dis 2000;43:15170. 30. Arshad A, Bansal A, Patel RC. Cardiac complications of human immunodeficiency virus infection: diagnostic and therapeutic

considerations. Heart Disease 2000;2;13345.

31. Lipshultz SE, Easley KA, Orav EJ, Kaplan S, Starc TJ, Bricker JT, Lai WW, Moodie DS, Sopko G, Colan SD. Cardiac dysfunction and mortality in HIV-infected children: The Prospective P2C2 HIV Multicenter Study. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group. Circulation 2000; 102:1542-8. 32. Cohen JS, Anderson DW, Virmani R et al. Congestive cardiomyopathy in association with AIDS. N Engl J Med 1986, 315: 628-630. 33. Himelman RB, Chang WS et al. Cardiac manifestations of Human Immunodeficiency virus infection, A 2 dimensional echocardiographic study. J Am Col Cardiol 1985, 6:1021- 1025. 34. Yunis NA, Stone VE. Cardiac manifestations of AIDS: a review of disease spectrum and clinical management. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 18:14554. 35. Herskowitz A, Willoughby SB, Baughman KL, Schulman SP, Bartlett JD. Cardiomyopathy associated with antiretroviral therapy in patients with HIV infection: a report of six cases. Ann Intern Med 1992;116:311 313. 36. Currie PF, Jacob AJ, Foreman AR et al. Heart muscle disease related to HIV infection; Prognostic implications BMJ. 1994;309:1605. 37. Al-Attar I, Orav J et al: Predictors of cardiac morbidity and related mortality in children with acquired immunodeficiency syndrome. J Am Coll Cardiol. 2003;41:1598

38. Lipshultz SE, Fisher SD. Cardiovascular risk factors, monitoring and therapy for human immunodeficiency virus infected patients. AIDS 17:S96, 2003. 39. Heidenreich PA, Eisenberg MJ, Kee LL, et al. Pericardial effusion in AIDS: incidence and survival. Circulation 1995;92:32293234. 40. Lewis W. AIDS: cardiac findings from 115 autopsies. Prog Cardiovasc Dis 1989;32:207215. 41. Corallo S, Multinelli MR et al. Echocardiography detects myocardial damage in AIDS; prospective study in 102 patients. Eur Heart J 1988; 9:887- 892. 42. Monsuez JJ, Kinney EL, Vittecoq D, Kitzis M. Comparison among

acquired immune deficiency syndrome patients with and without clinical evidence of cardiac disease. Am J Cardiol. 1988; 62:1311-1313. 43. Steffen HM, Muller R, Schrappe BM, Fatkenhuer G et al. The heart in HIV-1 infection: preliminary results of a prospective echocardiographic investigation. Acta Cardiol. 1990; 45:529-535. 44. Harman WG, Fisher SD, Lipshultz SE et al. Myocardial and pericardial disease in HIV: current treatment options. Cardiovasc Med. 2002; 4:497. 45. Nahass RG, Weinstein MP et al. Infective endocarditis in intravenous drug users; a comparison of HIV-1 positive and negative patients. J Infect Dis. 1994;162: 967 46. Fisher SD, Lipshultz SE Editors. Cardiac disease in AIDS therapy: 2nded, New York; Churchill Livingstone, 2003 p814-826.

47. Seonne L, Shellito J et al. Pulmonary hypertension associated with HIV infection. South Med J, 2001; 94:635. 48. Nunes H., Humbert M et al. Prognostic factors for survival in HIV associated pulmonary hypertension. Am J Resp Crit Care Med, 2003; 167: 1433. 49. Mehta NJ, Khan IA, Mehta RN, et al. HIV-related pulmonary hypertension: analytic review of 131 cases. Chest 2000;118:113341. 50. Johnsons RM et al. Kawasaki like syndrome and other vasculitis like syndromes in HIV infected patients. AIDS.2003; 17:S77. 51. Henry K et al. Severe premature coronary artery disease with protease inhibitors. Lancet, 1998; 351:1328. 52. Hadigan C, Wilson PW et al. Prediction of coronary heart disease risk in HIV infected patients with fat redistribution. Clin Infect Dis, 2003; 36: 909. 53. Bozette S, Tam HK et al. Cardiovascular and cerebrovascular events in patients treated for HIV infection. N Eng J Med, 2003; 348:702. 54. Paton P, Tabib A, Loire R, Tete R. Coronary artery lesions and human immunodeficiency virus infection. Res Virol 1993;144:22531. 55. Carr A, Samaras K, Thorisdottir A, Kaufman GR, Chisolm D, Cooper D. Diagnosis, prediction and and natural mellitus: course a of lipodystrophy, study. Lancet

hyperlipidemia

diabetes

cohort

1999;353:20939. 56. Grunfeld C, Kotler DP, Hamadeh R, Tierney A, Wang J, Pierso n RN. Hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med 1989; 86:2731.

57. Periard D et al: Atherogenic dyslipidemia in HIV infected individuals treated with protease inhibitors. Circulation 1999;100:700, 58. Milan Study on Atherosclerosis and Diabetes Group. Milan Study on Atherosclerosis and Diabetes Group. Prevalence of unrecognized silent myocardial ischemia and its association with atherosclerotic risk factors in noninsulin-dependent diabetes mellitus. Am J Cardiol 1997; 79: 1349. 59. Dub MP, Sprecher D, Henry WK, et al. Preliminary guidelines for the evaluation and management of dyslipidaemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: recommendations of the adult AIDS clinical trial group cardiovascular disease focus group. Clin Infect Dis 2000;31:121624. 60. Gluck T et al. Autonomic neuropathy in patients with HIV; course, impact of disease stage and medications. Clin Anton Res, 2007; 10:17 61. Duong M et al. Non Hodgkins Lymphoma of the heart in HIV infected patients. Clin Cardiol, 1997; 20:497. 62. Riddler SA, Smit E, Cole SR, et al. Impact of HIV infection and HAART on serum lipids in men. JAMA 2003; 289:29782982. 63. Grunfeld C, Kotler DP, Shigenaga JK, et al. Circulating interferonalpha levels and hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med 1991; 90:154162. 64. Segerer S, Bogner JR, Walli R, Loch O, Goebel FD. Hyperlipidemia under treatment with proteinase inhibitors. Infection 1999; 27:7781.

65. Friis-Moller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349:1993 2003. 66. Kingsley L, Smit E, Riddler S, Li R, Chmiel J, Palella F, Visscher B, Oishi J, Taylor E, Dobs A, and Evans R. Prevalence of lipodystrophy and metabolic abnormalities in the Multicenter AIDS Cohort Study (MACS). 67. Fontas E, van Leth F, Sabin CA, et al. Lipid profiles in HIV-infected patients receiving combination antiretroviral therapy: are different antiretroviral drugs associated with different lipid profiles? J Infect Dis 2004; 189:10561074. 68. Riddler SA, Smit E, Cole SR, et al. Impact of HIV infection and HAART on serum lipids in men. JAMA 2003; 289:29782982. 69. Dube MP, Stein JH, Aberg JA, et al. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis 2003; 37:613 627. 70. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment

Panel III). JAMA 2001; 285:24862497. 71. S Mishra, N Wig, CM Mittal, RM Pandey, G Karthikeyan, P Arora, VK Bahl. Diastolic Dysfunction in Human Immunodeficiency Virus (HIV)-

Infected Patients in North India. Indian Heart Journal 2003; 55: 166168. 72. Cecchi E, Parinii I, Chinaglia A et al. Cardiac complications in HIV infections. G Ital Cardiol 1997; 27: 917-924. 73. Barbaro G, Di Lorenzo G, Grisorio B et al: Cardiac involvement in the acquired immunodeficiency syndrome: A multicenter clinical-

pathological study. AIDS Res 14:1071,1998 74. Steffen HM, Muller R et al. Prevalence of echocardiographic abnormalities in human immunodeficiency virus 1 infection. Am J Noninvasive Cardiol 1991; 5:280-284. 75. Corodso JS et al. Left ventricular dysfunction in human

immunodeficiency virus infection. Int J Cardiol. 1998 Jan 5; 63(1): 7-45. 76. Paula Moyer. Left Ventricular Diastolic Dysfunction Occurs in Half of HIV-Positive Patients: Presented at Heart Failure. HELSINKI,

FINLAND -- June 20, 2006.