HCM SCD Risk stratification. Differences between ACC and ESC outlook.

1. HCM-SCD
RISK STRATIFICATION
Dr Aatish Rengan Preceptor: Dr Satyavir Yadav

2. Layout
• Incidence of SCD
• Mechanisms of SCD
• Risk factors for SCD
• Evolution of Risk Stratification strategies

3. Sudden Cardiac
Death
Responsible for ~ 50%
of all CV deaths
As per the Resuscitation
Outcomes Consortium
(ROC) registry of
OOHCA from 2005 to
2015; the incidence of all
EMS-assessed cardiac
arrests was 110.8 per
100,000.
Wong C et al. Epidemiology of SCD. Heart Lung Circ 2019.

4. SCD - HCM
The prevention of SCD represents the most complicated challenge with respect to HCM.
◦ SCD is the most common cause of death in HCM and often affects young and frequently asymptomatic
patients. (1)
◦ The annual SCD rate is <1%, but there are subgroups with much higher incidence.
◦ Most common cause of SCD in young athletes in the United States;
As per National Registry of SCD in Athletes - HCM accounted for 36% of all SCD events in young athletes (2)
Maron BJ et al. Circulation 2000.
Maron BJ et al. Circulation 2009.

5. Mechanisms of SCD in HCM
◦ Mediated primarily by VF
- Precipitated by runs of VT, rapid AF or accelerated AV conduction
◦ Asystole, PEA and advanced AV blocks have also been associated with SCD in HCM
Krikler DM et al. Br Heart J 1980
Chmielewski CA et al. Am Heart J 1977

6. Pathophysiology

7. Structural and electrical changes
Abnormal Ca handling
- Increased myofilament Ca+ sensitivity
- Persistence of Ca+ handling proteins
Myocyte disarray and fibrosis promoting re-entry
Intercalated disc disruption

8. Ischemia in HCM
SCD risk score and presence of
myocardial bridges were independent
risk factors for fatal ventricular
arrhythmias in patients with HCM.
The HCM–MB study. Güner A et al. Herz April 2023 Pelliccia F et al. J Clin Med 2022 Nov.

9. Autonomic dysfunction in HCM
U Limbruno et al. Eur Heart J 1998.
Selective impairment of HR variability with deep breathing and
Valsalva manoeuvre indicating decreased cardiac parasympathetic
activity.

10. Role of physical exertion
Effect of changes in the following have been implied:
- Sympathetic discharge
- Electrolyte/acid-base disturbances
Exercise-induced ventricular arrhythmias, present in 1-2% of
patients with HCM, are independently associated with SCD
(multivariable HR 3.14; P=0.01). – (2)
Maron BJ et al. Circulation 1982
Gimeno JR et al. Eur Heart J 2009

12. Risk factors

13. FAMILY
HISTORY
OF SCD

14. ◦ Aggregation of SCD in families of patients with HCM
◦ Most studies have used an age cut-off of 40-50 years and have considered only first-degree relatives (>1).
◦ In a systematic review conducted in 2010
Many studies did not demonstrate a significant association.
However, 3 recent large studies – Independent (but weak) predictor of SCD
The average hazard ratio of FHSCD was 1.27 (95% CI, 1.16–1.38).
Teare D. Br Heart J 1958
Maron BJ. Am J Cardiol 1978
Christiaans I et al. Systematic review of clinical risk markers. Europace 2010

15. ◦ HCM ICD registry, 383 patients with HCM underwent ICD
placement for primary prevention based on the presence of
atleast 1 of the conventional risk factors, with an appropriate
intervention rate for VT/VF of 3.6% per year over the
follow-up period.
◦ A substantial proportion of these patients underwent ICD
implantation based on the presence of only 1 conventional
risk factor.
◦ The rate of appropriate ICD interventions for patients
undergoing implantation based only on family history
was substantial (2.7 per 100 person-years) Maron BJ et al. JAMA 2007

16. Role of genetic studies
The effect of FHSCD on SCD is related to the genetic nature
of the disease.
Affected relatives share the same genetic defect and, to some
degree, have similar environmental exposures.
Few early studies of HCM pedigrees implicated certain
mutations as “malignant.”
However, subsequent studies of unselected consecutive
patients with HCM found no significant association
between the rate of SCD events and “malignant”
mutations.
Whether genetic information improves risk stratification
for SCD over and above phenotypic markers is not
known.
Marian AJ et al. J Cardiovasc Electrophysiol. 1998

17. DEGREE
OF LVH

19. ◦ Maximum Left Ventricular Wall Thickness (MLVWT)
Maximum end-diastolic dimension of any segment of LV measured in SAX view.
◦ In a systematic review of risk markers of SCD in HCM conducted in 2010, the average HR for severe LVH
was 3.1 ( 95% CI 1.81–4.4)
Christiaans I et al. Systematic review of clinical risk markers. Europace 2010

20. LIMITATIONS
Significant inter-observer variability on echocardiography.
Almost all the studies have considered it as a binary variable instead of a continuous variable.
The thickness of a single myocardial segment may not adequately represent the true burden of hypertrophy.
Hence, alternate scoring systems – Eg: Wigle scoring system. (1)
MLVWT measurements by echocardiography and MRI are discrepant. – (2)
Using MRI to estimate the HCM-SCD Risk led to reclassification of upto 14% of patients - (3)
Elliot PM et al. The Lancet 2001.
Bois JP et al. Am J Cardiol 2017.
Spiewak M et al. Sci Rep 2021.

21. Elliot PM et al. The Lancet 2001.
Wigle Scoring System

22. UNEXPLAINED
SYNCOPE

23. NEURALLY
MEDIATED
SYNCOPE
SUSTAINED
VENTRICULAR
ARRHYTHMIAS
ORTHOSTATIC
HYPOTENSION
EXERCISE-
RELATED
LVOTO
BRADY
ARRHYTHMIAS
Spirito et al in 2009 - Syncope of unknown origin, when it occurred in circumstances not clearly consistent
with a neurally mediated event, ie, without apparent explanation at rest or during ordinary daily activities, or
during an intense effort”.

24. ◦ Spirito et al demonstrated that relative risk of SCD in patients with recent unexplained syncope (<6months)
was five-fold higher than that in patients without syncope.
However, older patients (≥40years of age) with remote episodes of syncope (>5years before initial
evaluation) did not show an increased risk of SCD. (1)
◦ In a multicentre longitudinal cohort study of 3675 patients followed up for 24313 patient-years,
On univariable Cox regression analysis, Unexplained syncope - Significantly associated with SCD. (2)
Spirito P et al. Circulation 2009
C. O’Mahony et al. Eur Heart J 2014

25. NSVT

26. ◦ Most studies that demonstrated a significant association between NSVT and SCD defined NSVT as ≥3
consecutive ventricular beats at a rate of ≥120 beats/min lasting <30 seconds.
◦ The risk of SCD associated with NSVT may be lower in older patients.
Monserrat et al - NSVT in patients aged ≤30 years: 4-fold increase in the risk of SCD (univariable HR, 4.35;
95% CI, 1.54–12.28; P=0.006)
But no effect in older patients (univariable HR, 2.16; 95% CI, 0.82–5.69; P=0.1).
◦ Another study suggested that NSVT is predictive of SCD only when it occurs repeatedly or is associated
with symptoms.
Monserrat J et al. J Am Coll Cardiol 2003.
Spirito P et al. Circulation 1994.

27. Earlier studies failed to show a significant
association between NSVT and SCD, however
the wide confidence intervals indicated that an
association could not be excluded.
With increasing patient numbers in
more recent studies, NSVT proved to be a
significant independent risk factor for SCD,
especially in the young.
Christiaans I et al. Systematic review of clinical risk markers. Europace 2010

28. n = 160 HCM (ICD implanted)
86 (54%) patients had NSVT runs
21% patients with NSVT vs 8% without NSVT – Experienced ICD treated VT/VF
NSVT was significantly associated with ICD-treated VT/VF (adjusted HR, 3.98; P=0.0093)
NSVT was most predictive of future ICD shock for VT/VF when :
- FASTER (Rate > 200)
- LONGER (> 7 beats)
- FREQUENT (> 1 episode)

29. LVOTO

30. RR 2.1 (95% CI 1.1-3.7)
Likelihood of SCD was greater among patients
with LVOTO than among those without
obstruction, although the difference in the
annual rate of SCD was small (0.6% per year)

31. • 917 HCM patients
• Median follow-up of 61 months (30-99 months)
• Multivariable analysis - LVOTO was an independent predictor of SD/ICD, with HR 2.4 (p=0.003)
• LVOTO (>= 30mmHg) - Reduced 5-year survival from SCD and ICD discharge (91.4% vs. 95.7%).
• Magnitude of LVOTO was related to a higher occurrence of SCD/ICD,
RR per 20 mmHg = 1.36 (p = 0.001)

32. ◦ Similarly, in a study of 307 HCM patients with a mean follow up of 9.4 years
◦ On multivariate analysis – LVOTO independent predictor of SCD (p=0.003)
5-year :
89% vs 97%
10-year :
82% vs 92%
15-year :
78% vs 87%
Maki S et al. Am J Cardiol 1998.
Patients with LVOTO > 30mm Hg had a poorer SCD-free survival

33. Impact of septal reduction therapy on SCD
◦ A study from Toronto - 338 patients - Myectomy - only 4% mortality from SCD at 5 years - (1)
◦ Another study - Compared to matched non-operated HOCM patients, myectomy patients had superior SCD-
free survival (p=0.003) - (2)
Woo A et al. Circulation 2005
Ommen SR et al. J Am Coll Cardiol 2005
10 year SCD-free survival: 99% vs 89%

34. ◦ A similar trend has been observed also after ASA, with lower SCD rates (0.5%/year in the entire cohort,
0.6%/year in the group with expected high-risk) than the expected risk of 4% for the high-risk patients. – (1)
◦ In a meta-analysis comparing septal reductive therapies for HCM, similar low rates of all-cause mortality
and SCD were found following either ASA or surgical myectomy. – (2)
After adjustment for available baseline characteristics, the odds ratios for treatment effect on all-cause
mortality and SCD were 0.28 (95% CI 0.16–0.46) and 0.32 (95% CI 0.11–0.97), respectively, favoring ASA.
Jensen MK et al. Heart 2013
Leonardi AR et al. Circulation 2010.

35. SBP
RESPONSE
TO
EXERCISE

36. ◦ A blunted systolic blood pressure response to exercise (SBPRE) was first noted in a study of 6 patients with
HCM in 1970
◦ Subsequently, in 129 patients - maximal symptom-limited treadmill exercise test.
Approximately, 1/3rd of patients exhibited an abnormal SBPRE - associated with a younger age and
a family history of SCD (FHSCD), but not LVOTO or severe hypertrophy.
◦ The exact mechanism behind exercise-induced hypotension is unclear, but hemodynamic studies suggest that
in the majority of cases, an inappropriate drop in systemic vascular resistance despite an appropriate
increase in cardiac output, is responsible.
Frenneaux MP et al. Circulation 1990
Counihan PJ et al. Circulation 1991

37. Sadoul N et al - Prognostic significance of abnormal SBPRE in 161 HCM patients aged <40 yrs.
Abnormal SBPRE :
Hypotensive SBPRE - Initial increase in systolic BP with a subsequent fall by peak exercise or a continuous
decrease in systolic BP of >20 mm Hg.
Flat response - Rise in systolic BP of <20 mm Hg during the whole exercise period.
Mean follow-up of 44 months - SCD in 12 patients:
3 (3%) in the normal blood pressure response group VS 9 (15%) in the ABPR group (P<.009)
No significant difference in the incidence of other recognized risk factors

38. However, not independently associated with SCD in any multivariable survival analysis
In the systematic review by Christiaans I et al, abnormal SBPRE failed to show a significant association with
SCD.
Christiaans I et al. Systematic review of clinical risk markers. Europace 2010

39. LV Apical Aneurysm (LVAA)
◦ Estimated prevalence in HCM: 2-5%
2D echo often unreliable in detecting smaller aneurysms compared to CMR
Rate of missed diagnosis compared to CMRI – Around 50% - (1,2)
◦ Contrast echocardiography - Equivalent detection rates compared to CMR – (3)
Recommended in patients with suboptimal 2D echo images.
◦ On follow-up of 93 HCM patients with LVAA, the SD/ICD event rate was 4.7%/year. (4)
However, size of the aneurysm was not shown to affect the risk of SCD (5)
Maron MS et al. Circulation 2008.
Yang K et al. Eur Heart J CV Imaging 2020.
Lee DZJ et al. JASE 2021.
Rowin EJ et al. JACC 2016.
Adamczak DM et al. Cardiol Rev 2018.

40. Systolic Dysfunction (Burnt-out HCM)
◦ In a multi-centre cohort of 3675 HCM patients – follow-up period of 24313 patient years
Exploratory univariable analysis - Fractional shortening was not significantly associated with SCD risk. – (1)
◦ However, compared to HCM with preserved EF, HCM-EF<50% was seen to have significantly higher
appropriate ICD interventions, resuscitated cardiac arrests and sudden death event rate.
20% of patients with EF <50% eventually had appropriate ICD therapy and importantly, over two-thirds of those
events occurred with EF 35% to 49% – (2)
C. O’Mahony et al. Eur Heart J 2014.
Rowin EJ et al. JACC 2020.

41. Other risk markers
◦ LA size, AF
LA size – Summative measure of abnormal diastolic function, MR and atrial arrhythmias
In patients without documented AF, LA size (>48mm) - Independent determinant of SCD risk - (1)
In a meta-analysis, AF – increased risk of SCD in HCM (RR 2.05, p = 0.01) – (2)
◦ Age
Traditionally - SCD preferentially in asymptomatic/mildly symptomatic children and adults < 35 years.
Spirito et al found that SCD risk decreases significantly with age – (3)
Minami Y et al. J Cardiol 2016
Rattanawong P et al. Journal of Interventional Cardiac Electrophysiol 2018
Spirito P et al. Circulation 2009.
Rowin EJ et al. JACC 2020.

42. CMR - LGE
◦ Chan RH et al assessed LGE in 1293 HCM patients – Median follow up of 3.3 years
Continuous relationship between extent of LGE and SCD/ICD event risk
LGE ≥15% of LV mass - 2-fold increase in SCD event risk in otherwise low-risk patients
LGE ≥15% of LV mass - Estimated likelihood for SCD events of 6% at 5 years
Absence of LGE was associated with lower risk for SCD events (adjusted HR, 0.39; P=0.02).
◦ Meta-analysis of 7 studies - Presence of LGE - increased risk for SCD (OR: 3.41; p < 0.001).
After adjusting for baseline characteristics, extent of LGE remained strongly associated with the
risk of SCD (HR adjusted: 1.36/10% LGE; p < 0.005)
Weng Z et al. JACC 2016.

43. The distribution of the LGE also plays an important predictive role
◦ The number of nonseptal LGE segments has been shown to be significantly related to VT/VF.
By contrast, septal LGE was not related to VT/VF in patients with HCM and LGE.
Amano Y et al. J Comput Assist Tomogr 2017.
Klopotowski M et al. Journal of Cardiology 2016.

44. ◦ 44 Normal individuals
34 Athletes
87 HCM-patients
29 HCM-patients with sudden death or cardiac arrest (HCM-CA).
◦ A risk score was proposed.
Optimal separation between HCM-CA <40 years and athletes was obtained by a risk score >/= 6
(Odds Ratio 345, sensitivity 85%, specificity 100%, p< 0.0001)

45. Evolution of Risk
Stratification

46. 2003 2011
2003 ACC/ESC HCM Clinical Consensus Statement
1. LVOTO
2. LGE on CMR
3. LVAA
4. Double/compound
mutations

47. 2014
Risk prediction model using predictors independently
associated with SCD in published multivariable survival
analyses.
Inclusion of factors like MLVWT and LVOTO as
continuous variables.
Unique contribution of each risk factor to the
predicted SCD risk.

49. ◦ The clinical implications of using the HCM-SCD Risk model were examined in 3066 patients with the
necessary data.
◦ The 5-year SCD risk estimates that correctly identified the maximum number of SCD endpoints at 5 years
and simultaneously minimized ICD implantation in patients without the SCD endpoint were :
≥6% for patients with ≥2 conventional risk factors
≥4% for patients with a single risk factor
◦ A 5-year SCD risk of ≥4% identified 71% of SCD endpoints with 30% ICD implants in patients
without SCD at 5 years.
- NNT 16
C. O’Mahony et al. Eur Heart J 2014

51. 2020
The 2020 ACC/AHA guidelines revised the
previous 2011 recommendations
Integrated clinical + imaging based
recommendations for ICD.
Additions:
- Apical aneurysm (Major)
- EF </= 50% (Major)
- LGE >/= 15% on CMR
*Abnormal BP response was removed

52. Maron MS et al. JAMA 2019

53. Retrospective analysis of 784 HCM patients
During follow-up - 47 (6%) patients developed an SCD event

55. Excluded from all studies. So no
data on the incidence of SCD/risk
stratification

57. CASE
◦ Mr AJ 27 year old
◦ NYHA II dyspnea on exertion
◦ H/o Syncope – On walking – More during summers – 3 episodes
◦ No H/o cardiac arrest
◦ Family History : (?) Valvular disease – Operated (No documents)
Sudden cardiac death at 25 years of age
◦ Holter – No NSVTs
◦ ECHO: - Normal LV function, MLVWT – 22mm
- Peak LVOTO : 27mmHg at rest, 50 mmHg on Valsalva [On Metoprolol 50mg]

58. TAKE-HOME MESSAGES
HCM-SCD risk stratification is still evolving.
The predicted SCD risk from clinical markers should be further augmented with imaging findings
like CMR-LGE.
Individualised risk estimation using systems like HCM-SCD Risk which assimilate weighted
contributions from all proven risk factors need to be honed further to improve sensitivity.
Genetics may play a role in individualising risk prediction in the future.

59. Dr Barry J Maron and his son, Dr Martin S Maron

60. THANK YOU