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.