Ravi Karra, MD Duke University

1. Genetic
Cardiomyopathy &
Sarcoidosis Clinic:
Is There Room to
Subspecialize?
Ravi Karra, MD
ravi.karra@duke.edu

2. Yes!

3. Circulation. 2022. 145 (18): e895-e1032.

4. Circulation. 2022. 145 (18): e895-e1032.

5. underly
ing
cause
of HF
matters
.
Felker et al.
NEJM. 2000.
342:77-1084.

6. Cause-specific treatments can
improve outcomes.

7. Duke Cardiomyopathy
Center
Amyloid
Sarcoid
Genetic
Peripartum
Cardio-Onc
Infectious
Transplant
LVAD
Critical Care
Advanced
Heart Failure
General
Heart Failure
Titration
Clinic
General HF &
Disease
Management
SDAC
Research
Training
&
Education
Duke Heart Failure
Clinical
Care
Establish Centers of Excellence
National Consortiums / Registries
Enhance Site-Based Research at forefront of precision medicine
Translational research – prospective biorepositories, etc
Trainee opportunities to develop focused expertise and leadership
Opportunities for enhanced CME
Multi-disciplinary involvement across specialties and campus
Primary Care &
Urgent Care
CV Medical Care
Surgery & Medicine
Specialty Care
Imaging, Cath, EP, Genetics,
Prevention, HCM, Cardio-OB, etc
Onc, rheum, ID, renal, OB,
palliative care, etc
CT Surgery, General Surgery
Referral Partners
Network
Dyspnea
Clinic
HFpEF
PHTN
Identification of Patients
Interested in Research

8. Overall structure for a multidisciplinary Duke Comprehensive Sarcoid Center

9. Sarcoidosis Multidisciplinary Team
Ravi Karra MD, MHS
Advanced Heart Failure
Albert Y. Sun MD
Electrophysiologist
Jayanth R. Doss MD, MPH
Rheumatologist
Hakim Azfar Ali, MD
Pulmonologist
Matilda W. Nicholas MD, PhD
Dermatologist
Johana R. Fajardo DNP, FHFSA
Advanced Heart Failure
Carolyn Glass MD, PhD
Pathologist Dilraj Grewal MD
Ophthalmologist
Suma Shah MD
Neurologist
Elijah A. Lackey MD
Neurologist
Matthew Kappus MD
Hepatologist

10. High Risk or Probable/Confirmed Sarcoid
* Check CBC, ALT/AST, Cr, HCV, HBV
**After repeat CBC, ALT/AST, Cr
Taper to MTX 15 mg weekly*
Complete 1 year of Rx
Image at 3-6 months
Inactive disease
Image
Shared Decision Making to Stop Rx
Inactive disease
Taper Protocol
Pred 0.5 mg/kg daily (max 40 mg)
Add MTX 25 mg weekly*
TNF-a inhibitor, MMF, Azathioprine
Image at 3 months
Active disease
Interval imaging at 3 months
Active disease
Interval imaging at 3 months
Active disease
Multidisciplinary discussion
Inflammation Protocol
Inactive disease
Inactive disease
Inactive disease
Active disease
Active disease

12. Opportunity for Discovery
7 patients with
active sarcoidosis
Isolation of
PBMCs
Single cell
Multiome
Sequencing

13. T cells
B cells
Myeloid
Cells
CSLCs
Mechanism-driven diagnostics &
therapeutic strategies.
M. El-

14. Circulation: Genomic and Precision Medicine
R
E
SE
A
R
C
HL
E
TT
E
R
Prevalence of Pathogenic Variants in Dilated
Cardiomyopathy–Associated Genes in Patients
Evaluated for Cardiac Sarcoidosis
Nosheen Reza ,MD*; Michael G. Levin ,MD*; Mahesh K. Vidula ,MD; Paco E. Bravo ,MD; Scott M. Damrauer ,MD;
Marylyn D. Ritchie ,PhD; Regeneron Genetics Center; C.Anwar A. Chahal ,MD,PhD; Anjali Tiku Owens ,MD
S
arcoidosis is a multisystem inflammatory disorder,
triggered by environmental, genetic, and immu-
nologic factors, that results in the formation and
maintenance of non-necrotizing granulomatous depo-
sition. Autopsy and cardiac imaging studies estimate
that among patients with sarcoidosis, 25% have cardiac
involvement (CS). Although there is a lack of consensus
diagnostic criteria for CS, cardiac magnetic resonance
imaging (CMR) and 18F-fluorodeoxyglucose positron
emission tomography (FDG-PET) are the best nonin-
vasive diagnostic tools for detecting myocardial inflam-
mation in CS. However, even in cases of high imaging
likelihood of CS, histological analysis has confirmed the
presence of findings consistent with arrhythmogenic
cardiomyopathy.1
Previous studies have demonstrated
phenotypic overlap between arrhythmogenic right ven-
Health System and provided consent regarding access
to biological specimens, genetic sequencing, and linkage
to available electronic health record data. This study was
approved by the Institutional Review Board of the Univer-
sity of Pennsylvania and complied with the principles set
out in the Declaration of Helsinki. The data that support
the findings of this study are available from the corre-
sponding author upon reasonable request.
DNAwasextracted fromstoredbuffycoats,andexome
sequences were generated by the Regeneron Genet-
ics Center (Tarrytown, NY)3
and mapped to GRCh38
(Genome Reference Consortium Human Build 38) as
previously described. Samples with low exome sequenc-
ing coverage, high missingness, dissimilar reported
and genetically determined sex, and genetic evidence
of sample duplication were not included. Samples with
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Circulation: Genomic and Precision Medicine
R
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HL
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Cardiac Sarcoidosis Mimickers: Genetic Testing in
Undifferentiated Inflammatory Cardiomyopathies
Matteo Castrichini ,MD; Kolade M. Agboola ,MD; Hridyanshu Vyas ,MBBS; Omar F. Abou Ezzeddine,MD,CM,MS;
Konstantinos C. Siontis ,MD; John R. Giudicessi ,MD,PhD; Andrew N. Rosenbaum ,MD; Naveen L. Pereira ,MD
C
ardiac sarcoidosis (CS) is a difficult to diagnose
inflammatory heart disease, which can present with
heart failure, ventricular arrhythmias, and atrioven-
tricular block.1
Emerging evidence suggests that genetic
cardiomyopathies can mimic inflammatory cardiomyopa-
thies, including CS.2
In this context, the utility of genetic
testing has not been completely explored,3
and data are
limited regarding the prevalence of genetic cardiomyop-
athies in patients with presumed CS.4
In the largest studyto date,we retrospectively included
213 patients evaluated from May 2020 to October 2022
in our CS Clinic diagnosed with presumed CS (169 with
isolated CS; 44 with systemic involvement) as inferred
by either fluorodeoxyglucose positron emission tomog-
raphy—
computed tomography or cardiac magnetic reso-
nance or both. Clinical, genetic, and imaging data were
extracted from the electronic medical record. The study
was approved by an institutional review committee and
p.Arg723Cys) and (c.5135G>A; p.Arg1712Gln),
and TTN (n= 2; c.70405C>T; p.R23469X) and
(c.91774C>T; p.R30592X) genes. Two patients
had two different P/ LP variants each, one involving
MYBPC3 and MYH7,and the other one with 2 different
TTN variants. Variants of uncertain significance were
identified in 21 (45%) patients, among whom rare vari-
ants of uncertain significance (5 patients), variants of
uncertain significance present in high tier cardiomy-
opathy genes (14 patients), and variants of uncertain
significance that qualified for family segregation stud-
ies (5 patients) were identified.
Although by univariate analysis there were differences
in the baseline characteristics of the population who
underwent genetic testing versus those who did not, as
summarized in the T
able, by multivariable logistic regres-
sion analysis,only the presence of coronary artery disease
(OR,0.25 [95% CI,0.09–0.68]) and extracardiac sarcoid-
Table. Baseline Characteristics of Patients With Presumed
Cardiac Sarcoidosis
Genetic testing
performed (n=47)
Genetic
testing not
performed
(n=166)
P
value*
P/ LP (10)
VUS/ nega-
tive (37)
Male n (%) 6 (60) 28 (76) 102 (62) 0.123
Age, y 49±12 57±12 61±11 0.135
Family history for car-
diomyopathy/sudden
cardiac death n (%)
3 (30) 4 (11) 9 (5) 0.054
Extracardiac
sarcoidosis n (%)
1 (10) 3 (8) 40 (24) 0.024
CAD n (%) 0 5 (14) 52 (31) 0.005
HF n (%) 6 (60) 28 (76) 118 (71) 0.567
Ventricular
arrhythmias n (%)
5 (50) 24 (65) 106 (64) 0.824
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15. 4/18/24, 2:11 PM Suddenly, It LooksLikeWe’rein aGoldenAgefor Medicine- TheNew York Times
https:/ / www.nytimes.com/ 2023/ 06/ 23/ magazine/ golden-age-
medicine-biomedical-innovation.html
We may be on the cusp of an era of astonishing innovation — the limits of
which aren’t even clear yet.
By David Wallace-Wells
June 23, 2023
Hype springs eternal in medicine, but lately the horizon of new possibility seems
“I’ve been running my research lab for almost 30 years,”
almost blindingly bright.
says Jennifer Doudna, a biochemist at the University of California, Berkeley. “And I
can say that throughout that period of time, I’ve just never experienced what we’re
seeing over just the last five years.”
A Nobel laureate, Doudna is known primarily for Crispr, the gene-editing Swiss
Army knife that has been called “a word processor” for the human genome and that
she herself describes as “a technology that literally enables the rewriting of the
code of life.” The work for which Doudna shared the Nobel Prize was published
more than a decade ago, in 2012, opening up what seemed like an almost limitless
horizon for Crispr-powered therapies and cures. But surveying the recent
landscape of scientific breakthroughs, she says the last half-decade has been more
remarkable still: “I think we’re at an extraordinary time of accelerating
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4/18/24, 2:11 PM Suddenly, It LooksLikeWe’rein aGoldenAgefor Medicine- TheNew York Tim
https:/ / www.nytimes.com/ 2023/ 06/ 23/ mag
medicine-biomedical-innovation.
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16. ClinicalTria
ls.org
“Active”
”Interventio
nal”,
“Cardiomyopa
thy”

17. ClinicalTria
ls.org
“Active”
”Interventio
nal”,
“Cardiomyopa
thy”
“Genetic”

18. Lessons Learned & Thank you.
• Uncertainty is an opportunity
• Make friends
• Structured assessments are critical
• Malleability
• If you build it, they will come