HCMR - Novel Predictors of Outcome in Hypertrophic Cardiomyopathy.

While the majority of patients with hypertrophic cardiomyopathy (HCM) remain
asymptomatic, the prognosis is poor in a subset of affected individuals who
present with Sudden Cardiac Death (SCD) or progress to heart failure (HF).
Current clinical methods to assess risk of these adverse events and to target
therapy are limited. The currently accepted risk predictors for SCD as
indication for primary prevention with implantable cardioverter defibrillators
(ICD) include: (1) family history of HCM-related SCD, (2) unexplained recent
syncope, (3) massive left ventricular hypertrophy (LVH) (thickness >=30 mm), (4)
multiple bursts of non-sustained ventricular tachycardia on ambulatory
electrocardiography and (5) hypotensive or attenuated blood pressure response
to exercise.1 However, these risk factors are incomplete as sudden death events
still occur in clinically identified patients with 0 or 1 risk factor,
currently considered low risk.2 ICD placement for primary prevention based on
these 5 risk factors was associated with appropriate therapy rates of 17% over
5 years and rates of inappropriate shocks and complications of 27% and 20%,
respectively.2 Thus, improvement is needed over and above current clinical risk
stratification in order to reduce morbidity and lifetime costs of treatment. In
addition, currently used risk factors do not reflect key underlying
pathophysiologic processes such as myocardial fibrosis. Fibrosis and
replacement scarring due to small vessel ischemia are prominent features of HCM
and are implicated in promoting HF (due to diastolic dysfunction or LV
remodelling and systolic dysfunction) and creating risk for SCD. Therefore,
this study will identify potential targets for therapeutic intervention using
existing or novel drug therapy, leading to new approaches for altering the
underlying abnormal substrate responsible for SCD and HF. Accordingly, a recent
NIH working group report on research in HCM3 specifically recommended a
prospective natural history study to enable identification of such risk
markers.

Primary:
To understand the relationship between novel risk markers (based on the
following) and clinical outcome.

Secondary:
Developing a score from the predictive model that can be used to assess risk
given a patient*s combination of risk factors.

This is an international, multi-centre, observational, prospective study of
patientsinvolving sites in the UK, Italy , Netherlands and Germany with
clinically diagnosed HCM, studied at baseline with will be invited to attend
one study visit followed by a yearly telephone call. At this visit there will
be collection of demographic data, clinical risk factors, CMR imaging for novel
markers from CMR, genotyping, and serum biomarkers of collagen turnover and
myocardial injury, enrolled. Enrolment will take place over a 2-year period
and follow-up by annual telephonefollowed for 3-5 years (mean of 4 years), by
annual telephonefollowed for at least 10 with annual telephone follow-up.

Risks
1. Blood Draw and IV Placement:
The risk of IV line placement and blood draw are of bruising, bleeding, and
local infection. A vagal reaction and fainting due to either procedure is quite
rare (<1%).
2. CMR:
CMR is a safe and non-invasive technique with no known risk when appropriately
supervised. It does not involve ionising radiation (X-rays). Potential
participants with ferromagnetic objects in their bodies or with implanted
devices which can be damaged by the CMR magnet will be excluded. All
participants entering the scanner room are screened for such objects. The site
is fully equipped for resuscitation (including defibrillation) in the unlikely
event of a medical emergency during scanning.
While most people do not experience discomfort in a MRI environment, the
enclosed space of the scanner can potentially feel uncomfortable, especially
for more elderly participants. Discomfort from lying still for a long period of
time will be minimised with comfortable padding and positioning. People with a
history of severe claustrophobia would be excluded from participation in the
study. Participants will be given a chance to see the scanner before the study
starts. All participants would be introduced carefully to the scanner and
allowed to leave at any stage, should they wish to do so. Once in the scanner,
participants would be able to indicate immediately if they wish the scanning to
cease by squeezing a bulb placed in their hands, or by requesting it verbally.
As the MRI scanner is noisy, participants can be provided with ear plugs and/or
headphones to reduce noise and aid communication between them and the
investigators.
3. Gadolinium:
Gadolinium contrast is widely used for clinical indications in CMR and is safe.
Occasionally it may cause a mild headache, rash and very rarely (< 1 in 1000) a
more severe allergic reaction. These side effects are reversible upon stopping
the infusion. However, in people with reduced kidney function, it can lead to a
rare condition, nephrogenic systemic fibrosis (NSF); hence, as per departmental
guidelines based on Food and Drug Administration guidelines, all research
participants with estimated glomerular filtration rate (eGFR) <30ml/min (stage
3-5 renal disease) should not be given gadolinium. For this study, all
potential participants with eGFR <30ml/min will not be recruited. If there is
no laboratory blood result for creatinine within the last 30 days or
investigators make a clinical judgement that a new creatinine result is needed,
a pre*scan blood test to check their kidney function will be performed. No
gadolinium will be given before this result is available. The SISICF explains
this to participants.

Benefits:
For the participants, this study would require their time and would not
directly provide any benefit to the participants themselves.