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2024, Number 4

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Cardiovasc Metab Sci 2024; 35 (4)

Rare genetic cardiovascular diseases: descriptive epidemiological data in a Mexican third-level cardiology hospital outpatient clinic

Ibarra-Ibarra, Blanca Rebeca1

Language: English
References: 23
Page: 135-144
PDF size: 426.81 Kb.


ABSTRACT

Introduction: rare cardiovascular diseases are conditions with low prevalence in the general population that affect the cardiovascular system. Most have a genetic etiology with a heritable potential denominated as Rare Genetic Cardiovascular Diseases (RGCVD). Currently, there are scarce epidemiological studies on RGCVD, and the overall prevalence is unknown. Objective: descriptive epidemiological analysis of RGCVD, emphasizing the overall prevalence estimation in a cardiovascular hospital. In addition, the cardiovascular phenotype distribution and other related demographic characteristics were analyzed. Material and methods: the study consists of a retrospective descriptive epidemiological analysis from January to December 2019 in the outpatient clinic of a cardiovascular third-level hospital in Mexico City. RGCVD patients were identified with an exhaustive review of all clinical records. The overall prevalence of RGCVD was estimated. In addition, the number of diseases, cardiovascular phenotype distribution, and other demographic data of these diseases were analyzed. Results: RGCVD comprised 794 of 31,487 patients in the outpatient clinic, corresponding to 104 diseases. The overall prevalence of RGCVD was 2.5% (95%CI, 2.3-2.7) patients. The prevalence of monogenic and chromosomal disorders was 2.1 and 0.4%, respectively. Congenital heart diseases were the most frequent cardiovascular phenotype (42.4%), and the less frequent were cardiac tumor disorders (0.9%). Conclusions: the study identified that almost one in 40 patients in the outpatient clinic of a cardiology hospital had an RGCVD. The study also provides useful epidemiological information for further research and planning cardiovascular health services.



ABBREVIATIONS:

  • CI = Confidence Interval.
  • ICD = International Classification of Diseases.
  • OMIM = Online Mendelian Inheritance in Man.
  • RGCVD = Rare Genetic Cardiovascular Diseases.



INTRODUCTION

Rare diseases affect between 3.5 and 5.9% of the world's population, impacting around 350 million people at any time in life. Rare diseases are a heterogeneous group of disorders with a genetic etiology in almost 72%.1-3 There is no global consensus about the definition of a rare disease, but in general terms, a rare disease is defined as a disease that affects < 50/100,000 people.4

Rare genetic cardiovascular diseases affect the cardiovascular system with or without extracardiac manifestations, with an individually low prevalence, mainly caused by rare and ultra-rare genetic variants with heritable potential.2,5,6

There are currently scarce epidemiological studies on rare genetic cardiovascular diseases that delineate their distribution and situation in different world regions, clinical settings, and healthcare systems.7 Moreover, most studies are biased toward estimating the prevalence of some diseases, providing a fractioned and limited perspective of rare genetic cardiovascular diseases' global panorama.3,8 These are routinely seen in cardiovascular clinical practice. However, the overall rare genetic and nongenetic cardiovascular prevalence in cardiology is hitherto unknown.

It is crucial to estimate the total number of people affected with rare genetic cardiovascular diseases to provide helpful information for improving medical care in the future. Furthermore, this information could establish some bases to encourage translational research that promotes the creation of health policies consistent with the needs of patients suffering from these diseases. Therefore, the objective herein was to conduct a descriptive epidemiological analysis of the rare genetic cardiovascular diseases in the outpatient clinic of a third-level cardiology hospital, emphasizing the estimation of their overall prevalence. Additionally, cardiovascular phenotype distribution, the outpatient prevalence per disease, type of genetic disease, type of rare disease, and other related demographic characteristics were analyzed to evaluate the situation of rare genetic cardiovascular diseases in a cardiovascular clinical setting.



MATERIAL AND METHODS



STUDY DESIGN AND SETTING

The design was a retrospective, descriptive epidemiological study of the full range of patients with rare genetic cardiovascular diseases in a third-level cardiovascular hospital outpatient clinic in Mexico City (Instituto Nacional de Cardiología Ignacio Chávez) from January to December 2019. The hospital is a recognized national reference for the attention of pediatric and adult cardiovascular diseases.



DEFINITIONS, STUDY POPULATION, AND DATA COLLECTION

The operational definition of a rare genetic cardiovascular disease was a rare disease cataloged in the online rare diseases database Orphanet2 with a genetic etiology (monogenic or chromosomal disorders) affecting the cardiovascular system with or without extra cardiovascular clinical features. The diagnoses of patients with rare genetic cardiovascular diseases were identified through an exhaustive review of all the diagnoses settled in the electronic clinical records of the 31,487 patients who visited the outpatient clinic. A medical geneticist conducted the review. The study included confirmed clinical diagnoses of patients with rare genetic cardiovascular diseases. The medical geneticist assessed each diagnosis to determine if it met the specific criteria of each rare genetic cardiovascular disease, regardless of whether a confirmatory genetic test was conducted. Diagnoses of common cardiovascular diseases or rare diseases without cardiovascular involvement were excluded from the study. In addition, the clinical data for each patient with a rare genetic cardiovascular disease, including the diagnosis (disease name), cardiovascular phenotype, age, and sex, were collected for further analysis. Each rare genetic cardiovascular disease name was matched with its related preferred disease term and ORPHAcode, obtained from Orphanet.2 In diseases without a specific ORPHAcode, the ORPHAcode of a group of disorders was assigned according to the phenotype.



TYPE OF GENETIC DISORDER

Identified rare genetic cardiovascular diseases were classified according to the type of genetic disorder in two categories: chromosomal disorders and monogenic disorders. Chromosomal disorders include numerical and structural chromosomal abnormalities and genomic rearrangements. Monogenic include Mendelian inheritance patterns and non-Mendelian patterns. The information regarding the etiology was obtained from Orphanet2 and OMIM (Online Mendelian Inheritance in Man).9



TYPE OF RARE DISEASE

In order to analyze the situation of the rare genetic cardiovascular diseases identified in the outpatient clinic, each rare cardiovascular disease was categorized into three types of rare diseases according to the disease prevalence reported in Orphanet.2 The prevalence reported for each disease could be related to the prevalence in the general population or birth prevalence. Therefore, the type of rare diseases was categorized as follows: rare (prevalence between < 1/2,000 - > 1/50,000),4 ultrarare (prevalence between ≤ 1/50,000 - < 1/1'000,000),10 and unknown prevalence.



CARDIOVASCULAR PHENOTYPE DISTRIBUTION

To analyze the distribution of the cardiovascular phenotype of the identified patients with rare genetic cardiovascular diseases, the cardiovascular phenotype of each patient was classified into one of the six groups (arrhythmic and conduction disorders, cardiac tumor disorders, cardiomyopathies, congenital heart diseases, vascular disorders, and other cardiovascular disorders) and its corresponding morphological subgroup.



STATISTICAL ANALYSIS

The overall prevalence of rare genetic cardiovascular diseases, the prevalence per disease, and the prevalence of monogenic and chromosomal disorders were estimated using the total number of patients who attended the outpatient clinic in 2019 as a denominator. The 95% confidence interval (CI) was estimated for overall, monogenic, and chromosomal disorders prevalences. The prevalence per disease was calculated per 10,000 patients. Continuous variables were expressed as median (25th - 75th percentile). Categorical variables were expressed as absolute and relative frequencies, as appropriate. The differences in continuous variables among groups of cardiovascular phenotypes were calculated with the Kruskal-Wallis H test and, in categorical variables, with the χ2 test. Data and statistical analyses were performed in Stata Statistical Software: Release 16 (StataCorp LLC. 2019).



RESULTS

Of the total population of patients who attended the outpatient clinic in 2019 (n = 31,487), 794 patients had a diagnosis of a rare genetic cardiovascular disease. The overall period prevalence of rare genetic cardiovascular diseases was 2.5% (95%CI, 2.3-2.7) of the patients in the outpatient clinic of the analyzed third-level cardiovascular hospital. The patients with rare genetic cardiovascular diseases corresponded to 104 disease names (Table 1). The frequency of patients and the prevalence in the outpatient clinic per 10,000 patients for each rare genetic cardiovascular disease are shown in Table 1. Of the patients with rare genetic cardiovascular diseases, 51% were women, and the median age was 23 (13-38). Thirty-nine percent of patients correspond to pediatrics ages (0-18 years).

Eighty-seven out of 104 diseases observed corresponded to monogenic disorders, and 17 were chromosomal disorders (Table 1). Therefore, the number of patients affected with monogenic disorders was 668/794 (84.1%), and patients with chromosomal disorders accounted for 126/794 (15.9%). The prevalence of monogenic and chromosomal disorders of the rare genetic cardiovascular diseases in the outpatient clinic was 2.1% (95%CI, 2.0-2.3) and 0.4% (95%CI, 0.3-0.5), respectively.

According to the reported prevalence for each disease in Orphanet,2 33 diseases correspond to the definition of rare diseases with a prevalence between < 1/2,000 and > 1/50,000, 38 correspond to ultrarare diseases (≤ 1/50,000 - < 1/1,000,000), and 33 had an unknown prevalence in the general population or at birth (Table 1). Ultrarare diseases and rare genetic cardiovascular diseases with an unknown prevalence comprise a diverse spectrum, including skeletal dysplasias, cardiac neoplasm syndromes, unbalanced reciprocal translocation syndromes, muscular dystrophies, inborn errors of metabolism, and other syndromes, as shown in Table 1.

The cardiovascular phenotype presented in each rare genetic cardiovascular disease patient was classified to determine its distribution. The frequency per cardiovascular phenotype groups and subgroups is shown in Table 2. The most frequent cardiovascular phenotype was congenital heart diseases (42.4%; n = 337/794), followed by vascular disorders (27.2%; n = 216/794), arrhythmic and conduction disorders (16.4%; n = 130/794), cardiomyopathies (11.2%; n = 89/794), and the less frequent phenotypes were other cardiovascular disorders (1.9%; n = 15/794) and cardiac tumor disorders (0.9%; n = 7/794). There was a statistically significant difference among the cardiovascular phenotype groups in age (χ5 = 106; p= 0.0001) (Figure 1) and sex (χ5 = 17.9; p = 0.003) (Figure 2). The youngest and oldest cardiovascular phenotype groups were cardiac tumor disorders (4 [1-13] years) and cardiomyopathies (37 [24-50] years), respectively (Figure 1). In addition, cardiac tumor disorders had a higher proportion of females (85.7%) (Figure 2). Sixty-two percent of all patients (n = 489/794) with rare genetic cardiovascular diseases corresponded to three cardiovascular phenotype subgroups. The cardiovascular phenotype subgroup related to thoracic aortic aneurysm and dissection had the largest number of patients, corresponding to 26.6% of all patients (n = 211/794), followed by obstructive congenital heart disease lesions (20.3%; n = 161/794) and primary electrical diseases (14.7%; n = 117/794) (Table 2). These three subgroups of cardiovascular phenotypes correspond principally to Marfan syndrome, Loeys-Dietz syndrome, Noonan syndrome, Williams syndrome, Romano-Ward syndrome, Brugada syndrome, and others.



DISCUSSION

Scarce studies have addressed the number and prevalence of rare cardiovascular diseases because of their low prevalence and difficulty in recognition.1,7,8 However, knowing the prevalence of rare genetic cardiovascular diseases is of utmost importance since there is an increase in prevention and follow-up algorithms,11,12 new treatments, and gene therapies that may benefit patients.13 Rare genetic cardiovascular diseases are frequently encountered in clinical practice, but the overall prevalence of rare genetic cardiovascular conditions in a clinical setting was previously unknown in Mexico and worldwide. In the present research, the overall period prevalence of rare genetic cardiovascular diseases was 2.5%; in other words, almost 1 in 40 patients has a rare genetic cardiovascular disease in a cardiovascular outpatient clinic. Although the prevalence may appear low relative to other cardiovascular diseases, it is not insignificant, especially considering that a significant proportion of rare genetic cardiovascular diseases harm the quality of life, reduce life expectancy, and have economic implications that could cause higher medical care costs.14-16

In the present study, the prevalence of monogenic rare genetic cardiovascular diseases was 2.1%. In this regard, a recent study estimated the prevalence of monogenic cardiovascular diseases in patients referred to cardiac catheterization with an unbiased whole-exome sequencing approach. The prevalence of patients with pathogenic and likely-pathogenic variants with a clinical phenotype was 1.7%.17 Nevertheless, the estimated prevalence includes both common genetic diseases and rare genetic cardiovascular diseases without reporting the overall estimated prevalence for those rare diseases. The higher prevalence of monogenic disorders observed in the present study could be related to a broader spectrum of conditions in the cardiovascular outpatient clinic and the inclusion of pediatric ages.

A curated database initiative (PhenoDis)5 has annotated the existence of 327 rare cardiac diseases so far,5 without counting those that affect the vascular system or other rare cardiovascular diseases. The present study detected the broad spectrum of rare genetic cardiovascular diseases that can occur in cardiovascular clinical practice. The spectrum includes rare genetic cardiovascular diseases affecting the heart structure and functioning, blood vessels, cardiac conduction, autonomic systems, and others. A total of 104 different rare genetic cardiovascular disease diagnoses were identified, not limited to a few widely known syndromes. We should be aware that a great proportion of the rare genetic cardiovascular diseases found in the present study have an unknown prevalence or are considered ultrarare diseases with an extremely low prevalence (≤ 1/50,000 - < 1/1'000,000) in the general population.10 Ultrarare diseases are routinely excluded from public health policies and comprise highly heterogeneous phenotypes with complex molecular mechanisms. Therefore, it is essential to highlight the importance of its recognition to promote comprehensive diagnostic approaches, the formation of doctors specialized in them, drug development, novel therapies, and the creation of health policies consistent with the needs of the patients suffering from these diseases.18

The cardiovascular phenotype distribution observed among rare genetic cardiovascular diseases showed some expected results, such as a higher frequency of congenital heart diseases19 and a lower frequency related to rare genetic disorders with cardiac tumors.20 Unexpectedly, cardiomyopathy disorders had a lower frequency compared to other cardiovascular phenotypes. In this regard, it is widely known that hypertrophic cardiomyopathy as a composite is one of the most common genetic diseases, with a prevalence between 1/200 and 1/500 in the general population.21 Although not all the subtypes of hypertrophic cardiomyopathies are rare,12 a higher proportion of cases was expected than observed. Several factors related to characteristics inherent to these types of rare genetic cardiovascular diseases, such as variable expressivity, attenuated phenotypes, incomplete or reduced penetrance, atypical phenotypes, absence of genetic family history, or lack of genomic diagnosis that could make its recognition, referral, and diagnosis difficult may be contributing to this.21-23 A finding to consider was the proportion of cases corresponding to thoracic aortic aneurysms and dissection disorders (Marfan syndrome, Loeys-Dietz syndrome, and others) that represented almost a third of all cases with rare genetic cardiovascular diseases in the outpatient clinic. The early recognition and diagnosis of these diseases are crucial to conducting proper follow-up, genetic counseling, treatment, and surgical procedures to prevent fatal outcomes.

The retrospective design has well-known limitations, and probably some rare genetic cardiovascular diseases could have been masked among highly prevalent diseases or were not suspected yet.22,23 Nevertheless, the retrospective design offers a good alternative for detecting low-prevalence disorders in the absence of registries, insufficient epidemiological data, and missing specific International Classification of Diseases (ICD) codes for rare diseases.3 Moreover, no studies have been conducted regarding the prevalence of rare genetic cardiovascular disease in a cardiovascular clinical setting or other hospitals. Although the cardiology hospital studied is a cardiovascular reference in Mexico, the prevalence per disease in the outpatient clinic reported in the present study remained as newly descriptive data to inform about the situation of these diseases and could not be compared with the general population or regional disease prevalences. However, the number and prevalence observed in the present study could increase in the future with the improvement and implementation of more diagnostic technologies and the incorporation of cardiogenetics clinics. Despite the limitations, the present study sets a step forward to close knowledge gaps concerning rare cardiovascular disease prevalence and, hopefully, encourage further research.



CONCLUSIONS

Rare diseases face considerable challenges because of their low prevalence in the general population. Scarce studies have focused on knowing the number and distribution to delineate the magnitude in different clinical contexts. The current study has provided the first estimate of the overall prevalence of rare genetic cardiovascular diseases in a cardiovascular hospital. In this hospital, almost one in forty patients was affected. Moreover, the present study identified the vast spectrum of rare genetic cardiovascular diseases and their most common cardiovascular phenotype in a cardiovascular clinical setting.

Further research in other cardiovascular hospitals and the general population is needed to achieve a global panorama concerning these diseases. Recognition and visibility of rare diseases are the first steps toward better clinical care. Also, it is imperative to create comprehensive clinical registries for rare genetic and nongenetic cardiovascular diseases. This study reminds us that rare genetic cardiovascular diseases are rare, complex, and not easy to recognize but not invisible.


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AFFILIATIONS

1 Laboratory of Translational Medicine, UNAM-INC Unit, Cardiogenetics clinic, Department of Outpatient Clinic, Instituto Nacional de Cardiología Ignacio Chávez. Mexico City, Mexico. ORCID: 0000-0002-5979-7507



Declaration of confidentiality and patients consent: all the clinical data obtained from clinical records were treated with confidentiality and de-identified for analysis following the Declaration of Helsinki. The study was classified as non-risk because of the retrospective, observational, and descriptive design by the Institutional Research Committee, which qualified for an exemption from review and waived the requirement for informed consent.

Clinical trial registration and approval number: the study was not a clinical trial and did not involve interventions of any kind in patients. The Institutional Research Committee evaluated and communicated an exemption, and no sanction by committees was required (INCAR-DG-DI-CI-096-2022).

Funding: no funding or financial support to declare.

Declaration of interests: the author declares no conflicts of interest.

Acknowledgement: the author thanks MCS. Alexis Ibarra-Ibarra for proofreading assistance.



CORRESPONDENCE

Blanca Rebeca Ibarra-Ibarra, MD, MSc, PhD. E-mail: blanca.ibarra@cardiologia.org.mx




Received: 06/26/2024. Accepted: 11/07/2024.

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