**2.4.3 Non-invasive techniques**

**Electrocardiography** (ECG) is a useful screening tool in patients with HIV infection, and ECG changes may precede echocardiographic abnormalities. Patients with abnormal ECG patterns should be further investigated [Tang et al., 2009].

Electrocardiography is often nonspecific (eg, sinus tachycardia, nonspecific ST or T-wave changes). Occasionally, heart block (atrioventricular block or intraventricular conduction delay), ventricular arrhythmia, or injury patterns with ST- or T-wave changes mimicking myocardial ischemia or pericarditis (pseudoinfarction pattern) may indicate poorer prognosis [Gorgels 2007].

**A chest X- ray** can offer data about the size and shape of hart, as well as identification of fluid in or around the heart that might indicate heart failure [Round 2007].

**Echocardiography** has been shown to be extremely useful for the diagnosis and monitoring of HIV associated myocardial disease. Echocardiography is performed to exclude other causes of heart failure (eg, valvular, amyloidosis, congenital) and to evaluate the degree of cardiac dysfunction (usually diffuse hypokinesis and diastolic dysfunction). It also may allow gross localization of the extent of inflammation (ie, wall motion abnormalities, wall thickening, and pericardial effusion). In addition, echocardiography may distinguish

Myocarditis in HIV Positive Patients 159

Aty et al., 2005]. Late gadolinium enhancement (LGE) - CMR has been shown to have additional value in the detection of active myocarditis as defined by histopathology

LGE in the setting of myocarditis has a "nonischemic" pattern, typically affecting the subepicardium and the midmyocardial wall. This focal enhancement becomes diffuse over a period of days to weeks, then decreases during healing and may become invisible after recovery [Mahrholdt et al., 2004]. Alternatively, large areas of scarring might still be visible after healing, causing distinctive enhancing linear mid-wall striae. CMR-guided endomyocardial biopsy can result in a greater yield of positive findings than routine right

This technique has not yet been fully evaluating in asymptomatic HIV infected subjects to

**Nuclear imaging:** Antimyosin scintigraphy (using antimyosin antibody injections) can identify myocardial inflammation with high sensitivity (91-100%) and negative predictive power (93-100%) but has low specificity (31-44%) and low positive predictive power (28- 33%). In contrast, gallium scanning is used to reflect severe myocardial cellular infiltration and has a good negative predictive value, although specificity is low [Tang et al., 2009]. In preliminary studies, a positive gallium scan improved the diagnostic yield of biopsy fourfold (baseline incidence of myocarditis - 8%; incidence associated with a positive scan – 36%). Gallium is an inflammatory avid isotope, whereas antimyosin antibodies are capable of labeling myocytes. Because histologic myocarditis consists of active inflammation in the presence of myocyte necrosis, indium 111 antimyosin antibodies may be useful in detecting

In Romania as in many other developing countries over the world cardiac MRI cannot be used widely for diagnosis. In the last several years within our cohort of adolescents and young adults HIV infected since their childhood we have noticed an increased number of patients with symptoms that suggest cardiac involvement. Dilative cardiomyopathy noticed more often in children infected by HIV was diagnosed especially postmortem at necropsy. As long as these patients present an increased rate of survival we are challenged to perform

During the last 2 years we have the opportunity to evaluate 10 patients with HIV and symptoms of cardiac involvement by performing: ECG, echocardiography, and nuclear imaging using technetium 99 (99Tc). The 10 patients, 5 women and 5 men, were aged between 17 and 55 years. Echocardiography demonstrated in 4 cases normal left ventricular diastolic dimensions and small increases in septal thickness and in other 6 cases increased left ventricular diastolic dimensions and normal septal thickness. From the 4 patients with minimal echocardiography changes, nuclear imaging using technetium 99 showed no wall motions disorders and no changes in myocardial perfusions in 3 patients. In one patient we found no changes in echocardiography and ECG, while myocardial scintigraphy with 99Tc showed changes in wall motility (akinesia) at rest and on stress and ischemic areas at the antero-septal wall and myocardial apex (4%), while at rest the affected area by myocardial scintigraphy was about 2%, as we can noticed in figure no. 1 [Cambrea et al., 2009]. From those 6 patients who presented changes on echocardiography, nuclear imaging with 99Tc 2 patients demonstrated dilatative cardiomyopathy with no ischemic area, as shown in figure

[Mahrholdt et al., 2004].

ventricular biopsy [Mahrholdt et al., 2004].

this condition [O'Connell 1987].

**2.5 Personal contribution**

establish the prevalence of unrecognized myocarditis.

Specific outcome data in HIV infected patients are missing.

accurate diagnosis of cardiac involvement during their life.

between fulminant and acute myocarditis by identifying near-normal left ventricular diastolic dimensions and increased septal thickness in fulminant myocarditis (versus increased left ventricular diastolic dimensions and normal septal thickness in acute myocarditis), with marked improvement in systolic function in time [Tang et al., 2009].

De Castro et al., in 1994 performed a study of 136 HIV-infected patients without clinical, electrocardiographic or echocardiographic evidence of cardiovascular dysfunction on admission who were prospectively studied with serial echocardiograms; 93 of these patients had AIDS. During a mean follow-up period of 415 days, seven patients, all in the AIDS subgroup, developed clinical and echocardiographic findings of acute global left ventricular dysfunction; six of these seven patients died of congestive heart failure. Necropsy findings in five of these patients revealed acute lymphocytic myocarditis in three, cryptococcal myocarditis in one, and interstitial edema and fibrosis in one.

**Cardiac computed tomography (CT)** can have a role in the management of the undifferentiated heart failure patient, principally in excluding the presence of significant obstructive epicardial disease using CT angiography. Current generation 64-slice scanners demonstrate excellent diagnostic accuracy for both proximal coronary vessels and smaller distal vessels [Leber et al., 2005, Raff et al., 2005, Fine et al., 2006]. These recent studies especially demonstrate a high (greater than 95%) negative predictive value for the exclusion of significant epicardial stenosis.

Hence, although it has not been prospectively evaluated in the newly diagnosed heart failure population, the data would indicate that this modality can be used to stratify the patient with heart failure into an ischemic or non-ischemic etiology group.

**Cardiac MRI** (CMR) shows the accumulation of contrast in the myocardium as a consequence of the breakdown of the myocyte membrane resulting from the inflammatory process. The uptake of contrast usually has a characteristic patchy pattern for about the first 2 weeks after the acute event, later becoming progressively more disseminated. [Friedrich 1998] Moreover, this pattern of contrast uptake is easily distinguished from the subendocardial pattern of uptake seen in acute myocardial infarction.

CMR with contrast in association with cine-MRI is a useful tool for the diagnosis of myocarditis and provides an alternative to endomyocardial biopsy.

The availability of this diagnostic technique in the context of an acute episode might obviate the use of other, invasive diagnostic techniques which are not exempt from associated disease.

Roditi et al., in 2000 evaluated 20 patients with T1 spin-echo cine MR angiography and gadolinium-enhanced spin-echo imaging. Focal myocardial enhancement was associated with regional wall motion abnormalities in 10 of the 12 patients with suspected or proven myocarditis. The authors concluded that focal myocardial enhancement combined with regional wall motion abnormalities (hypokinesis, akinesis, or dyskinesis) strongly supported a diagnosis of myocarditis.

A combined CMR approach using T2-weighted imaging and contrast-enhanced T1 weighted images yields high diagnostic accuracy and thus, is a useful tool in the diagnosis and assessment of patients with suspected acute myocarditis [Abdel-Aty et al., 2005]. Friedrich et al. in 1998 were the first to propose CMR for the noninvasive diagnosis of acute myocarditis. Using T1-weighted images, they found that the myocardium in patients with suspected myocarditis has greater signal intensity relative to skeletal muscle [Friedrich et al., 1998]. T2-weighted images early after symptom onset can show focal increases of subepicardial and mid-wall myocardial signal, defining areas of myocardial edema [Abdel-

between fulminant and acute myocarditis by identifying near-normal left ventricular diastolic dimensions and increased septal thickness in fulminant myocarditis (versus increased left ventricular diastolic dimensions and normal septal thickness in acute myocarditis), with marked improvement in systolic function in time [Tang et al., 2009]. De Castro et al., in 1994 performed a study of 136 HIV-infected patients without clinical, electrocardiographic or echocardiographic evidence of cardiovascular dysfunction on admission who were prospectively studied with serial echocardiograms; 93 of these patients had AIDS. During a mean follow-up period of 415 days, seven patients, all in the AIDS subgroup, developed clinical and echocardiographic findings of acute global left ventricular dysfunction; six of these seven patients died of congestive heart failure. Necropsy findings in five of these patients revealed acute lymphocytic myocarditis in three, cryptococcal

**Cardiac computed tomography (CT)** can have a role in the management of the undifferentiated heart failure patient, principally in excluding the presence of significant obstructive epicardial disease using CT angiography. Current generation 64-slice scanners demonstrate excellent diagnostic accuracy for both proximal coronary vessels and smaller distal vessels [Leber et al., 2005, Raff et al., 2005, Fine et al., 2006]. These recent studies especially demonstrate a high (greater than 95%) negative predictive value for the exclusion

Hence, although it has not been prospectively evaluated in the newly diagnosed heart failure population, the data would indicate that this modality can be used to stratify the

**Cardiac MRI** (CMR) shows the accumulation of contrast in the myocardium as a consequence of the breakdown of the myocyte membrane resulting from the inflammatory process. The uptake of contrast usually has a characteristic patchy pattern for about the first 2 weeks after the acute event, later becoming progressively more disseminated. [Friedrich 1998] Moreover, this pattern of contrast uptake is easily distinguished from the

CMR with contrast in association with cine-MRI is a useful tool for the diagnosis of

The availability of this diagnostic technique in the context of an acute episode might obviate the use of other, invasive diagnostic techniques which are not exempt from associated

Roditi et al., in 2000 evaluated 20 patients with T1 spin-echo cine MR angiography and gadolinium-enhanced spin-echo imaging. Focal myocardial enhancement was associated with regional wall motion abnormalities in 10 of the 12 patients with suspected or proven myocarditis. The authors concluded that focal myocardial enhancement combined with regional wall motion abnormalities (hypokinesis, akinesis, or dyskinesis) strongly supported

A combined CMR approach using T2-weighted imaging and contrast-enhanced T1 weighted images yields high diagnostic accuracy and thus, is a useful tool in the diagnosis and assessment of patients with suspected acute myocarditis [Abdel-Aty et al., 2005]. Friedrich et al. in 1998 were the first to propose CMR for the noninvasive diagnosis of acute myocarditis. Using T1-weighted images, they found that the myocardium in patients with suspected myocarditis has greater signal intensity relative to skeletal muscle [Friedrich et al., 1998]. T2-weighted images early after symptom onset can show focal increases of subepicardial and mid-wall myocardial signal, defining areas of myocardial edema [Abdel-

patient with heart failure into an ischemic or non-ischemic etiology group.

subendocardial pattern of uptake seen in acute myocardial infarction.

myocarditis and provides an alternative to endomyocardial biopsy.

myocarditis in one, and interstitial edema and fibrosis in one.

of significant epicardial stenosis.

disease.

a diagnosis of myocarditis.

Aty et al., 2005]. Late gadolinium enhancement (LGE) - CMR has been shown to have additional value in the detection of active myocarditis as defined by histopathology [Mahrholdt et al., 2004].

LGE in the setting of myocarditis has a "nonischemic" pattern, typically affecting the subepicardium and the midmyocardial wall. This focal enhancement becomes diffuse over a period of days to weeks, then decreases during healing and may become invisible after recovery [Mahrholdt et al., 2004]. Alternatively, large areas of scarring might still be visible after healing, causing distinctive enhancing linear mid-wall striae. CMR-guided endomyocardial biopsy can result in a greater yield of positive findings than routine right ventricular biopsy [Mahrholdt et al., 2004].

This technique has not yet been fully evaluating in asymptomatic HIV infected subjects to establish the prevalence of unrecognized myocarditis.

**Nuclear imaging:** Antimyosin scintigraphy (using antimyosin antibody injections) can identify myocardial inflammation with high sensitivity (91-100%) and negative predictive power (93-100%) but has low specificity (31-44%) and low positive predictive power (28- 33%). In contrast, gallium scanning is used to reflect severe myocardial cellular infiltration and has a good negative predictive value, although specificity is low [Tang et al., 2009].

In preliminary studies, a positive gallium scan improved the diagnostic yield of biopsy fourfold (baseline incidence of myocarditis - 8%; incidence associated with a positive scan – 36%). Gallium is an inflammatory avid isotope, whereas antimyosin antibodies are capable of labeling myocytes. Because histologic myocarditis consists of active inflammation in the presence of myocyte necrosis, indium 111 antimyosin antibodies may be useful in detecting this condition [O'Connell 1987].

Specific outcome data in HIV infected patients are missing.

## **2.5 Personal contribution**

In Romania as in many other developing countries over the world cardiac MRI cannot be used widely for diagnosis. In the last several years within our cohort of adolescents and young adults HIV infected since their childhood we have noticed an increased number of patients with symptoms that suggest cardiac involvement. Dilative cardiomyopathy noticed more often in children infected by HIV was diagnosed especially postmortem at necropsy. As long as these patients present an increased rate of survival we are challenged to perform accurate diagnosis of cardiac involvement during their life.

During the last 2 years we have the opportunity to evaluate 10 patients with HIV and symptoms of cardiac involvement by performing: ECG, echocardiography, and nuclear imaging using technetium 99 (99Tc). The 10 patients, 5 women and 5 men, were aged between 17 and 55 years. Echocardiography demonstrated in 4 cases normal left ventricular diastolic dimensions and small increases in septal thickness and in other 6 cases increased left ventricular diastolic dimensions and normal septal thickness. From the 4 patients with minimal echocardiography changes, nuclear imaging using technetium 99 showed no wall motions disorders and no changes in myocardial perfusions in 3 patients. In one patient we found no changes in echocardiography and ECG, while myocardial scintigraphy with 99Tc showed changes in wall motility (akinesia) at rest and on stress and ischemic areas at the antero-septal wall and myocardial apex (4%), while at rest the affected area by myocardial scintigraphy was about 2%, as we can noticed in figure no. 1 [Cambrea et al., 2009]. From those 6 patients who presented changes on echocardiography, nuclear imaging with 99Tc 2 patients demonstrated dilatative cardiomyopathy with no ischemic area, as shown in figure

Myocarditis in HIV Positive Patients 161

Fig. 2. Myocardic scintigraphy - dilatative cardiomyopathy with no ischemic area.

[Deyton et al., 1989; Zimmerman et al., 1994].

[Holladay et al., 1992].

ventricular dysfunction [Olson 2003].

Aside from nonspecific or infectious myocarditis, the differential diagnosis of LV dysfunction in the AIDS patient includes drug toxicity from either abuse of illicit substances or iatrogenic disease from agents used in the therapy for AIDS. AIDS patients often take a great variety of prescription and nonprescription drugs and use illicit drugs. Alcohol, cocaine, or heroin may contribute to LV dysfunction in many cases [Virmani et al., 1988; Regan et al., 1990; Soodini et al., 1991]. Pharmacotherapy is also potentially associated with LV dysfunction in AIDS patients. Therapeutic agents implicated as potential cardiac toxins include zidovudine [Herskowitz et al., 1992b; d'Amati et al., 1992], and interferon alfa-2

If neoplastic infiltration is suspected as a cause of LV dysfunction, cardiac computed tomography or magnetic resonance imaging may be a useful adjunct to echocardiography for characterizing cardiac involvement. Neoplastic infiltration of the heart by Kaposi sarcoma is frequently seen at autopsy and usually associated with widespread disease in the terminal phases of AIDS [Silver et al., 1984]. Non-Hodgkin lymphoma is also observed in this setting and also associated with widespread disease

In addition to HIV-related cardiac conditions, differential diagnosis also includes non-HIV disease, because the latency of HIV disease may be long and patients are at risk for development of hypertensive heart disease, coronary artery disease, or other causes of left

no. 2. The other 4 patients presented with dilative cardiomyopathy and ischemic areas on stress, as demonstrated in figure no. 3. All 10 patients had received HAART including protease inhibitors for at least 5 years and significant changes in lipid profile.

Fig. 1. Myocardic scintigraphy - ischemic areas at the antero-septal wall and myocardial apex.