Establishment of a Dedicated Inherited Cardiomyopathy Clinic: From Challenges to Improved Patients' Outcome.

Background Inherited cardiomyopathies (ICs) are relatively rare. General cardiologists have little experience in diagnosing and managing these conditions. International societies have recognized the need for dedicated IC clinics. However, only few reports on such clinics are available. Methods and Results Clinical data of patients referred to our clinic during its first 2 years for a personal or family history of (possible) IC were analyzed. A total of 207 patients from 196 families were seen; 13% of probands had their diagnosis changed. Diagnosis was most commonly altered in patients referred for possible arrhythmogenic dominant right ventricular cardiomyopathy (62.5%). A total of 90% of probands had genetic testing, of whom 27.3% harbored a likely pathogenic or pathogenic variant. Of patients with confirmed hypertrophic cardiomyopathy, 31 (28.7%) were treated for left ventricular outflow tract obstruction, including septal reduction in 13. Patients with either hypertrophic cardiomyopathy or left ventricular noncompaction and a history of atrial fibrillation were started on oral anticoagulation. Oral anticoagulation was also discussed with all patients with hypertrophic cardiomyopathy and apical aneurysm. Patients with a definite diagnosis of arrhythmogenic dominant right ventricular cardiomyopathy were started on β-blockers and given restrictive exercise prescriptions. A total of 17 patients with hypertrophic cardiomyopathy and 5 patients with likely pathogenic or likely variants in arrhythmogenic genes received primary prevention implantable cardioverter-defibrillators. No implantable cardioverter-defibrillators were warranted for arrhythmogenic dominant right ventricular cardiomyopathy. A total of 76 family members from 24 families had cascade screening, 32 of whom carried the familial variant. A total of 21 members from 13 gene-elusive families were evaluated by clinical screening, 3 of whom had positive screening. Conclusions Specialized IC clinics may improve diagnosis, management, and outcomes of patients with (possible) IC and their family members.

arrhythmogenic dominant right ventricular cardiomyopathy

dilated cardiomyopathy

family history of sudden cardiac death

filamin C

hypertrophic cardiomyopathy

Heart and Vascular Institute

inherited cardiomyopathy

lamin A/C

likely pathogenic or pathogenic

left ventricular noncompaction

left ventricular outflow tract obstruction

myosin‐binding protein C3

myosin heavy chain 7

oral anticoagulation

plakophilin 2

RNA‐binding motif protein 20

transthoracic echocardiogram

variant of uncertain significance

Clinical Perspective

What Is New?

Specialized inherited cardiomyopathy (IC) clinics can improve diagnosis, management, and outcomes of patients with IC and their family members.

What Are the Clinical Implications?

There is a need for dedicated clinics for IC with appropriate personnel and expertise.

Efforts should be made through continuing education for cardiologists to learn how to identify individuals and families who may benefit from referral to a dedicated IC clinic.

All patients with a personal or family history of (possible) IC should be referred to a dedicated IC clinic.

Inherited cardiomyopathies (ICs) include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), left ventricular noncompaction (LVNC), restrictive cardiomyopathy, and 3 types of arrhythmogenic cardiomyopathy, including arrhythmogenic dominant right ventricular cardiomyopathy (ARVC), arrhythmogenic dominant left ventricular cardiomyopathy, and arrhythmogenic cardiomyopathy with biventricular involvement. Genetic testing and advanced imaging have shown that the prevalence of IC is higher than previously thought (eg, HCM prevalence of 1:200–300 versus 1:500). , , Yet, ICs are still relatively rare and general cardiologists have little experience in diagnosing and managing individuals with these conditions and screening their family members. Consequently, experts and international societies, such as the American Heart Association, have recognized the need for dedicated clinics for IC. There are few reports on the establishment of such clinics and their impact on patients’ outcomes. , , Therefore, we sought to describe our experience in establishing a dedicated IC clinic and its benefits to patients and their family members.

Methods

The authors declare that all supporting data are available within the article. Further details of the analyses of the study are available from the corresponding author on request.

Development of the Program

As one of the largest tertiary cardiac and teaching centers in New England, the Heart and Vascular Institute (HVI) medical leadership recognized the clear need for a specialized program for IC as part of their vision of providing a full array of services for the residents of the state and neighboring areas. Before the program launch, there was only one program for IC in the state of Connecticut. The existing program provided access to a few regions in Connecticut, and patients from other regions were referred to out‐of‐state centers (mostly to Boston, MA).

The business/administrative stakeholders were focused on understanding the associated revenue streams and on assessing the potential profitability of such a service line. Before the program launch, HVI finance team developed a business plan. It is crucial for the plan to project the program’s financial success not only based on direct revenues from consult and follow‐up visits of patients and their families but also on the substantial downstream revenue that such a program would generate from advanced imaging, device implantations, and invasive procedures. On the basis of the prevalence of the in‐scope conditions, the number of the potential patients in the geographical area can be estimated. Extrapolating the associated downstream activities (eg, septal myectomy and implantable cardioverter‐defibrillator [ICD]) based on available reference data, finance teams were able to deem such a program as economically viable. Finance teams often focus on direct revenues only if not provided with disease prevalence estimates and the percentage of patients who will require downstream evaluations and management. This limits the perspective required to determine that such a program is economically viable. Hence, dialog between the medical and financial stakeholder was a key success factor. Also, as ICs have been shown to be underdiagnosed, the business plan considered an increase in local awareness among the local cardiologists and primary care physicians by the program, resulting in a gradual increase in referral. This was expected to have an effect beyond providing the existing market with a local alternative (share of wallet) and to generate “net new” revenues from patients who would have otherwise remained undiagnosed. The first step in building the program was recruiting a cardiologist with specialized training and experience in cardiovascular genetics as the director of the program. In parallel, a cardiothoracic surgeon trained at septal myectomy was also recruited. Once hired, the director also worked across HVI services to identify clinicians who would be members of the multidisciplinary team, such as those who work in advanced heart failure, cardiothoracic surgery, electrophysiology, interventional cardiology, and cardiac imaging. When an identifiable resource was not available, HVI administration worked with the program director to recruit these clinicians or provide the required training and proctoring to existing resources. One such example is a genetic counselor with experience in cardiovascular genetics who was recruited to focus only on the program. To continue to grow the program, HVI promoted the program in local media and arranged meet and greets for the program director with cardiologist groups across Connecticut to introduce and highlight the program and increase awareness to ICs. The program director gave grand rounds for cardiologists and other medicine specialists in hospitals across Connecticut. The program director and genetic counselor also gave talks and webinars to patients. A website dedicated to the program was developed by the HVI.

Population

The data of patients referred to the clinic were routinely entered into a database and retrospectively analyzed. Patients were referred to the clinic for suspected ICs, including HCM, DCM, ARVC, LVNC, family history of cardiomyopathy, or family history of sudden cardiac death (FHSCD) suspected to be attributable to nonischemic cardiomyopathy. Individuals with an FHSCD attributable to a primary electrical disorder or without an autopsy were not included in this report. Only patients aged ≥18 years were seen in the clinic.

Diagnostic Workup

The diagnostic workup varied by the suspected condition, although all patients met with a certified genetic counselor who took a detailed family history to construct a 4‐generation pedigree. Patients underwent a transthoracic echocardiogram (TTE), cardiac magnetic resonance (CMR) (if no contraindication was present), and ambulatory ECG monitoring via a Holter monitor or event recorder. Patients with HCM and without left ventricular outflow tract obstruction (LVOTO) (gradient, <30 mm Hg at rest or with the Valsalva maneuver) underwent a stress TTE to assess for latent obstruction. Most patients with obstructive HCM (ie, gradient ≥30 mm Hg), including those with no or mild symptoms, also underwent stress TTE to assess their exercise capacity. Transesophageal echocardiography was also performed in selected cases to assess the mitral valve anatomy and regurgitation. Most patients with DCM or HCM underwent a cardiopulmonary exercise stress test. Patients with suspected ARVC also underwent an exercise treadmill test and signal average ECG, and in specific cases, pharmacological testing with isoproterenol to differentiate ARVC from idiopathic right ventricular outflow tract ventricular tachycardia. Imaging studies were repeated after 3 to 6 months of detraining in selected instances when the patient presentation was most consistent with an athlete’s heart. A stress TTE was also performed to help differentiate athlete’s heart from possible mild DCM. An electrophysiology study was performed and/or an insertable cardiac monitor was placed in selected cases.

Patients with a FHSCD were tested according to the diagnosis of the deceased family member and autopsy findings. The coroner and/or pathologist were contacted to obtain available genetic material if a molecular autopsy had not been performed.

Genetic Testing

Genetic testing for a proband was done using commercially available broad pan cardiomyopathy and arrhythmia panels. These panels are College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments certified and use next‐generation sequencing and hybridization with deletion and duplication analysis. Variants were classified using the American College of Medical Genetics and Genomics guidelines. The genetic cardiologist and genetic counselor interpreted the genetic tests using available data from ClinVar, ClinGen, PubMed, and other sources. In certain cases when a variant of uncertain significance (VUS) was identified, we contacted different genetic laboratories that had previously reported the variant.

The type of specimen available from the autopsy determined the genetic testing for molecular autopsy. We used the commercial Clinical Laboratory Improvement Amendments– and CAP‐approved panel mentioned above if blood was available and used exome sequencing, which also was CAP and Clinical Laboratory Improvement Amendments approved, through a commercial academic laboratory if only tissue was available.

Family members were evaluated by follow‐up pathways depending on the genetic testing results. First‐degree relatives of families with a likely pathogenic or pathogenic (LP/P) variant were offered single‐site genetic testing first. Genetically positive family members and those choosing not to undergo genetic testing were recommended to undergo clinical screening. Family members who were genetically negative for the LP/P variant were not referred for additional testing. A first‐degree family member whose genetic testing was negative or in whom a VUS was identified was referred for clinical screening based on current guidelines. , , Phenotypically positive members of families with a VUS favoring LP variant were offered single‐site genetic testing. The recommended pathway for genetic testing or clinical screening was outlined for family members via a letter from the genetic counselor after the proband had been genetically tested.

Statistical Analysis

Continuous variables are presented as mean (SD), and qualitative variables are expressed as count (percentage).

This study was approved by the Hartford Healthcare/Hartford Hospital institutional research board (HHC‐2021‐0324). Informed consent was waived.

Results

Patients

We evaluated 207 patients from 196 families during the clinic’s first 2 years (March 1, 2019, to March 31, 2021) for either a personal or family history of definite or possible IC (Table 1). Referrals increased progressively, except for the peak of the COVID‐19 pandemic (February to May 2020), as depicted in Figure 1. HCM accounted for 59.4% of referrals; 87.9% of patients were probands (Table 1).

Table 1

Patients’ Characteristics by Referral Diagnosis Conditions

Condition	No.	Proband, n (%)	Age, mean (SD), y	Male sex, n (%)	Diagnosis changed in probands, n (%)
All cohort	207	183 (87.9)	49 (16)	131 (62.9)	24 (13.1)
HCM	123	114 (92.7)	51 (16)	78 (63.4)	15 (13.2)
DCM	62	58 (93.5)	48 (14)	40 (63.4)	3 (4.8)
ARVC	10	8 (80.0)	45 (19)	8 (80.0)	5 (62.5)
iLVNC	3	3 (100)	47 (8)	1 (33.3)	1 (33.3)
Cardiomyopathy‐related FHSCD	9	0 (0)	35 (11)	4 (44.4)	0 (0)

ARVC indicates arrhythmogenic dominant right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; FHSCD, family history of sudden cardiac death; HCM, hypertrophic cardiomyopathy; and iLVNC, isolated left ventricular noncompaction.

Figure 1

Growth of program by quarter (Q).

ARVC indicates arrhythmogenic dominant right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; and HCM, hypertrophic cardiomyopathy.

Two or more years had elapsed since initial diagnosis to clinic referral in 44% of probands referred for HCM and 62% of probands referred for DCM. These patients could not recall or had not been given genetic counseling or recommendations for family screening.

Diagnosis Changed

Of probands, 13% had their diagnosis changed by our clinic. The diagnosis was changed in 62.5% of probands evaluated for (possible) ARVC (Table S1). The most common cause for overdiagnosis of ARVC was incorrect interpretation of the CMR. In about 13% of probands referred for (possible) HCM, the diagnosis was most commonly changed to hypertensive cardiomyopathy, athlete’s heart, or sigmoid septum of the elderly. In 2 cases, the diagnosis was changed to wild‐type transthyretin cardiac amyloidosis; and in 1 case, the diagnosis was changed to cardiac sarcoidosis. In 1 patient with genotype‐positive HCM, a diagnosis of congenital long QT 2 syndrome was added. In 1 of 3 patients referred for isolated LVNC, the diagnosis was changed after reviewing the CMR and TTE, which did not meet the diagnostic criteria for LVNC. In 3 patients referred for a personal history of DCM, the diagnosis was changed to athlete’s heart.

Patients With Family History of Cardiomyopathy‐Related Sudden Cardiac Death

Nine patients from 7 families were evaluated for cardiomyopathy attributable to cardiomyopathy‐related FHSCD based on autopsy findings. We were able to arrange molecular autopsies in 3 of these families. The molecular autopsy in a family whose proband died of DCM detected an LP variant in the filamin C (FLNC) gene (c.5199+1G>T). The proband’s mother and brother tested positive for the FLNC variant and had mild left ventricular dysfunction on CMR. There were 2 additional sudden cardiac deaths in the family. The first was the proband’s 20‐year‐old sister, whose death was attributed to “idiopathic ventricular fibrillation” after her autopsy showed a structurally normal heart. The second was the proband’s 29‐year‐old maternal uncle, whose autopsy showed DCM and is an obligatory carrier. An ICD for primary prevention was implanted in both the proband’s brother and mother, and cascade screening was performed for the extended family (Figure 2).

Figure 2

Cascade screening a family with sudden cardiac death caused by a likely pathogenic variant in filamin C gene (FLNC).

 

The second family’s proband’s autopsy showed DCM. The molecular autopsy identified an LP variant in plakophilin 2 (PKP2) (c. 1489C>T). The autopsy slides did not demonstrate evidence of ARVC on review. The association of PKP2 variants with DCM is controversial, leaving it unclear if this variant caused this family’s DCM and sudden cardiac death. The decedent’s brother and niece have subsequently been diagnosed with DCM and are being evaluated to determine the role of the variant in PKP2 in the familial DCM.

The third family’s proband’s autopsy showed biventricular dilatation and hypertrophy with multifocal left ventricular myocardial fibrosis and fibrosis of the His bundle. The molecular autopsy did not identify variants in genes associated with cardiomyopathy. The family is undergoing clinical screening.

Molecular autopsy was not available for 4 families. The remaining 5 family members of these families underwent clinical screening and genetic testing for ARVC (2 families), HCM (1 family), and DCM (1 family). Screening was positive in 2 family members who underwent a primary ICD implantation (Table S2).

Recruitment of a qualified genetic counselor lasted over a year because of the small applicant pool. During this time, genetic counseling was performed by the genetic cardiologist. Of probands, 90% (165/183) had genetic testing. Eighteen probands declined genetic testing for a variety of reasons, including logistics, COVID‐19 concerns, or absence of younger family members. An LP/P variant was identified in 27.3% of the 165 probands who underwent genetic testing (Table 2). Genes and frequency of LP/P variants identified for HCM and DCM are summarized in Tables 3 and 4, respectively. MYBPC3 (myosin binding protein C3) was most common gene in HCM (55.2%) (Table 3). TTN (titin), FLNC, and RBM20 (RNA‐binding motif protein 20) were the most common genes identified in DCM (Table 4), and PKP2 gene in ARVC. Tables S3 and S4 list variants and their classification by condition.

Table 2

Yield of Genetic Testing in Probands by Initial Diagnosis

Condition (n)	Probands undergoing genetic testing, n (%)	LP/P variant (% of those tested)	VUS (% of those tested)
All probands (183)	165 (90.2)	46 (27.3)	49 (30.3)
HCM (114)	99 (86.8)	29 (29.3)	22 (22.2)
DCM (58)	55 (94.8)	13 (23.6)	23 (41.8)
ARVC (8)	8 (100)	2 (25.0)	2 (25.0)
iLVNC (3)	3 (100)	1 (33.3)	1 (33.3)
FHSCD (0)	3 (33.3)*	2 (66.7)	1 (33.3)

ARVC indicates arrhythmogenic dominant right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; FHSCD, family history of sudden cardiac death; HCM, hypertrophic cardiomyopathy; iLVNC, isolated left ventricular noncompaction; LP/P, likely pathogenic or pathogenic; and VUS, variant of uncertain significance.

Molecular autopsy.

Table 3

HCM Genes and Frequency of LP/P Variants

Gene	Frequency, n (%)
MYBPC3	16 (55.2)
MYH7	5 (17.2)
TNNI3	4 (13.8)
ACTC1	2 (6.9)
GLA	1 (3.4)
PLN	1 (3.4)

ACTC1 indicates actin α cardiac muscle 1; GLA, galactosidase α; HCM, hypertrophic cardiomyopathy; LP/P, likely pathogenic or pathogenic; MYBPC3, myosin‐binding protein C3; MYH7, myosin heavy chain 7; PLN, phospholamban; and TNNI3, troponin I3.

Table 4

DCM Genes and Frequency of LP/P Variants

Gene	Frequency, n (%)
TTN	3 (22.1)
FLNC	2 (15.4)
RBM20	2 (15.4)
TTR	2 (15.4)*
BAG3	1 (7.7)
DES	1 (7.7)
DSG2	1 (7.7) †
DSP	1 (7.7) †
LMNA	1 (7.7)

BAG3 indicates BAG cochaperone 3; DCM, dilated cardiomyopathy; DES, desmin; DSG2, desmoglein 2; FLNC, filamin C; LMNA, lamin A/C; LP/P, likely pathogenic or pathogenic; RBM20, RNA‐binding motif protein 20;TTN, titin; and TTR, transthyretin.

One individual was homozygous for TTR, and another was heterozygous.

The same person had both of these genes.

Change in Management

Of patients with confirmed HCM, 31 were treated for LVOTO by discontinuation of vasodilators (n=7), initiation or up titration of β‐blockers, or addition of nondihydropyridines calcium channel blockers (n=20), initiation of disopyramide (n=17), and surgical (n=12) or alcohol (n=1) septal reduction. All patients with confirmed HCM and atrial fibrillation (AF) or flutter were started on oral anticoagulation (OAC). Three patients underwent AF catheter ablation. All patients with a history of AF who underwent surgical septal myectomy had a concomitant MAZE procedure, and 3 of these patients also underwent a left atrial appendage closure. OAC was also discussed with the 3 patients with an apical aneurysm and no diagnosis of AF or other indications for anticoagulation.

All patients with a definite diagnosis of ARVC were started on β‐blockers and were given a restrictive exercise prescription. Similar exercise prescriptions were given to phenotype‐negative gene carriers. One of the 2 patients with confirmed isolated LVNC had AF and was started on OAC despite a CHA2DS2‐VASC (Congestive heart failure, Hypertension, Age (>65=1 point, >75=2 points), Diabetes, previous Stroke/transient ischemic attack (2 points), vascular disease, and sex category (female gender)) score of 0 attributable to the increased risk of thromboembolism with AF in LVNC. All patients were offered a referral to a health psychologist.

Implantable Cardioverter‐Defibrillators

Seventeen of 114 patients with HCM and no ICDs underwent a primary prevention ICD implantation (transvenous [n=13], subcutaneous [n=3], and biventricular [n=1]). No ICDs were warranted in any patients with ARVC. In 2 of the 5 patients whose initial diagnosis of ARVC was altered by our clinic, a primary prevention ICD for ARVC had been previously recommended. Furthermore, one of them had undergone a primary prevention ICD implantation that was complicated by pocket infection and Staphylococcus aureus bacteremia requiring lead extraction. This patient was wearing a LifeVest when first seen in our clinic. In 3 cases of DCM, genetic testing detected LP/P variants in arrhythmogenic genes and hence we proceeded with a primary prevention ICD implantation (LMNA (lamin A/C) and FLNC) and a dual‐chamber pacemaker upgrade for biventricular ICD despite normal left ventricular function (desmin) (Table S5).

Family Screening

Forty‐six probands, including 2 with molecular autopsies, had a positive genetic result. A total of 76 family members from 24 families had single‐site genetic testing because of a known familial LP/P variant. The average number per family was 3 members (range, 1–11). Thirty‐two of these family members were found to carry the familial variant.

For those with negative genetic testing, those with a VUS, or those who were unwilling to have genetic testing, we recommended clinical screening of their family members. Twenty‐one members of 13 gene‐elusive families were evaluated by clinical screening. The average number of members per family was 2 (range, 1–3). We identified an additional family member by clinical screening in 3 families. We have recently started using genome or exome sequencing for these gene‐elusive families with multiple affected family members.

We tested other family members to help clarify the significance of a VUS when family members demonstrated the phenotype. For example, we used this method for a VUS in MYH7 (myosin heavy chain 7) (c.121G>A) to determine that it was not the cause of the family’s DCM (Figure 3).

Figure 3

Variant of uncertain significance (VUS) in myosin heavy chain 7 (MYH7) resolution in a family with dilated cardiomyopathy.

 

Discussion

The need for dedicated IC clinics has been increasingly acknowledged. In 2019, the American Heart Association published a Scientific Statement on the need and requirements for clinical cardiovascular genetic programs. Such programs still do not exist in most centers, and most patients with these inherited conditions are managed by cardiologists without special training in cardiac genetics. This report summarizes our experience in establishing an IC clinic to illustrate how such programs can benefit patients and their families.

A major obstacle to establishing such programs is health centers’ concern that IC clinics do not generate high revenue. Furthermore, genetic counselors in Connecticut and many other states cannot charge for their service. However, as demonstrated by our report, these programs bring patients and relatives into the health system, and these individuals require testing and procedures. Downstream revenue from imaging studies and procedures should be tracked to measure the financial viability of these programs as these are substantial and reflect the bulk of revenues generated by such programs.

Raising awareness of the program among potential referring physicians is another challenge as well as a growth opportunity. We provided educational sessions for physicians and the community, met with cardiology groups, and collaborated with the local children’s hospitals. These measures raised awareness and led to an exponential growth in referrals.

Referral for DCM broadened as the cardiologists became aware that genetic factors also predispose patients to develop DCM of a “known cause” (eg, alcoholic, myocarditis‐related, and postpartum cardiomyopathies). In fact, when taking a detailed 3‐generation family history, some individuals initially diagnosed with “idiopathic” or “sporadic” DCM were ultimately found to have family history of heart failure or sudden death. An LP/P variant was found in 1 of every 4 patients referred for DCM. Genetic testing in DCM also contributes to risk stratification when an LP/P variant is found in one of the arrhythmogenic genes (eg, FLNC, SCNA5A, RBM20, LMNA, or desmin). Indeed, the presence of an LP/P variant in the arrhythmogenic genes (ie, FLNC, LMNA, and PLN) has been incorporated into the recommendations for primary prevention ICD by the 2019 Heart Rhythm Society guidelines for arrhythmogenic cardiomyopathy. We recommend genetic testing for all patients with DCM. The yield of genetic testing for DCM in our clinic was ≈24% for LP/P variants, which is consistent with other studies. , , We found LP/P variants in arrhythmogenic genes (ie, LMNA, FLNC, and desmin) in 3 probands with DCM and in the mother and brother of a proband referred for FHSCD (FLNC). All these individuals received a primary prevention ICD.

In line with previous reports, diagnoses were frequently changed. , The diagnosis was most frequently changed primarily in patients referred for possible ARVC, where >60% had their diagnosis changed mainly because of overdiagnosis of ARVC via CMR. Overdiagnosis of inherited life‐threatening conditions may result in inappropriate exercise restriction and unnecessary medical procedures, such as ICD placement with its possible complications. Overdiagnosis of genetic diseases also creates unnecessary anxiety for the patient and family members.

Our clinic often changed patients’ clinical management. Over 25% of patients with HCM had their medications modified and/or underwent septal reduction to mitigate LVOTO. Some of these patients were only mildly symptomatic but had reduced exercise capacity on formal exercise testing. Others have also observed that most asymptomatic or minimally symptomatic patients with HCM have diminished exercise capacity during stress exercise treadmill test. Patients with mild symptoms (New York Heart Association class 2) or mildly impaired exercise capacity, but severe LVOTO on exercise echocardiography, may have improved long‐term outcomes with early septal myectomy. We routinely perform stress exercise treadmill test and cardiopulmonary exercise stress test on patients with HCM to determine exercise capacity and the presence of latent LVOTO.

CMR is not routinely performed in patients with HCM by all general cardiologists. We routinely perform a CMR in patients with left ventricular hypertrophy to differentiate HCM from other causes of hypertrophy, to characterize their phenotype, and for risk stratification. Extensive myocardial scarring, an apical aneurysm, or severe hypertrophy found on CMR prompted an ICD placement for primary prevention in 14 of 17 patients who received a primary prevention ICD. TTE failed to detect an apical aneurysm in 4 of 6 patients with an apical aneurysm on CMR. Apical aneurysm is an independent risk factor for sudden cardiac death in HCM and a class IIa indication for a primary prevention. Apical aneurysm is also associated with increased thromboembolic risk and may require OAC. We routinely discuss OAC (novel oral anticoagulants (NOACs) if not contraindicated) in all patients with HCM with an apical aneurysm and no contraindications. All 6 patients chose to start OAC.

The yield of genetic testing in DCM was 24%, similar to other reports , , ; however, our yield in HCM and ARVC was lower. This is likely attributable to our performing genetic testing on most patients referred for HCM or ARVC, even when the pretest probability was low based on the phenotype. Our practice reflects recent trends in genetic testing for IC because genetic testing is increasingly accessible and affordable.

Ninety‐seven family members from 37 families had either cascade screening for a known LP/P variant identified by our clinic and/or had clinical screening because of their family risk for cardiomyopathy with us or with one of our partners. For the family members who test negative for the familial (likely) pathogenic variant, there can be a sense of relief. For those who carry the familial variant, we offer close monitoring, and they have resources available to them should they develop the disease. Preventive measurements can be taken to prevent development of diseases, such as exercise prescription for PKP2 carriers and limited alcohol intake for TTN carriers. Close monitoring allows early diagnosis and interventions.

We cannot accurately estimate the rate of cascade clinical screening of family members of families with no identifiable disease‐causing variants because many family members do not reside locally; however, our impression is that family screening uptake is lower with negative genetic testing. We also think that patients are more likely to screen their children than to communicate risk to their adult family members. To address this, we provide all patients with a detailed description of the condition and screening recommendations to share with family members. If a causative variant is found, we offer pretest genetic counseling and genetic testing to all first‐degree family members who reside in North America.

More important, within our probands, about 50% had been diagnosed ≥2 years before attending our clinic and were either not given any recommendations or given incomplete recommendations for family screening (eg, only one‐time screening). Furthermore, genetic counseling had not been discussed with these patients.

One of our goals is increasing the performance of autopsy, which we believe should be done in all cases of unexplained sudden death in young individuals (eg, those aged <50 years). This is currently done in several places around the globe. Furthermore, with the high accessibility and low cost of genetic testing, molecular autopsy could be performed in all such cases. We included in this study only families with an autopsy consistent with cardiomyopathy. During the study period, we saw an additional 8 patients for FHSCD where autopsy was not performed. Unfortunately, coroners do not routinely discuss the possibility of inherited cardiovascular conditions as the cause of death and the need for family screening in such cases. We have been working with the local coroners and pathologists; however, we believe that this should be addressed on a national level.

Limitations

Our data on family screening may be incomplete, especially where family members reside out of state. As we sought to describe the first 2 years of our clinic, long‐term follow‐up is not included in this report. Last, the COVID‐19 pandemic has likely hindered referrals to the clinic and, as such, the study time period may underestimate the full potential and impact of such clinics.

Conclusions

Specialized IC programs may improve diagnosis, management, and outcomes of patients with suspected IC and their family members. Referral of patients to a specialized clinic should be considered for all patients with (suspected) IC.

Sources of Funding

None.

Disclosures

None.

Tables S1–S5

Click here for additional data file.