cardiac manifestations of hiv patients
DESCRIPTION
NON INVASIVE CARDIAC WORK UP OF HIV POSITIVE PATIENTSPonangi Udaya Prashant Consultant,CARE Hospitals Banjara Hills, Hyderabad Email: [email protected] GROUP OF HOSPITALSDISSERTATION SUBITTED FOR THE DEGREE OF D.M. CARDIOLOGY EXAMINATION (BRANCH II), UNIVERSITY OF MUMBAI May 2008,INTRODUCTIONHIV 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 CentTRANSCRIPT
NON INVASIVE
CARDIAC WORK UP OF
HIV POSITIVE
PATIENTS
Ponangi Udaya Prashant
Consultant, GLOBAL Hospitals, Hyderabad
Email: [email protected]
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/µL or (2) HIV-infected individuals who
have the presence of specific opportunistic infections like Pneumocystis carinii
pneumonia, Kaposi’s 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 prevalence’s 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 = CD4 count >500.
Stage 2 = CD4 count 200-499.
Stage 3 = CD4 count <200.
CLINICAL CATEGORIES:
CD4 T CELL
CATEGORIES
A
ASYMPTOMATIC,
ACUTE HIV or
PGL
B
SYMPTOMATIC,
NOT ‘A’ or ‘C’
CONDITIONS
C
AIDS-
INDICATOR
CONDITIONS
> 500/µL A1 B1 C1
200-499/µL A2 B2 C2
< 200/µL A3 B3 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 Moderate-to-severe angina
o Increasing nervous system symptoms (eg, ataxia, dizziness,
near-syncope)
o Subject's desire to stop
o Sustained ventricular tachycardia
o 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/lymphadenopathy- associated 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, India’s 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
helpful in determining need for therapy and monitoring
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/µl. The causative agents of secondary infections in HIV/AIDS are
characteristically opportunistic organisms such as P.carinii, atypical
mycobacteria etc. However non-opportunistic common bacterial and
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, cardiovascular, neurological, gastrointestinal and
hepatobiliary, renal 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/µl 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
B SUMPTOMATIC
NOT ‘A’ or ‘C’ CONDITIONS
C AIDS-
INDICATOR CONDITIONS
> 500/µL A1 B1 C1
200-499/µL A2 B2 C2
< 200/µL A3 B3 C3
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. Asymptomatic HIV infection.
2. Progressive Generalised Lymphadenopathy
3. Acute primary HIV infection
1. Bacillary angiomatosis
2. Vulvovaginal candidiasis, oral candidiasis
3. Cervical dysplasia, cervical carcinoma insitu.
4. Constitutional symptoms > 1 month
5. Oral hairy leukoplakia
6. Herpes zoster- 2 distinct episodes more than one dermatome
7. Idiopathic thrombocytopenic purpura
8. Listerosis
9. Pelvic inflammatory disease
10. Peripheral neuropathy
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
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/µL 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 non-
nucleoside 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) LVIDs- 2.0- 4.0 cms
Left ventricular internal diameter (end diastolic) LVIDd 3.5- 5.6 cms
Left ventricular wall thickness
Diastolic-septum 0.6- 1.0 cms
Diastolic-posterior wall 0.6- 1.0 cms
Systolic-septum 0.9- 1.8 cms
Systolic-posterior wall 0.9- 1.8 cms
Left ventricular fractional shortening,FS 28- 45%
Left ventricular ejection fraction, LVEF 55- 80%
Left atrial diameter 2.7- 3.8 cms
Aortic root diameter 2.0-4.0 cms
Right ventricular diameter (systolic-diastolic) 0.7-2.3 cms
ECHOCARDIOGRAPHIC FINDINGS21, 22
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 Men
Variable Reference
Range
Mildly
Ab-nomal
Mod-erately
Ab-normal
Severly
Ab-normal
Reference
Range
Mildly
Ab-normal
Moderately
Ab-normal
Severly
Ab-normal
LV diastolic diameter cm
3.9-5.3 5.4-5.7 5.8-6.1 >6.2 4.2-5.9 6.0-6.3 6.4-6.8 >6.9
LVIDD/BSA
Cm/m2
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
LVIDD/ height
Cm/m
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
Ab-
normal
Severly
Ab-
normal
Reference
Range
Mildly
Ab-normal
Moderately
Ab-
normal
Severly
Abnorm
al
Endocardial
fractiona
shortening %
27-45 22-26 17-21 <16 25-43 20-24 15-19 <14
Ejection
fraction %
>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 Reference
Range
Mildly
Abnormal
Moderately
Abnormal
Severely
Abnormal
RV basal diameter cm
2.0-2.8 2.9-3.3 3.4-3.8 >3.9
RV fractional change %
32-60 25-31 18-24 <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) thickened pericardium
ii) calcified pericardium
iii) abnormal septal motion, especially end diastolic
iv) abnormal LV filling pattern
v) LV expands only in early diastole
vi) Mid and late diastolic flattening of LVPW motion
vii) Restrictive pattern on Doppler study20,22
STRESS TEST:
HISTORY :
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 SPEED mph
METS GRADE CUMULATIVE TIME in min
1 1.7 4.6 10 3 2 2.5 7.0 12 6 3 3.4 10.1 14 9 4 4.2 10.3 17 12 5 5.0 14.9 18 15 6 5.5 20 18 7 6.0 22 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 Acute myocardial infarction (within 2 d)
o 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 Symptomatic severe aortic stenosis
o Uncontrolled symptomatic heart failure
o Acute pulmonary embolus or pulmonary infarction
o Acute myocarditis or pericarditis
o Acute aortic dissection
• Relative contraindications: Relative contraindications can be
superseded if the benefits of exercise outweigh the risks.
o Left main coronary stenosis
o Moderate stenotic valvular heart disease
o Electrolyte abnormalities
o 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 Tachyarrhythmias or bradyarrhythmias
o Hypertrophic cardiomyopathy and any other forms of outflow
tract obstruction
o Mental or physical impairment leading to an inability to exercise
adequately
o 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 70-
kg, 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 Kaposi’s 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 28–73%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 6–10% and 1–9%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/µl.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.
Myocarditis-
Dilated 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, 41-
HIV infection increases production of TNF α which
1. alters intra cellular calcium homeostasis
2. increases nitric oxide production
3. increases TGF β
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
medical therapy should be considered for biopsy. Endomyocardial biopsy may
reveal lymphocytic infiltrates suggesting Myocarditis or treatable opportunistic
infections, permitting aggressive th
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
nts not responding or worsening within 2 weeks of initiation of
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.
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
nts not responding or worsening within 2 weeks of initiation of
medical therapy should be considered for biopsy. Endomyocardial biopsy may
reveal lymphocytic infiltrates suggesting Myocarditis or treatable opportunistic
erapy of underlying pathogen.38
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. Kaposi’s 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 non–HDL-C
levels are calculated. This should be repeated within 3–6 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 1–2 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 HIV-
infected 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 NCEP’s third Adult Treatment Panel guidelines for the general
population69. The first step is to assess the patient’s 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, 22–26 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 (150–199 mg/dL),
dietary and exercise interventions are emphasized. When triglyceride levels
are high (200–499 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
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 MALE FEMALE TOTAL Percentage %
20- 29 8 8 16 17
30- 39 35 11 46 43
40- 49 19 6 25 27
50- 60 5 2 7 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.
SEX NO. OF PATIENTS PERCENT %
MALE 70 73
FEMALE 26 27
TABLE 3: DURATION OF ILLNESS
N=96
Duration of illness in years
Total No Patients Percentage %
< 1 24 25
1 – 5 59 62
> 5 12 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 Total No Percentage %
Angina 22 34
Dyspneoa 27 41
Palpitations 11 17
Giddiness, Syncope 5 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 No Patients Percentage of Total Patients %
Hypertension 2 2
Diabetes Mellitus 0 0
Smoking 12 12.5
Family H/O IHD 1 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
Clinical stage
B
Clinical Stage
C
Total No in Various HAART regimes
SLN 3 6 21 30 (32%)
SLE 0 0 5 5 (5%)
ALN 0 3 17 20 (21%)
ALE 1 0 1 2 (2%)
none 5 7 26 38 (40 %)
Total no in Clinical Stages
9 (9%) 16 (17%) 71 (74%) 96 (100%)
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
Percentage %
Category 1 (CD4>500) 25 26
Category 2
(CD4 = 499- 200)
42 45
Category 3 (CD4<200) 28 29
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 No of Patients Percentage %
<18 24 25
18 -25 67 70
25 - 30 3 3
>30 2 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 NO. OF PATIENTS PERCENTAGE
NORMAL X RAY 78 82
CARDIOMEGALY 4 4
OTHER CARDIAC FINDINGS
3 4
PULMONARY PATHOLOGY 9 9
BOTH CARDIO- PULMONARY
PATHOLGY
2 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 TOTAL patients
No patients on HAART
p value
DILATED CARDIOMYPATHY
4 (6%) 2 0.634
PERICARDIAL DISEASE 14 (21%) 8 0.748
LV SYSTOLIC DYSFUNCTION
15 (23%) 9 0.66
LV DIASTOLIC DYSFUNCTION
16 (24%) 10 0.9252
PULMONARY HYPERTENSION
9 (14%) 4 0.303
RV DYSFUNCTION 8 (12%) 5 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
1-5 years n =59
> 5 y ears n=12
Total P value
DILATED CARDIOMYPATHY 2 1 1 4 0.35
PERICARDIAL DISEASE 3 8 3 14 0.727
LV SYSTOLIC DYSFUNCTION 7 6 3 16 0.102
LV DIASTOLIC DYSFUNCTION 6 8 2 16 0.484
PULMONARY HYPERTENSION 6 4 0 9 0.02
RV DYSFUNCTION 4 4 0 8 0.18
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
0 0 4 4 0.006
PERICARDIAL DISEASE 4 5 5 14 0.8
LV SYSTOLIC
DYSFUNCTION
1 10 5 16 0.08
LV DIASTOLIC
DYSFUNCTION
2 9 5 16 0.31
PULMONARY
HYPERTENSION
1 4 4 9 0.424
RV DYSFUNCTION 1 2 5 8 0.09
RHD MS 1
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 No of Pateints Percentage %
Negative 68 71
Not done 14 15
Positive 8 8
Terminated early 6 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
Mean value of not
on HAART
p value
Total cholestrol 170 184 0.146
Total triglycerides 147 142 0.824
LDL cholestrol 102 120 0.018
HDL cholestrol 40 39 0.958
VLDL cholestrol 27 25 0.61
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
No on
HAART
p value
Hypercholestremia 6 (8%) 2 0.13
Low HDL 45 (62%) 27 0.419
High LDL 7 (10%) 2 .06
Hypertriglyceridemia 9 (12%) 6 .417
High VLDL 6 (8%) 4 0.7
. 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
prevalence’s of a significant cardiac morbidity or cardiac mortality among HIV-
positive 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
STUDY
PE
SYSTOLIC DSFUNCTION
ECHO
DD
DCM
PAH
RVD
DE Casto8 18% 5.5% 12% 1%
Himelman33 10% 11%
Cuire36 et al 7% 15% 4%
Barbaro73 et al 16% 8%
Cardoso75 JS 16.4% 64% 2%
Present study 21% 23% 24% 6% 9% 8%
The incidence of pericardial effusion in patients with asymptomatic
AIDS (defined as patients with CD4 count <200 cells/µL) 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/µ. 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,
prevalence’s 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-α 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 36.7±8 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:
FEMALE27%
8
35
8
0
5
10
15
20
25
30
35
40
20- 29 30
NO
OF
PA
TIE
NT
S
MALE73%
SEX RATIO
35
19
5
11
6
2
30- 39 40- 49 50- 60
AGE GROUPS
AGE SEX DISTRIBUTION
MALE
FEMALE
MALE
FEMALE
FIGURE 2:
FIGURE 3:
0
< 1
1 – 5
> 5
24
18
in y
ears
20 40 60
24
53
No of patients
DURATION OF HIV ILLNESS
Total No Patients
FIGURE 4:
FIGURE 5:
Dyspneoa
Palpitations17%
Giddiness, Sync
CARDIAC SYMPTOMS REPORTED BY PATIENTS
Angina34%
Dyspneoa41%
Giddiness, Syncope8%
CARDIAC SYMPTOMS REPORTED BY PATIENTSCARDIAC SYMPTOMS REPORTED BY PATIENTS
FIGURE 6:
0
5
10
15
20
25
30
SLN
3
No of patients
DISTRIBUTION OF HIV PATIENTS IN VARIOUS HAART
Category 2 (CD4 = 499
Category 3 (CD4<200)
30%
DISTRIBUTION OF PATIENTS BASED ON CD4 COUNT
SLN SLE ALN ALE none
01
56
0
3
7
21
5
17
1
26
HAART Category
DISTRIBUTION OF HIV PATIENTS IN VARIOUS HAART REGIMES
Category 1 (CD4>500)
26%
Category 2 (CD4 = 499- 200)
44%
DISTRIBUTION OF PATIENTS BASED ON CD4 COUNT
Category 1 (CD4>500)
Category 2 (CD4 = 499
Category 3 (CD4<200)
DISTRIBUTION OF HIV PATIENTS IN VARIOUS HAART
Clinical Stage A
Clinical stage B
Clinical Stage C
DISTRIBUTION OF PATIENTS BASED ON CD4 COUNT
Category 1 (CD4>500)
Category 2 (CD4 = 499- 200)
Category 3 (CD4<200)
FIGURE 7:
4%3%
10%
81%
10% 2%0%
X RAY FINDINGS IN HIV PATIENTSX RAY FINDINGS IN HIV PATIENTS
NORMAL X RAY
CARDIOMEGALY
OTHER CARDIAC FINDINGS
PULMONARY PATHOLOGY
BOTH CARDIAC AND PULMONARY
FIGURE 8:
6%
21%23%
24%
14%12%
0%
5%
10%
15%
20%
25%
30%
FREQUENCY OF ECHOCARDIOGRAPHY FINDINGS
ECHO observation
FIGURE 9:
NO OF PATIENTS
INCIDENCE OF CARDIAC DISEASE AND DURATION OF HIV
< 1 year
1-5 years
> 5 y ears n=13
0
1
2
3
4
5
6
7
8
DIL
AT
ED
CA
RD
IOM
YP
AT
HY
PE
RIC
AR
DIA
L D
ISE
AS
E
LV
SY
ST
OLIC
DY
SF
UN
CT
ION
LV
DIA
ST
OLIC
DY
SF
UN
CT
ION
PU
LM
ON
AR
Y
HY
PE
RT
EN
SIO
N
2
3
7
6 6
1
8
6
8
4
1
33
2
0
NO OF PATIENTS
CARDIAC DISEASE
INCIDENCE OF CARDIAC DISEASE AND DURATION OF HIV ILLNESS
RV
DY
SF
UN
CT
ION
4 4
0
0
INCIDENCE OF CARDIAC DISEASE AND DURATION OF HIV
FIGURE 10:
FIGURE 11:
0
1
2
3
4
5
6
7
8
9
10
No fo patients
INCIDENCE OF CARDIAC DISEASES BASED ON CD4 COUNT
0
20
40
60
80
100
120
140
160
180
200
Total cholestrol triglycerides
170
184
MEAN LIPID LEVELS IN HIV PATIENTS
DIL
AT
ED
C
AR
DIO
MY
PA
TH
Y
PE
RIC
AR
DIA
L
DIS
EA
SE
LV
SY
ST
OLIC
D
YS
FU
NC
TIO
N
LV
DIA
ST
OLIC
D
YS
FU
NC
TIO
N
PU
LM
ON
AR
Y
HY
PE
RT
EN
SIO
N
0
4
1
2
1
0
5
10
9
44
5 5 5
4
Cardiac disease
INCIDENCE OF CARDIAC DISEASES BASED ON CD4 COUNT
Total triglycerides
LDL cholestrol
HDL cholestrol
VLDL cholestrol
147
102
4027
142
120
39
MEAN LIPID LEVELS IN HIV PATIENTS
RV
DY
SF
UN
CT
ION
1
2
5
INCIDENCE OF CARDIAC DISEASES BASED ON CD4 COUNT
CD4 COUNT >500
CD4 COUNT 500-200
CD4 COUNT <200
VLDL cholestrol
27 25
MEAN LIPID LEVELS IN HIV PATIENTS
FIGURE 12:
0
Hypercholestremia
Low HDL
High LDL
Hypertriglyceredemia
High VLDL
2
2
10 20 30 40 50
6
45
7
9
6
27
6
4
No of patients
DYSLIPEDEMIA IN HIV PATIENTS
50
No on HAART
Total 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. Harrison’s
Principles of Internal Medicine. 16th Ed: New York; Mc graw Hill
medical publishers, 2005:1076 – 1140.
3. Fisher SD, Lipshultz SE. Cardiovascular abnormalities in HIV infected
individuals. In: Zipes DP Ed. Braunwald’s 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 &
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; 160:602–8.
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; 338:853–860.
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):1452-
1459.
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 T-
Lymphotropic 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
Virus–Infected Patients Receiving Antiretroviral Therapy: Clinical
Infectious Diseases 2002; 34:523–8
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 H. Echocardiography, 5th ed. Philadelphia:Lea &
Febiger,1994
21. Lang RM, Bierig M, Devereaux RB et al, American Society of
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: 1440-
1463.
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 Kaposi’s sarcoma and Whipple’s disease. Lancet 1983; i:
767–8.
29. Lewis W. Cardiomyopathy in AIDS: a pathophysiological perspective.
Prog Cardiovasc Dis 2000;43:151–70.
30. Arshad A, Bansal A, Patel RC. Cardiac complications of human
immunodeficiency virus infection: diagnostic and therapeutic
considerations. Heart Disease 2000;2;133–45.
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; 18:145–54.
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;92:3229–3234.
40. Lewis W. AIDS: cardiac findings from 115 autopsies. Prog Cardiovasc
Dis 1989;32:207–215.
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;118:1133–41.
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;144:225–31.
55. Carr A, Samaras K, Thorisdottir A, Kaufman GR, Chisolm D, Cooper D.
Diagnosis, prediction and natural course of lipodystrophy,
hyperlipidemia and diabetes mellitus: a cohort study. Lancet
1999;353:2093–9.
56. Grunfeld C, Kotler DP, Hamadeh R, Tierney A, Wang J, Pierso n RN.
Hypertriglyceridemia in the acquired immunodeficiency syndrome. Am
J Med 1989; 86:27–31.
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: 134–9.
59. Dubé 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;31:1216–24.
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 Hodgkin’s 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; 289:2978–2982.
63. Grunfeld C, Kotler DP, Shigenaga JK, et al. Circulating interferonalpha
levels and hypertriglyceridemia in the acquired immunodeficiency
syndrome. Am J Med 1991; 90:154–162.
64. Segerer S, Bogner JR, Walli R, Loch O, Goebel FD. Hyperlipidemia
under treatment with proteinase inhibitors. Infection 1999; 27:77–81.
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; 189:1056–1074.
68. Riddler SA, Smit E, Cole SR, et al. Impact of HIV infection and HAART
on serum lipids in men. JAMA 2003; 289:2978–2982.
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; 285:2486–2497.
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: 166-
168.
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.