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\begin{document}

\title{Titel: Reported physical symptoms during screening echocardiography is
not associated with the presence of suspected hypertrophic
cardiomyopathy.}



\author[1]{Mohammad Reza Movahed}%
\author[1]{Ashkan Bahrami}%
\author[2]{Sharon  Bates}%
\affil[1]{The University of Arizona Sarver Heart Center}%
\affil[2]{Anthony Bates Foundation}%


\vspace{-1em}



  
  \date{May 16, 2024}


\begingroup
\let\center\flushleft
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\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{Background:} The prevalence of hypertrophic cardiomyopathy (HCM)
can be silent and can present with sudden death as the first
manifestation of this disease. The goal of this study was to evaluate
any association between reported physical symptoms with the presence of
suspected HCM. \textbf{Method:} The Anthony Bates Foundation has been
performing screening echocardiography across the United States for the
prevention of sudden death since 2001. A total of 4,120 subjects between
the ages of 6 and 79 underwent echocardiographic screening. We evaluated
any association between any symptoms and suspected HCM defined as any
left ventricular wall thickness [?] 15 mm. \textbf{Results:} The total
prevalence of suspected HCM in the entire study population was 1.1\%.
The presence of physical symptoms were not associated with HCM (chest
pain in 4.3\% of participant with HCM vs. 9.9\% of the control, p=0.19,
palpitation in 4.3\% of participant with HCM vs. 7.3\% of the control.,
p=0.41, shortness of breath in 6.4\% of participant with HCM vs. 11.7\%
of the control., p=0.26, lightheadedness in 4.3\% of participant with
HCM vs. 13.1\% of the control., p=0.07, ankle swelling in 2.1\% of
participant with HCM vs. 4.0\% of the control., p=0.52, dizziness in
8.5\% of participant with HCM vs. 12.2\% of the control., p=0.44).
\textbf{Conclusion:} Echocardiographic presence of suspected HCM is not
associated with a higher prevalence of physical symptoms in the
participants undergoing screening echocardiography. This finding
confirmed that HCM can be asymptomatic in many patients and a
questionnaire cannot distinguish the HCM population from a control
group.%
\end{abstract}%



\sloppy


\textbf{Titel: Reported physician symptoms during screening
echocardiography is not associated with the presence of suspected
hypertrophic cardiomyopathy.}

\textbf{Short title: Symptoms in suspected HCM}

Authors: Mohammad Reza Movahed, MD., 1 Ashkan Bahrami, MD, 2 Sharon
Bates MS.3

1. University of Arizona Sarver Heart Center, Tucson

2. University of Arizona College of Medicine, Phoenix

3. Anthony Bates Foundation,

Correspondence to:

Mohammad Reza Movahed, MD, PhD

Clinical Professor of Medicine

University of Arizona Sarver Heart Center

1501 N. Campbell Ave.

Tucson, AZ 85724

Email: rmova@aol.com

Tel: 949 400 0091

Key words: cardiomyopathy; hypertrophic cardiomyopathy; HCM; HOCM;
hypertrophic obstructive cardiomyopathy; echocardiography; screening

Conflict of interest: None

\textbf{Abstract}

\textbf{Background:} ~The prevalence of hypertrophic cardiomyopathy
(HCM) can be silent and can present with sudden death as the first
manifestation of this disease. The goal of this study was to evaluate
any association between reported physical symptoms with the presence of
suspected HCM.

\textbf{Method:} ~The Anthony Bates Foundation has been performing
screening echocardiography across the United States for the prevention
of sudden death since 2001. A total of 4,120 subjects between the ages
of 6 and 79 underwent echocardiographic screening. We evaluated any
association between any symptoms and suspected HCM defined as any left
ventricular wall thickness~[?]~15 mm.

\textbf{Results:~} The total prevalence of suspected HCM in the entire
study population was 1.1\%. The presence of physical symptoms were not
associated with HCM (chest pain in 4.3\% of participant with HCM vs.
9.9\% of the control, p=0.19, palpitation in 4.3\% of participant with
HCM vs. 7.3\% of the control., p=0.41, shortness of breath in 6.4\% of
participant with HCM vs. 11.7\% of the control.,
p=0.26,~~lightheadedness~in 4.3\% of participant with HCM vs. 13.1\% of
the control., p=0.07, ankle swelling in 2.1\% of participant with HCM
vs. 4.0\% of the control., p=0.52, dizziness in 8.5\% of participant
with HCM vs. 12.2\% of the control., p=0.44).

\textbf{Conclusion:~~} Echocardiographic presence of suspected HCM is
not associated with a higher prevalence of physical symptoms in the
participants undergoing screening echocardiography. This finding
confirmed that HCM can be asymptomatic in many patients and a
questionnaire cannot distinguish the HCM population from a control
group.







\textbf{Introduction:}

Hypertrophic cardiomyopathy (HCM) is a cardiac condition that is defined
by hypertrophy of the left ventricle, hypercontractility,~decreased
compliance, and poor relaxation~(1-3). HCM presents as a progressive
and~chronic~condition that may become devastating and life-changing,
affecting the quality of life dramatically. Chest pain, palpitations,
exertional dyspnea,~shortness of breath, ankle
swelling,~fatigue,~dizziness, lightheadedness, and syncope are the most
common symptoms identified~(2-5). Sudden cardiac death (SCD), Heart
failure (HF), atrial fibrillation(AF), and~stroke~are all related to
HCM(6-8). Symptoms might be mistaken with those of other diseases, and
an accurate diagnosis may take years. The assumed~prevalence
is~approximately 1:500 adults~(9), however only around 100,000 among the
estimated 700,000 HCM patients in the United States have been
diagnosed~(10). Many asymptomatic HCM patients are diagnosed
accidentally or through screening~(3). Clinical history comprises a
complete cardiac history and a~3-generation family history for
determining HCM or sudden death relatives~(3, 11, 12). Functional and
fitness~capacity assessment, focusing on training regimen and exertion
symptoms---chest pain, palpitations,~dyspnea,~and syncope~(3, 13).

Significant advancement seems to have been achieved in comprehending the
disease from both~genetic and clinical perspectives~(14), although
methods of diagnosis have improved~(15). Despite genotype
positive-phenotype negative people have not being included into HCM
prevalence estimations, these individuals are at an elevated risk of
acquiring the disease, however,~the progression to clinically severe
disease remains unpredictable {[}8,9,10{]}.

By improving timely treatment, proper prognostic classification,
and~earlier diagnosis~can allow for an overall decrease in
disease-related mortality/morbidity~(16). When it was originally
discovered, HCM was considered to be an uncommon disease that largely
affected young people and had a poor~prognosis due to the potential risk
for~SCD~(17, 18). Currently, it is understood that HCM may impact
patients of any age whereas the overall prognosis of a diagnosed HCM
patient is usually favorable, with about two-thirds enjoying an ordinary
lifespan with almost no morbidity and an average HCM-related mortality
that is approximately 0.7\%/year ~(19-21). Some patients, however, are
at an elevated risk of SCD or developing atrial fibrillation (AF)/heart
failure (HF). As a result, identifying these individuals is a critical
priority~(2, 22).

Echocardiography is the gold standard for HCM screening, diagnosis,
follow-up, and~prognostic classification~(2, 22, 23). Recent SCD risk
calculators authorized by the AHA and the~ESC~(2, 22), include
echocardiographic measures. Advanced echocardiographic techniques
(two-dimensional speckle tracking, tissue Doppler) are able to
distinguish HCM from different causes of hypertrophy and recognize
people who are susceptible to developing HF or~SCD. 3D~echocardiography
provides greater information about hypertrophic distribution, the
mechanism of dynamic~LV obstruction, and LV mass~(23).

Our study aims to explore the connection, between reported symptoms and
suspected HCM (Hypertrophic Cardiomyopathy) during echocardiographic
screening. While echocardiography is a tool we believe it could be more
useful if we can determine whether specific symptoms are linked to a
higher likelihood of detecting HCM. By understanding the relationship
between symptoms and suspected HCM we can improve risk assessment. ~Our
main objective is to contribute to the growing body of knowledge about
HCM, which will lead to more effective practices and earlier detection
of this life-threatening condition.

\textbf{Materials and Methods:}

\textbf{The study population:}

Since its establishment, in 2001 the Anthony Bates Foundation has played
a leading role in efforts to prevent cardiac death through
echocardiographic screening. For this cohort study, we examined data
collected as part of this initiative. A total of 4,120 individuals
ranging in age from 6 to 79 years participated in screening across
regions of the United States. The study was a retrospective study of
that was approved by the institutional review board with exempt status.

\textbf{Data collection:}

Prior to receiving an echocardiogram, everyone was required to
complete~a questionnaire about their health symptoms. The questionnaire
included the symptoms of shortness of breath, chest pain, dizziness,
fatigue, and palpitations. Participants had to answer questions about
all symptoms, whether~mild or common. Informed consent was obtained to
participate in the screening. Individuals less than 18 years of age
needed parental informed consent. Echocardiography was performed by many
donated handheld echocardiography devices and the final diagnosis was
confirmed by volunteer cardiologists.

\textbf{Echocardiographic assessment:}

Our main objective was to investigate the link between self-reported
symptoms and the presence of suspected Hypertrophic Cardiomyopathy
(HCM). To identify cases with suspected HCM we employed the accepted
criterion of a ventricular wall thickness [?] 15 mm, which is an important
diagnostic indicator for this heart condition.

\textbf{Statistical analysis:}

We conducted an analysis to examine the correlation, between
self-reported symptoms and the presence of suspected HCM. We evaluated
the strength and significance of this relationship using techniques such
as regression and chi-square tests. Age, gender, and other related
demographic factors were also considered as variables that could impact
the outcomes of our analysis.. We used SPSS version 17 for our data. A
p-value of \textless{} 0.05 is deemed significant.

\textbf{Result} :

The demographic data of patients including age, sex, and race have been
evaluated. The age range of the participants was between 4 and 74 years,
and most of the individuals were 18, 16, and 17 years old, respectively
(Figure .1). Male gender were the majority of the participant. (Figure
.2).

The overall prevalence of possible HCM was found to be 1.1\% throughout
the entire population. There was no correlation between HCM and the
occurrence of any physical symptoms. Chest pain in 4.3\% of participants
with HCM vs. 9.9\% of the control, p=0.19, palpitation in 4.3\% of
participants with HCM vs. 7.3\% of the control., p=0.41, shortness of
breath in 6.4\% of participant with HCM vs. 11.7\% of the control.,
p=0.26,~ lightheadedness in 4.3\% of participant with HCM vs. 13.1\% of
the control., p=0.07, ankle swelling in 2.1\% of participant with HCM
vs. 4.0\% of the control., p=0.52, dizziness in 8.5\% of participant
with HCM vs. 12.2\% of the control, p=0.44~(Figure .3).~Our findings
suggest that based on this study's population symptoms reported during
echocardiography screening may not serve as indicators, for detecting
the presence of HCM.

\textbf{Discussion:}

We investigated the link between reported symptoms and suspected HCM in
our study. The findings are remarkable because they call into question
what we thought we knew and provide light on how difficult it can be to
diagnose this disorder. In summary, 1.1\% of the population had
suspected HCM. Physical symptoms were not associated with HCM (chest
pain in 4.3\% of participants vs. 9.9\% of the control, p=0.19,
palpitation in 4.3\% vs. 7.3\%, p=0.41, shortness of breath in 6.4\% vs.
11.7\%, p=0.26, lightheadedness in 4.3\% vs. 13.1\%, p=0.07, ankle
swelling in 2.1\% vs. 4.0\%, p=0.52, dizziness According to our
findings, several physical symptoms such as chest pain, palpitations,
shortness of breath, lightheadedness, ankle edema, and dizziness do not
correlate with the existence of HCM, as validated by echocardiography.
This discovery has far-reaching implications for HCM diagnosis and
management.

The primary takeaway from our research is that symptoms linked with HCM
should not be used to as the main, primary, and only way of diagnosing
the disease. Rather, our data indicate that a comprehensive screening
and diagnostic approach is required, and also it was presented that
cardiac imaging is used to make diagnoses and clinical recommendations
for HCM patients~(3), while echocardiography is the primary imaging
modality for the majority of patients~(3), Cardiac Magnetic Resonance
(CMR) imaging can enhance or replace it in unclear cases, additionally
imaging can confirm (or rule out) alternative diagnoses, assess
phenotypic severity, and identify structural~cardiac abnormalities
(e.g., valvular,~systolic, and~diastolic~function) through the American
College of Cardiology/American Heart Association recommendation in 2020
by Ommen et al.(3). This conclusion is significant given the prevalence
of HCM in the population and the possible hazards of sudden cardiac
death, furthermore, HCM contributed to one in every thirty SCAs among
the young and middle-aged overall population, resulting in a yearly SCA
prevalence ranging from 0.2\% to 0.3\% in unselected HCM patients in the
community through study by Aro et al.(25)~in 2017. The preliminary
diagnosis of HCM had been~missed in the great majority of SCA cases
prior to cardiac arrest~(25). The low predicted risk of SCA among young
together with middle-aged HCM patients, on the other hand, demonstrates
the disease's generally benign course in the great majority of people
who are affected~(25), and also it was claimed in large clinic
population studies performed by Cannan et al.~(26)~and Kofflard et
al.~(27), Unfortunately, SCD continues to be of considerable concern. It
could be the disease's earliest symptom, especially in competitive
and~young~athletes which were declared in a~large registry study over US
conducted by~B. J. Maron et al.~(28), and accompanying consequences even
in individuals with no obvious symptoms, in the context of the situation
that a substantial portion of HCM patients have been discovered~to have
asymptomatic or the least potential symptoms if their echocardiogram
confirmed HCM disease which was conducted by Udelson et al(29). and
O'Gara et al.~(30), although through retrospective cohort in 2017 by
Rowin et al.(31)~this point declared that the majority of patients
(70\%) seemed asymptomatic or slightly symptomatic according to New York
Heart Association (NYHA)~classifications one and two~(31), also in a
large community-based study have done by Kofflard et al.(32)~in 2003
(44\%) of patients were asymptomatic~(32).

Because this disorder can run in families, screening those with a family
history of HCM or those who have SCD is critical. While family history
is still used in screening, our research demonstrates that focusing
solely on symptoms is not a reliable method of identifying persons with
HCM.~~In studies conducted by Miller et al.~(33)~in 2013 and Toma\selectlanguage{polish}š\selectlanguage{english}ov et
al.~(34)~in 2014, It was demonstrated that HCM patients and
relatives~verified the value of genetic testing according to the
management of close relatives and discovered that the suggested
echocardiographic parameters had only a limited advantage for
recognizing causes of disease~mutation carriers~(33, 34). In terms of
detection and screening, echocardiography is the gold standard~(2, 22,
23). Our findings highlight the need to use echocardiography to confirm
HCM in people who have symptoms of the illness. Echocardiography is a
reliable approach for detecting HCM~(3). It is critical in avoiding
delayed or inaccurate diagnoses~(3, 25).

In the screening, diagnosis, follow-up, and prognostic categorization of
HCM, echocardiography is considered to be the gold standard~(2, 22, 23).
Recent risk calculators for SCD that have been approved by the AHA and
the ESC~(2, 22)~contain echocardiographic measures. Innovative
echocardiographic techniques, such as two-dimensional speckle tracking
and tissue Doppler, are able to differentiate hypertrophy caused by HCM
from that caused by other conditions and identify individuals at risk of
developing HF~or SCD. A greater amount of information can be obtained
using 3D echocardiography about hypertrophic distribution, the cause of
dynamic LV obstruction, and LV mass~(23).

When identifying HCM with echocardiography, we focus on a set of
symptoms rather than just looking at symptoms, which is an important
part of our study. This method allows us to assess how symptoms and
disease are related, which increases the importance of our research. It
provides insight into whether or not various symptoms are associated
with HCM.

In contrast to previous studies, our study takes into account a wide
variety of ages has a big sample size, and represents that the
participants ranged in age from 4 to 74 years old, with the majority of
them being 18, 16, and 17 years old. There were fewer African-Americans
than other races, and there were more men than women, although HCM is
age dependant and might include racial/ethnic disparities depending on
whether clinically or~subclinical~evident instances are evaluated~(35).
However,~in a study done by Maron et al.(10)~in 20 the mean age of HC
diagnosis was about the fifth decade of life, with women constituting
43\% of the overall HC cohort(10),~ This increases the applicability and
relevance of our findings to patient populations. Taking this approach
allows us to acquire a better understanding of the relationship between
symptoms and HCM, providing useful insights for distinct patient groups.

Because of the overlap of symptoms with systemic diseases, diagnosing
HCM can be difficult. Symptoms such as chest pain, palpitations,
shortness of breath, lightheadedness, ankle swelling, and dizziness can
be caused by a variety of illnesses, some of which are benign. This
overlapping symptomatology can make it difficult to diagnose HCM
quickly. The highlighted importance of metabolic storage disorders or
inborn errors of metabolism (IEM)~ such as Glycogen storage disorders
including Danon disease,PRKAG2 cardiomyopathy,Pompe disease (glycogen
storage disease type 2),and Forbes disease (glycogen storage disease
type 3), also lysosomal storage disorders like Anderson-Fabry disease,
furthermore mitochondrial cytopathies, cardiac amyloidosis that could
mimic HCM (`HCM phenocopies')~(36, 37).

The most prevalent symptoms are chest pain and~dyspnea~(38). Due to
diastolic dysfunction, elevated LV end-diastolic~pressure can produce
dyspnea, especially during exercise~(38). Myocardial hypoperfusion and
oxygen demand can induce chest pain. Palpitations are prevalent and can
cause syncope and~dizziness~(38). Syncope is rare but serious because it
commonly precedes SCD.~(32, 39). However, through a case report by
Elsouri et al.~(40)~in 2023, the two-dimensional technique failed to
capture septal hypertrophy many times~(40). In this scenario,
three-dimensional methods like cardiac MRI showed enhanced sensitivity
and specificity. In patients between 40 and 70 with,~dizziness, dyspnea
on exertion (DOE), and chest pain, the~HCM should be considered, and
cardiac MRI should be performed if symptoms recur after TTE imaging
shows no abnormalities~(40), according to the only study conducted on a
case report in 2023~(40), our study, due to the large sample size
examined, its results are very important for clinical experts in
diagnosis and treatment and potentially a great help to the
health-policy makers to formulate Early detection and screening programs
will prevent mortality and complications of HCM.

Our discoveries have consequences. The fact that these common symptoms
do not always signal the presence of HCM highlights the importance of a
screening approach. Symptoms alone may not be sufficient, and further
measures such as screening or regular echocardiograms for at-risk
patients may be required.~Individuals may remain asymptomatic until they
are discovered through screening or when consequences occur in some
cases. This emphasizes the significance of complete screening for those
who are at risk even in the absence of symptoms.

\textbf{Limitations:}

Despite the significance of our findings, it is critical to acknowledge
our study's limitations. Retrospective cohort studies, by definition,
include data collection limits and potential biases. Furthermore, our
study focused on symptoms and their relationship to HCM without taking
clinical or genetic factors into account. In the future, research must
address these limitations and go deeper into the complexities of HCM
diagnosis and management.

\textbf{Conclusion:}

To summarize, our study challenges the approach to diagnosing HCM by
demonstrating that certain symptoms do not always suggest a diagnosis of
HCM via echocardiography. This discovery has far-reaching consequences,
underscoring the importance of a multimodal strategy to screening for
HCM in high-risk people. This strategy should include genetic screening
and routine echocardiography. Early detection and treatments continue to
be critical in reducing disease progression, sudden cardiac death, and
related consequences. While our work provides some insight into this
issue, more research is needed to improve our understanding of HCM and
its diagnosis and to have ideal and more practical screening.

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Figure . Age of the study population\selectlanguage{english}
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Figure 2. Demographics of the screened population: Gender\selectlanguage{english}
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