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\begin{document}

\title{An unusual case of heart failure due to ANCA-negative vasculitis: A case
report and focused review of the literature}



\author[1]{Cristian Orlando Porras Bueno}%
\author[2]{Clara  Saldarriaga Giraldo}%
\author[2]{Gustavo Roncancio Villamil}%
\author[3]{Maria  Alvarez Barreneche}%
\affil[1]{Universidad Autónoma de Bucaramanga}%
\affil[2]{Clínica Cardio VID}%
\affil[3]{Universidad Pontificia Bolivariana}%


\vspace{-1em}



  
  \date{May 15, 2024}


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\textbf{Introduction:}

Less than 10\% of people with vasculitis experience cardiac impairment;
however, all primary vasculitides can target the
heart\textsuperscript{1}. Regarding antineutrophil cytoplasmic antibody
(ANCA)-associated vasculitis, both granulomatosis with polyangiitis
(GP), microscopic polyangiitis (MP), and eosinophilic granulomatosis
with polyangiitis (EGPA) can affect any cardiac tissue
\textsuperscript{1}.

Among ANCA-associated vasculitis, EGPA is the one that most frequently
affects the heart \textsuperscript{2}. Nevertheless, in EGPA, cardiac
manifestations are more common in ANCA-negative patients. Eosinophilic
myocarditis is the most common, but restrictive or dilated
cardiomyopathy, pericarditis, coronary artery vasculitis, valvular
defects, rhythm disturbances, left ventricular dysfunction, and
intracardiac thrombosis, among other things, can also
occur\textsuperscript{3}. Heart involvement in GP and MP is seen in a
small percentage of patients, with pericarditis and supraventricular
arrhythmias being the most common cardiac manifestations, occurring in
1\% to 6\% of patients \textsuperscript{1}. Nevertheless, cardiac
thrombosis is a less frequent manifestation, occurring in less than 1\%
of patients \textsuperscript{1}.

\textbf{Case description}

A 28-year-old man without a familiar history of cardiomyopathies or
ethanol consumption, only with a medical history of HIV category A1
diagnosed two years ago, who has been receiving antiretroviral therapy
(ART) with tenofovir disoproxil fumarate plus emtricitabine and
efavirenz since HIV diagnosis, was consulted due to cough, hemoptysis,
fatigue, palpitations, and dyspnoea in the previous four weeks. At
admission, he was tachycardic; on auscultation, rales were detected in
all lung fields, and gallop was also auscultated. Also found were
augmented jugular venous pressure with hepatojugular reflux,
hepatomegaly, and lower limb edoema.

The hemogram was normal. The transthoracic echocardiogram showed a
decreased left ventricular ejection fraction (LVEF) of 10\%, and a left
ventricular thrombus (LVT) of 40 by 38 mm. The chest computed tomography
(CT) showed bilateral pleural effusion, multilobar alveolar occupancy,
diffuse alveolar haemorrhage (DAH), pericardial effusion and the LVT.
The contrasted enhanced cardiac magnetic resonance (CMR) revealed a
normal right atrium with an area of 22 cubic centimetres
(cm\textsuperscript{2}); however, the left atrium was dilated with an
area of 39 cm\textsuperscript{2}. Also, the right and left ventricles
were dilated with augmented diastolic diameters of 45 mm and 75 mm,
respectively, in the setting of dilated cardiomyopathy (DCM). It also
revealed a LVEF of 18\%, subendocardial fibrotic areas in the LV apex
and with a diffuse pattern in the right ventricle (RV) with a 20\%
myocardial fibrosis burden. The contrasted enhanced CMR also revealed a
40 by 38 mm apical mass that does not present perfusion at rest or late
enhancement in relation to the LVT previously seen. (Figure 1).

Tuberculosis, histoplasmosis, cryptococcosis, aspergillosis, and acute
infections due to aerobic bacteria, toxoplasmosis, cytomegalovirus,
hepatitis B, hepatitis C, and Epstein-Barr virus were ruled out. Also
ruled out were lupus, rheumatoid arthritis, cryoglobulinemia, and
positive ANCA-associated vasculitis. Besides, a pleural and pericardial
biopsy plus lobectomy from the subsegmental anterior segment of the
right lower lobe was performed, which revealed DAH and pulmonary
capillaritis (Figure 2). The pericardial and pleural biopsies only
showed tissue congestion. In addition, a cardiac biopsy was performed,
the result of which was normal.

The medical staff diagnosed ANCA-negative vasculitis. A course of
intravenous methylprednisolone was administered for 3 days, followed by
oral administration. Also, cyclophosphamide was administered due to the
progression of DAH in a new CT. Warfarin was started for the LVT.

During follow-up, after one month, the patient experienced symptom
resolution. Besides, the control echocardiogram showed an improvement of
the LVEF with a new value of 25\%. It also showed improvement in LVT,
evidencing a decrease in their measurements to 29 by 33 mm. Furthermore,
the new chest CT showed improvement in the lung involvement previously
evidenced.

\textbf{Discussion}

Although LVT can occur both in ischaemic and non-ischaemic
cardiomyopathies, the vast majority of them are diagnosed after
myocardial infarction, especially when an anterior apical scar and
reduction of systolic function are developed \textsuperscript{4}.
However, although limited data is available on the epidemiology of LVT
in patients affected by non-ischemic heart diseases, within this
subgroup, DCM is the most common underlying
cardiomyopathy\textsuperscript{4}, as in our case. Besides, LVT has also
been occasionally described in Takotsubo cardiomyopathy, amyloidosis,
hypereosinophilic syndrome, and Chagas' disease \textsuperscript{4},
being an infrequent manifestation of vasculitis, especially in
ANCA-associated vasculitis \textsuperscript{1}. In our case, the most
probable diagnosis was MP with negative ANCA serology due to the
presence of DAH, pulmonary capillaritis, DCM, heart failure, and LVT.
The absence of eosinophilia, asthma, chronic rhinosinusitis, or other
manifestations discharges EGPA.

Regarding pulmonary capillaritis, it is a histopathologic diagnosis that
is not pathognomonic of a particular problem; it typically indicates the
presence of a systemic vasculitis or collagen vascular disease, and
hence, treatment should concentrate on the underlying condition that
caused it, as in our case \textsuperscript{5}.

In relation to heart failure in MP, it has been described with a
prevalence between 6.8\% \textsuperscript{6} and
17.6\%\textsuperscript{7}. Additionally, heart involvement in GP is
uncommon, although pericarditis and cardiomyopathy are the most frequent
cardiac pathologies, whereas arrhythmias, coronary arteritis, cardiac
thrombus, valve lesions, and intracardiac masses are less frequently
seen\textsuperscript{8}.

Respecting HIV and cardiomyopathy, prior to the development of ART, the
patients suffered from cardiomyopathy with manifest left ventricular
systolic dysfunction; however, after its development, the onset of
cardiomyopathy had a more incisive course, being more frequently of
ischemic aetiology and with a high prevalence of diastolic left
ventricular dysfunction \textsuperscript{9}. Our patient was in category
A1 and had been adhering to ART (tenofovir disoproxil fumarate,
emtricitabine, efavirenz) since HIV diagnosis, which made an HIV-related
cardiomyopathy unlikely.

Also, while ART generally appears to help the HIV-related
cardiomyopathic process by reducing viral effects on the myocardium,
some antiretroviral drugs may have long-term negative myocardial
effects, including mitochondrial toxicity \textsuperscript{9,10}.
However, cardiomyopathy due to mitochondrial toxicity with ART therapy
was described mainly with zidovudine, zalcitabine, and didanosine, in
the group of reverse transcriptase inhibitors \textsuperscript{10}.
Besides, defects in mitochondrial DNA replication and energetics have
been reported with zidovudine \textsuperscript{11,12}, clevudine and
lodenosine \textsuperscript{13,14}. Also, patients receiving ART with
protease inhibitors had increased cardiovascular mortality and
readmission rates at 30 days \textsuperscript{15}. In our case, the
patient was not receiving any of these reverse transcriptase inhibitors
with potential cardiotoxicity, and he was not receiving protease
inhibitors, so ART cardiotoxicity was very unlikely.

Regarding CMR, it allows the assessment of ventricular function and the
analysis of myocardial tissue, which can help, as in our case, to reveal
or rule out underlying aetiologies of heart failure like ischaemic
cardiomyopathy, myocarditis, hypertrophic and DCM, cardiac amyloidosis,
and sarcoidosis, among others \textsuperscript{16,17}. In addition, CMR
imaging is the gold standard for LVT \textsuperscript{4}. In our case,
despite subendocardial LGE in the CMR, these results were not considered
to be related to an ischemic aetiology because the involvement was
biventricular, suggesting two coronary territories in a patient who did
not have a medical history of risk factors for coronary artery disease
in young people such as smoking, dyslipidemia, diabetes mellitus,
arterial hypertension, or obesity, among others \textsuperscript{18},
nor angina with moderate or high-intensity physical activity in his
medical history.

These considerations, together with the finding of DAH, guided the
medical team to consider and rule out systemic conditions such as
tuberculosis, fungal, viral, and bacterial infections, as well as
autoimmune conditions such as rheumatoid arthritis, cryoglobulinemia,
anti-glomerular basement membrane disease, and Chagas disease, as
previously mentioned; the finding of pulmonary capillaritis was the one
that finally led us to consider systemic vasculitis, ruling out those
that compromise large and medium vessels due to clinical and laboratory
findings, as well as anti-glomerular basement membrane disease,
cryoglobulinemic vasculitis, IgA vasculitis and urticarial
hypocomplementary vasculitis within those of small vessels. Also, Beh\selectlanguage{ngerman}çet
and Cogan syndromes were ruled out.

Thus, a negative ANCA vasculitis was diagnosed; of the 3 existing ones
(GP, MP, and EGPA), MP was the most probable diagnosis since it presents
pulmonary capillaritis more frequently than EGPA \textsuperscript{5},
and the patient did not present chronic rhinosinusitis, asthma, or
prominent peripheral eosinophilia leading to EGPA \textsuperscript{3}.
Besides, our patient did not present granulomatous inflammation of the
upper and lower airways or pauci-immune necrotizing glomerulonephritis,
which are typically seen in GP, which, like MP, is one of the most
common disorders associated with pulmonary
capillaritis\textsuperscript{5}.

Finally, regarding ANCA vasculitis management, our patient was in a
severe disease state, for which he received an intravenous pulse of
glucocorticoids followed by high-dose oral glucocorticoids plus
cyclophosphamide as remission induction therapy, according to the
American College of Rheumatology guidelines \textsuperscript{19}. Our
patient also received management of his heart failure in accordance with
current European and American guidelines \textsuperscript{20,21}. He
presented an improvement in the LVEF with a new value of 25\% in the
control echocardiogram. He also presented an improvement in the LVT,
evidencing a decrease in their measurements, and also an improvement in
the lung involvement previously evidenced in a new chest CT.

\textbf{Conclusion}

In patients with DAH and pulmonary capillaritis associated with cardiac
pathologies with negative ANCAS serology, the diagnosis of ANCA-negative
vasculitis should be considered, especially in MP or GP, when
granulomatous inflammation of the upper and lower airways or
pauci-immune necrotizing glomerulonephritis is present. However, when
conditions such as peripheral eosinophilia, chronic rhinosinusitis, and
asthma are present, it would point to an EGPA.

\textbf{Author contributions}

Porras Bueno Cristian Orlando: Wrote and reviewed the manuscript and was
involved in data acquisition and analysis.

Saldarriaga Giraldo Clara Ines: Conceived and designed the study and
reviewed the manuscript.

Roncancio Villamil Gustavo Eduardo: Conceived and designed the study and
reviewed the manuscript.

Álvarez Barreneche María Fernanda: Conceived and designed the study and
reviewed the manuscript.

\textbf{References}

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\textbf{Figures}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1.} A) CMR with late gadolinium ehnancement revealing DCM
in the LV with subendocardial fibrotic areas in the LV apex and with a
diffuse pattern in the RV (red arrows), as an LV thrombus (yellow
arrow). B) CMR in T1 mapping showing the same findings. Abbreviations:
DCM: Dilated cardiomyopathy. CMR: Cardiac magnetic resonance. LV: Left
ventricle. RV: Right ventricle\textbf{.}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2.} A. At 10x magnification, pulmonary histopathology
stained with H\&E, showing multiple intra-alveolar haemorrhages with the
presence of hemosiderophages in relation to DAH. B. At 100x
magnification (H\&E), oedematous walls with polymorphonuclear cells,
reactive endothelial cells, and type II pneumocyte hyperplasia in
relation to pulmonary capillaritis. Abbreviations: H\&E: Haematoxylin
and eosin. DAH: Diffuse alveolar haemorrhage.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1---Clinical-Case-Reports/Figure-1---Clinical-Case-Reports}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2---Clinical-Case-Reports/Figure-2---Clinical-Case-Reports}

\end{center}
\end{figure}

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