Targeting LOXL2 and Cardiac Fibrosis for Post-acute Heart Failure Treatment- A Prospective Study

A previous study demonstrated that a multidisciplinary cardiac rehabilitation (CR) program was associated with reduced medium- to long-term all-cause mortality in a retrospective propensity score-matched study. The investigators will further investigate the predictors including LOXl2, cardiac MRI, and endothelial function that will benefit from a successful CR.

Acute heart failure (HF) is a major cause of morbidity and mortality worldwide. The Taiwan national health insurance launched HF post-acute care program with a multi-discipline treatment strategy to improve care quality and reduce the readmission rate on July 1, 2017. A previous study showed heart failure disease management program (HFDMP) is beneficial for reducing recurrent events of HF readmission, especially in the ischemic cardiomyopathy population. The key element of HFDMP is cardiac rehabilitation and exercise training. Lysyl oxidase-like 2 (LOXl2) is an enzyme, which crosslinks collagen in fibrotic processes such as liver cirrhosis, lung fibrosis, cardiac fibrosis, and heart failure. An animal study showed the correlation between cardiac fibrosis and LOXl2 serum level. In a previous clinical prospective cohort study (CMRPG8H1271), the investigators recruited 40 patients who were discharged from acute decompensated heart failure. During the follow-up period, 10 patients suffered from cardiovascular mortality. The investigators found that the LOXl2 level is higher in patients with mortality than without.

Cardiac fibrosis is characterized by systolic or diastolic dysfunction that results from the accumulation of extracellular connective tissue proteins in the heart's interstitium. Both clinical evidence and experimental studies have suggested that fibrotic changes in the heart are reversible.

The investigators hypothesize that multi-disciplinary cardiac rehabilitation could reverse cardiac fibrosis by decreasing LOXl2 levels and improving endothelial function via reversing endothelial to mesenchymal transition (EndMT). The investigators will enroll 126 post-acute HF patients in 3 years. The investigators will follow up on endothelial function, and LOXl2 level 6 months later. The investigators will also arrange cardiac MRI sequences, such as balanced steady-state free precession (SSFP) and late gadolinium enhancement (LGE) for the diagnosis of cardiac fibrosis. A cardiopulmonary exercise test will be arranged after discharge for phase II cardiac rehabilitation. The investigators will use all-cause mortality and HF hospitalization as our primary endpoint, life quality scores (KCCQ12), and peak VO2/kg as our secondary endpoint.

Eligibility Criteria:
Inclusion Criteria:

1. Patients must give written informed consent before any assessment is performed.
2. Inpatients \>= 20 years of age, male or female.
3. Patients with a diagnosis of heart failure New York Heart Association (NYHA) class II-IV with BNP \>=100 pg/mL or NT-porBNP \>= 400 pg/mL ( \>= 900 pg/mL if concomitant atrial fibrillation)
4. Left ventricular ejection fraction \<= 40% by echocardiography or other methods

Exclusion Criteria:

1. Estimated survival time \< 6 months
2. Long-term bedridden for more than 3 months
3. Cannot tolerate exercise test due to muscular skeletal disorder.
4. Cannot cooperate all functional studies
5. Ventilator dependent
6. Terminal heart status
7. Family rejects to participate in this project
8. Primary severe valvular heart disease