\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[T2A]{fontenc}
\usepackage[ngerman,polish,english]{babel}



\usepackage{float}








\begin{document}

\title{Hypertrophic Cardiomyopathy secondary to Tacrolimus in a kidney
transplant patient: A case report and focused review of the literature}



\author[1]{Guillermo Hernández Silva}%
\author[2]{Ricardo Giovanni  Puerto Chaparro }%
\author[3]{Javier Álvaro Martínez Melo}%
\author[3]{Cristian Orlando Porras Bueno}%
\author[1]{Javier Eduardo Martínez Rodríguez }%
\author[3]{Sharon Julieth González Trillos}%
\affil[1]{Instituto del Corazón de Bucaramanga}%
\affil[2]{Fundación Oftalmológica de Santander}%
\affil[3]{Universidad Autónoma de Bucaramanga}%


\vspace{-1em}



  
  \date{November 01, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
In receptors of solid organ transplant, calcineurin inhibitors has
become a pillar of immunosuppressive treatment. Several case reports
have shown hypertrophic and dilated cardiomyopathy as a side effect of
tacrolimus. We present the case of a woman receptor of a kidney
transplant who developed hypertrophic cardiomyopathy due to Tacrolimus.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

Solid organ transplantation is a complex phenomenon made possible by our
better understanding of the immune system and the technological advances
of modern medicine. Transplantation carries an intrinsic risk of
graft-rejection that must be controlled. For this reason,
immunosuppressive therapy is always initiated in these
patients\textsuperscript{1}. Among the immunosuppressive drugs used in
solid organ transplantation, calcineurin inhibitors (CNIs), primarily
Tacrolimus, have proven an effective and relatively safe option for
these patients, with low rates of graft-rejection \textsuperscript{1}.

However, patients taking Tacrolimus are not exempt from adverse effects,
some of which can be potentially life threatening, if they're not
identified early. Some of the most important side effects described in
medical literature include nephrotoxicity, high blood pressure,
post-transplant diabetes mellitus (PTMD), new-onset diabetes after
transplantation (NODAT), dyslipidemia, and modification of
cardiovascular-risk profile \textsuperscript{2}. Also, multiple
electrolyte disorders as hyperkalemia, hypomagnesemia, hypercalciuria
and metabolic acidosis have been described \textsuperscript{3}.
Cardiovascular side effects as NODAT, dyslipidemia and hypertension with
clinically significant increase and consequently an increment in the
risk of stroke, myocardial infarction and heart failure have been
described \textsuperscript{4}.

Tacrolimus - induced cardiomyopathy is an uncommon but important
cardiovascular side effect of this drug, which has been described
predominantly in pediatric transplant receptors \textsuperscript{5}.
However, it has been also reported in adults receptors of renal,
hepatic, cardiac and small bowel transplantation \textsuperscript{6-9}.
Hypertrophic cardiomyopathy due to Tacrolimus has been cataloged as non
familial acquired cardiomyopathy by the European Society of Cardiology
(ESC) \textsuperscript{10}, while the American Heart Association (AHA)
classifies it as a secondary cardiomyopathy \textsuperscript{11}.

\textbf{Case description}

A 65-year-old woman with a history of hypertension, diabetes, and
chronic kidney disease secondary to polycystic renal disease was the
subject of a cadaveric-donor kidney transplantation. Pre-transplant
electrocardiogram and echocardiogram were reported as normal.
Immunosuppressive therapy was initiated with tacrolimus and (besides a
short period of time when it was suspended due to medication related
tremors) was administered uninterruptedly for five years without
novelty. During this time, tacrolimus plasma levels remained within a
range of 5.1-11.2 ng/mL (medium of 6.39 ng/mL).

In her fifth year of treatment, the patient developed lipothymia as well
as dyspnea with physical activity, asthenia and adynamia. Due to her
symptoms, a new echocardiogram was performed, which revealed findings
compatible with obstructive hypertrophic cardiomyopathy:
interventricular septum thickness of 15 mm and a left ventricular
posterior wall thickness of 11 mm (Figure 1) coupled with left
ventricular outflow tract obstruction signs (Figure 2 and 3) confirmed
by an end -systolic gradient (64 mmHg) in continuous Doppler through the
left ventricular outflow tract. No significant variants were detected in
the panel testing for genes ACTC1 (sarcomere gene), FLNC, LAMP2, MYL2
(sarcomere gene), PRKAG2 (related with glycogen storage disease), TNNI3
(sarcomere gene), TTR, CSRP3, GLA (related with Fabry disease), MYBPC3
(sarcomere gene), MYL3, PTPN11, TNNT2 (sarcomere gene), DES, JPH2, MYH7
(sarcomere gene), PLN, TNNC1, TPM1 (sarcomere gene) which are related
with genetic Hypertrophic Cardiomyopathy.

Initially considering surgical myectomy and cardiac resynchronization
therapy as measures to improve patient's quality of life, a coronary
arteriography was performed with findings of moderate coronary artery
disease which was treated with stents placed in her right coronary and
circumflex arteries. Nevertheless, patient's symptoms worsened, and
echocardiographic findings progressed. A review of the medical
literature arose consideration of the possibility that tacrolimus use
was the cause of our patient's obstructive cardiomyopathy and medication
was discontinued. After switching immunosuppression therapy to an mTOR
inhibitor (sirolimus), symptoms resolved after about 1 year, and
echocardiographic findings reversed progressively after 2 years.

\textbf{Discussion}

A relationship between blood levels of Tacrolimus and an increasing
thickness of left ventricular wall have been described more frequently
with blood levels above 15 ng/mL, however it was also significant with
blood levels between 10 and 15 ng/mL and below 10 ng/mL as in our
case\textsuperscript{5}. Also, these patients, usually present
nonspecific symptoms such as asthenia, adynamia and lipothymia. However,
a wide variety of signs and symptoms related with congestive heart
failure as dyspnea, orthopnea, anorexia, fatigue, tachypnea,
tachycardia, pulmonary edema and hepatomegaly have been described
\textsuperscript{8,12}.

\textbf{Epidemiology}

We conducted a review of the medical literature available in a number of
major clinical databases (PubMed, New England Journal of Medicine, JAMA,
Nature, Annals of internal Medicine, Google Scholar and SciELO). We
found 18 articles, consisting of case reports and observational studies,
which described Hypertrophic Cardiomyopathy as a side effect of
Tacrolimus occurring in a wide age range (Table 1). While similar cases
have been described in patients aged between 58 to 62
years\textsuperscript{8,13,14}, there are reports of this adverse effect
occurring in much younger patients. For example, Turska et al. mention a
17-month-old child with hypertrophic cardiomyopathy\textsuperscript{15},
and another case describes a premature newborn with hypertrophic
cardiomyopathy whose mother had received tacrolimus during pregnancy
\textsuperscript{16}. There were no differences between men and women
regarding occurrence of tacrolimus induced cardiomyopathy, with reports
of this adverse effect in both sexes.

\textbf{Clinical presentation}

Several cases presenting dyspnea, fatigue and symptoms and signs due to
obstructive Hypertrophic Cardiomyopathy have been
described\textsuperscript{8,12}; while our patient main complaint was
lipothymia, these other symptoms were also present. Less frequently,
asymptomatic cases have been reported, with clinical presentation being
a new heart murmur identified during follow up \textsuperscript{17,18}.
Although hypertrophic cardiomyopathy due to tacrolimus is the most
frequent type of cardiomyopathy described, few cases of dilated
cardiomyopathy have been also described \textsuperscript{19,20}.

\textbf{Therapeutic approach}

Possibly, because hypertrophic myocardiopathy secondary to tacrolimus is
a rare adverse effect, currently there are no guidelines indicating how
it should be treated. However, several case reports and observational
studies have shown reversal of this side effect with tacrolimus
suspension and replacement with another immunosuppressive drug such as
Cyclosporine or an mTOR inhibitor \textsuperscript{14,17,18,20-22}.
After switching immunosuppressive therapy to sirolimus, our patient
symptoms and echocardiographic findings resolved.

\textbf{Conclusion}

Hypertrophic Cardiomyopathy secondary to Tacrolimus is an uncommon
potential life-threatening adverse effect described in solid organ
transplant receptors receiving this calcineurin inhibitor. Thus,
physicians should pay attention to patients receiving this drug,
especially when symptomatic patients are detected, in order to allow a
proper diagnosis of a potential cardiomyopathy and to establish
accurately its management and treatment, because it has been observed
that this adverse effect is reversible with its suspension.

\textbf{Author contributions}

Guillermo Hern\selectlanguage{ngerman}ández Silva: Studied the conception and designed the
study, also reviewed the manuscript.

Ricardo Giovanni Puerto Chaparro: Studied the conception and designed
the study, also reviewed the manuscript.

Javier Álvaro Martínez Melo: Studied the conception and designed the
study, also reviewed the manuscript.

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

Javier Eduardo Martínez Rodríguez: Wrote, reviewed the manuscript and
also was involved in acquisition of data and analysis of data.

Sharon Julieth González Trillos: Wrote, reviewed the manuscript and also
was involved in acquisition of data and analysis of data.

\textbf{References}

\textbf{1.} Stolp J, Zaitsu M, Wood KJ. Immune Tolerance and Rejection
in Organ Transplantation. Methods Mol Biol. 2019; 1899:159-180.

\textbf{2.} Noble J, Terrec F, Malvezzi P, Rostaing L. Adverse effects
of immunosuppression after liver transplantation. Best Pract Res Clin
Gastroenterol. 2021;54-55:101762. doi: 10.1016/j.bpg.2021.101762

\textbf{3.} Farouk SS, Rein JL. The Many Faces of Calcineurin Inhibitor
Toxicity-What the FK?. Adv Chronic Kidney Dis. 2020;27(1):56-66. doi:
10.1053/j.ackd.2019.08.006

\textbf{4.} Robert N, Wong GW, Wright JM. Effect of cyclosporine on
blood pressure. Cochrane Database Syst Rev. 2010;(1):CD007893. Published
2010 Jan 20. doi: 10.1002/14651858.CD007893.pub2

\textbf{5.} Nakata Y, Yoshibayashi M, Yonemura T, et al. Tacrolimus and
myocardial hypertrophy. Transplantation. 2000;69(9):1960-1962.
doi:10.1097/00007890-200005150-00039

\textbf{6.} Bowman LJ, Brennan DC, Delos-Santos R, Larue SJ, Anwar S,
Klein CL. Tacrolimus-induced cardiomyopathy in an adult renal transplant
recipient. Pharmacotherapy. 2015;35(12):1109-1116. doi:10.1002/phar.1666

\textbf{7.} Dehghani SM, Haghighat M, Imanieh MH, et al. Tacrolimus
related hypertrophic cardiomyopathy in liver transplant recipients. Arch
Iran Med. 2010;13(2):116-119\textbf{.}

\textbf{8.} Liu T, Gao Y, Gao YL, et al. Tacrolimus-related hypertrophic
cardiomyopathy in an adult cardiac transplant patient. Chin Med J
(Engl). 2012;125(7):1352-1354.

\textbf{9.} Atkison P, Joubert G, Barron A, et al. Hypertrophic
cardiomyopathy associated with tacrolimus in paediatric transplant
patients. Lancet. 1995;345(8954):894-896.
doi:10.1016/s0140-6736(95)90011-x

\textbf{10.} Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D,
Arnett D, et al. Contemporary definitions and classification of the
cardiomyopathies: An American Heart Association Scientific Statement
from the Council on Clinical Cardiology, Heart Failure and
Transplantation Committee; Quality of Care and Outcomes Research and
Functional Genomics and Translational Biology Interdisciplinary Working
Groups; and Council on Epidemiology and Prevention. Circulation.
2006;113(14):1807--16.

\textbf{11.} Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F,
Charron P, et al. Classification of the cardiomyopathies: A position
statement from the european society of cardiology working group on
myocardial and pericardial diseases. Eur Heart J. 2008;29(2):270--6.

\textbf{12.} Atkison P, Joubert G, Barron A, et al. Hypertrophic
cardiomyopathy associated with tacrolimus in paediatric transplant
patients. Lancet. 1995;345(8954):894-896.
doi:10.1016/s0140-6736(95)90011-x

\textbf{13.} Noda K, Ukichi T, Furuya K, et al. Tacrolimus-induced
hypertrophic cardiomyopathy in a patient with dermatomyositis.
Rheumatology (Oxford). 2017;56(11):2037-2038.
doi:10.1093/rheumatology/kex310

\textbf{14.} Bowman LJ, Brennan DC, Delos-Santos R, LaRue SJ, Anwar S,
Klein CL. Tacrolimus-Induced Cardiomyopathy in an Adult Renal Transplant
Recipient. Pharmacotherapy. 2015;35(12):1109-1116. doi:10.1002/phar.1666

\textbf{15.} Turska-Kmie\selectlanguage{polish}ć \selectlanguage{english}A, Jankowska I, Paw\selectlanguage{polish}ł\selectlanguage{english}owska J, et al. Reversal
of tacrolimus-related hypertrophic cardiomyopathy after conversion to
rapamycin in a pediatric liver transplant recipient. Pediatr Transplant.
2007;11(3):319-323. doi:10.1111/j.1399-3046.2006.00633.x

\textbf{16.} M\selectlanguage{ngerman}éndez-Abad P, Zafra-Rodríguez P. Miocardiopatía
hipertrófica en un recién nacido pretérmino con madre trasplantada renal
{[}Hypertrophic cardiomyopathy in preterm newborn with kidney
transplanted mother{]}. Arch Argent Pediatr. 2018;116(6):e749-e752.
doi:10.5546/aap.2018.e749

\textbf{17.} Jarzembowski TM, John E, Panaro F, et al. Reversal of
tacrolimus-related hypertrophic obstructive cardiomyopathy 5 years after
kidney transplant in a 6-year-old recipient. Pediatr Transplant.
2005;9(1):117-121. doi:10.1111/j.1399-3046.2005.00260.x

\textbf{18.} Chang RK, McDiarmid SV, Alejos JC, Drant SE, Klitzner TS.
Echocardiographic findings of hypertrophic cardiomyopathy in children
after orthotopic liver transplantation. Pediatr Transplant.
2001;5(3):187-191. doi:10.1034/j.1399-3046.2001.00052.x

\textbf{19.} Kakhi S, Phanish MK, Anderson L. Dilated Cardiomyopathy in
an Adult Renal Transplant Recipient: Recovery Upon Tacrolimus to
Sirolimus Switch: A Case Report. Transplant Proc. 2020;52(9):2758-2761.
doi:10.1016/j.transproceed.2020.06.011

\textbf{20.} McLeod J, Wu S, Grazette L, Sarcon A. Tacrolimus-Associated
Dilated Cardiomyopathy in Adult Patient After Orthotopic Liver
Transplant. J Investig Med High Impact Case Rep.
2017;5(2):2324709617706087. Published 2017 Apr 27.
doi:10.1177/2324709617706087

\textbf{21.} Kakhi S, Phanish MK, Anderson L. Dilated Cardiomyopathy in
an Adult Renal Transplant Recipient: Recovery Upon Tacrolimus to
Sirolimus Switch: A Case Report. Transplant Proc. 2020;52(9):2758-2761.
doi:10.1016/j.transproceed.2020.06.011

\textbf{22} . Pappas PA, Weppler D, Pinna AD, et al. Sirolimus in
pediatric gastrointestinal transplantation: the use of sirolimus for
pediatric transplant patients with tacrolimus-related cardiomyopathy.
Pediatr Transplant. 2000;4(1):45-49.
doi:10.1034/j.1399-3046.2000.00083.x

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

\end{center}
\end{figure}

\textbf{Figure 1.} Longitudinal parasternal end - diastolic plane:
Asymmetric septal hypertrophy (interventricular septum thickness 15 mm).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2.} Apical mid-systolic long-axis view: Systolic
turbulence in the left ventricular outflow tract.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 3.} Continuous Doppler through the left ventricular
outflow tract: end -systolic gradient of 64 mmHg.\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}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3---Clinical-case-reports/Figure-3---Clinical-case-reports}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

