Surrogate Markers of Cardiac Disease: A Vital Tool in Patients
without Traditional Heart Failure Symptoms
Clinically HF is defined by abnormality of cardiac structure or function
leading to failure of the heart to deliver oxygen at a rate commensurate
with the requirement of the metabolizing tissues141. Assessing this
would require either invasive testing or are not practical for routine
clinical practice. For the purpose of guidelines and clinical practice,
HF is clinically defined as a syndrome in which patients have typical
symptoms (e.g. breathlessness, swelling and fatigue) and signs (e.g.
elevated jugular venous pressure, pulmonary crackles and displaced
cardiac apex) resulting from abnormality of cardiac structure or
function. It has been reported that the diagnosis of HF even in patients
with traditional HF can be difficult because many symptoms of HF are
non-discriminating and of limited diagnostic value142-144. However,
demonstration of the underlying cardiac cause remains the central tenant
of diagnosis of HF and is usually myocardial disease causing systolic
ventricular dysfunction but can be from other causes. Identification of
the underlying cardiac problem is also crucial for therapeutic reasons,
as the precise pathology determines the specific treatment used.
The main terminology used to describe HF is historical and is based on
measurement of LVEF. The worse the systolic dysfunction the lower the
LVEF which is considered important in HF management not only because its
prognostic importance (the lower the LVEF the poorer the survival) but
because most clinical trials selected patients based upon LVEF. The used
of LVEF in conjunction with signs and symptoms typical of HF drives
clinical practice and are used in clinical trials to determine outcomes
of many therapies. Clinical assess of HF severity is based on the New
York Heart Association (NYHA) functional classification and just like
LVEF has been used to select patients in almost all randomized treatment
trials of HF treatment. The details of the NYHA classification are
beyond the scope of this review but a categorized into four classes with
NYHA class one having no symptoms attributable to heart disease and
class four with severe symptoms. Though NYHA drives clinical care and is
used in outcomes research, studies have shown that symptom severity
correlates poorly with ventricular function57,
145. HF signs and symptoms used in
conjunction with NYHA classification can be challenging as they are
nonspecific and therefore do not completely discriminate between HF and
other problems and thus can be insensitive142-144,
146. Multiple studies have shown that
symptoms and signs of HF may be particularly difficult to identify and
interpret in obese individuals, in the elderly, and in patients with
chronic lung disease147-150. The
assessment of HF signs and symptoms in patients with neuromuscular
disease is even more challenging due to skeletal muscle and pulmonary
disease limiting ambulation and masking HF symptoms.
A review of the DMD literature frequently includes comments on HF but
very few report HF systems and many of the studies cite both skeletal
muscle myopathy with muscle weakness and loss of ambulation as well as
respiratory muscle weakness masking HF signs and symptoms. Nigro et al,
reported that even with clinically evident cardiac disease 72% have no
HF symptoms. When looking at a group of DMD patients the most severe
cardiomyopathy only 57% reported cardiac
symptoms19. However,
the cardiac symptoms were not specified or defined. Newer reports in DMD
monitoring frequently comments on the importance of monitoring for signs
of HF yet many report concerns that skeletal and respiratory muscle
weakness limits the ability to assess for HF symptoms. Given that the
majority of DMD patients show no classic HF symptoms even in advance
stages clinical care that rely on these symptoms are frequently delayed
and result in late initiation of cardiac therapy39. The recommended HF
symptoms to monitor by various DMD parent organization includes being
more tired than usual, weight loss, vomiting, belly pain, not sleeping
well, trouble doing normal daily activities and chest pain. These signs
and symptoms unfortunately are nonspecific and are frequently absent.
DMD patients frequently report lower extremity edema and orthopnea but
denied HF symptoms of paroxysmal nocturnal dyspnea, chest pain,
palpitations, lightheadedness or syncope despite having advance disease151.
To illustrate the challenges of assessing HF symptom in DMD patients
with both skeletal and respiratory muscle weakness our patient started
seeing cardiology at age starting at 6 years of age with yearly visits
and echocardiogram. Early on, his visits included normal LV function by
echocardiogram and no cardiac symptoms. By age 14 years he developed
mild ventricular dysfunction with a LVEF of 48% (down from 61% a year
ago) but denied any HF symptoms and started on lisinopril and visit
interval decreased. His function continued to decline despite escalating
cardiac therapy including lisinopril, eplerenone and carvedilol (Fig 9).
By age 16 years, his LV function was severe and a CMR confirmed diffuse
areas of fibrosis wth an LVEF of 25% and he was started on milrinone
infusion therapy. He still denied HF symptoms besides general fatigue
and weakness. A follow-up CMR reported no change to his LVEF so he was
placed on an LVAD at age 18 years due to the inability to wean him off
of milrinone. Over the last year his LVEF continue to be around 20% and
now his right ventricular function has become severe. Similar to this
patient, a review of our clinical DMD patients with abnormal LVEF, none
reported classic HF symptoms and HF classification using NYHA
classification was not able to be applied due to skeletal and
respiratory muscle weakness in the majority of patients. This case
scenario demonstrates the lack of HF symptoms despite advanced DMD-CM
and limited utility of TTE LVEF to detect early disease and potentially
lead to delayed treatment. As such, recent DMD cardiac care guidelines
have attempted to address this issues and recommends using advance
cardiac imaging early in the disease process64,
65, 67.