Physiologic Assessment of Microvascular Function in Patients With Cardiac Amyloidosis

Amyloidosis is rare systemic disorder characterized by the extracellular deposition of misfolded protein in various organ system, including heart. Among the several types of amyloid fibrils, the light chain and transthyretin amyloid proteins most commonly affect the heart.

Cardiac amyloid deposits result in increased ventricular wall thickness and produce a restrictive cardiomyopathy presenting primarily as biventricular congestive heart failure. Anginal symptoms and signs of ischemia have been reported in some patients with cardiac amyloidosis without obstructive epicardial coronary artery disease (CAD). Autopsy studies have shown amyloid deposits around and between cardiac myocytes in the interstitium, the perivascular regions, and the media of intramyocardial coronary vessels. Amyloidosis is thus a prime example of a disorder with the potential to cause coronary microvascular dysfunction via 3 major mechanisms: (1) structural (amyloid deposition in the vessel wall causing wall thickening and luminal stenosis), (2) extravascular (extrinsic compression of the microvasculature from perivascular and interstitial amyloid deposits and decreased diastolic perfusion), and (3) functional (autonomic and endothelial dysfunction).

Previous basic research presented that adipose arteriole or atrial coronary arterioles showed endothelial dysfunction even after brief exposure to physiologic amounts of light chain, and also showed increased oxidative stress, reduced NO bioavailability, and peroxynitrite production. All these previous evidences imply that coronary microvascular dysfunction and subsequent global ischemic insult can be precursor of overt diastolic or systolic dysfunction in patients with cardiac amyloidosis.

However, there have only 1 study which evaluated microvascular function in vivo using N13-ammonium positron emission tomography (PET). In that study, Dorbala et al. demonstrated that amyloidosis patients showed depressed global resting myocardial blood flow (MBF), stress MBF, and CFR and higher minimal coronary vascular resistance, compared with patients with left ventricular hypertrophy. However, low availability, high cost, and limited resolution of N13 ammonium PET precludes the generalizability of the results.

Since thermodilution-derived coronary flow reserve and index or microcirculatory reserve using pressure-temperature wire has been well validated prognostic index in assessment of patients with coronary artery disease or functionally insignificant epicardial coronary stenosis, invasive physiologic assessment might more specifically assess macro- and microvascular function in patients with cardiac amyloidosis. Moreover, adding physiologic measurement in the current frame in diagnosis of cardiac amyloidosis might enhance risk stratification of patients.

Therefore, the current study will perform physiologic assessment including fractional flow reserve, coronary flow reserve, and index of microcirculatory resistance in patients with cardiac amyloidosis, and explore correlation among the physiologic indices and conventional measurements of echocardiography, perfusion MRI, serum light chain amount, or NT-proBNP. In addition, the differences of physiologic indices according to disease severity of cardiac amyloidosis, which measured by endomyocardial biopsy findings will be also explored. Since there was no previous study which performed invasive physiologic assessment in amyloidosis patients, this study will be performed as pilot study. Target sample size will be at least 30 patients.

• Correlation between IMR and echocardiographic parameters [Time frame: within 3 months of diagnosis]
• Correlation between IMR and serum biochemicalmarkers [Time frame: within 3 months of diagnosis]
• Distribution of CFR or IMR according to pathologic severity of myocardial involvement [Time frame: within 3 months of diagnosis]
• Comparison of CFR or IMR value in amyloidosis patient with or without relative perfusion defect in myocardial perfusion imaging (ex> adenosine-SPECT or perfusion MRI) [Time frame: within 3 months of diagnosis]
• Comparison of CFR or IMR value in different type of amyloidosis (AL type, hereditary type, AA type, senile type) [Time frame: within 3 months of diagnosis]
• Comparison of CFR or IMR value in amyloidosis patient according to current staging by Troponin T, NT-proBNP and free light chain difference [Time frame: within 3 months of diagnosis]
• Optimal cut-off values of physiologic indices (CFR, IMR) for prediction of all-cause mortality [Time frame: 2 Years]
• Association between physiologic indices and pathologically measured percent area involvement in myocardial interstitium [Time frame: within 3 months of diagnosis]