In April 2017, I was diagnosed with heart failure, with an ejection fraction of only 35% (normal is over 60%, and just six months prior, it was 65%). I spent most of my days lying in bed, and during a six-minute walk test, I could only work less than a hundred meters. In the hospital, I needed to use a wheelchair to move around. This was particularly shocking since I had been quite active just six months earlier. I was only 22 years old, and the cause of my heart failure was extremely rare.
In 2013, I underwent mitral valve repair surgery due to infective endocarditis. After that, I had mild to moderate mitral regurgitation, but my heart function remained normal, with occasional issues of arrhythmia that I managed well. Starting in September 2016, I began taking one tablet of metoprolol (Betaloc) daily. By January 2017, I started feeling frequent episodes of rapid heartbeat and palpitations, so I stopped taking metoprolol .
In April 2017, during a particularly humid period, I suddenly experienced chest pain, and my physical condition deteriorated day by day. Initially, I suspected it was a myocardial infarction, but tests for biomarkers, including CK–MB isoenzyme and BNP, remained normal. It wasn’t until April 18 that an echocardiogram revealed my ejection fraction was only 35%, confirming the heart failure diagnosis.
If you look at heart failure as a broad category, various guidelines indicate that, on average, the one-year mortality rate for patients discharged from heart failure centers in China was 4.5% in 2021. The mortality rate for heart failure is higher than for many cancers, and the related treatments generally focus on extending survival. Cases where ejection fraction returns to normal are extremely rare. At that time, I felt that life had turned gray.
In 2017, the classic treatment for heart failure consisted of three types of medications, usually taken together: aldosterone receptor antagonists (diuretics), beta-blockers (to reduce heart rate), and ACE inhibitors/ARBs (to lower blood pressure). I had been taking metoprolol, a beta-blocker, for over six months. Ironically, I developed heart failure while on a medication meant to treat it. After discussing this with my doctor, he prescribed me an aldosterone receptor antagonist and an ACE inhibitor, sympathetically noting, “You’re still so young; let’s see how this goes.”
That evening, I began researching related information and came across a paper published in 2013 by Min Pu et al., titled “Effects of Early, Late, and Long-term Nonselective β-Blockade on Left Ventricular Remodeling, Function, and Survival in Chronic Organic Mitral Regurgitation.”https://www.ahajournals.org/doi/pdf/10.1161/CIRCHEARTFAILURE.112.000196 The study explored the effects of non-selective beta-blockers on left ventricular remodeling caused by mitral regurgitation. They used another beta-blocker, Carvedilol, in their experiment.
The study involved 87 rats, with 44 in the control group and 43 in the experimental group. All rats underwent modeling for mitral regurgitation, and the experimental group was given the beta-blocker Carvedilol. Alarmingly, the heart function of the rats in the beta-blocker group started to decline significantly compared to the control group from the sixth week onward, with deaths occurring in the experimental group starting at 17 weeks. Min Pu and his team conducted this experiment because there was a hypothesis in the academic community that beta-blockers could protect the heart and mitigate left ventricular remodeling caused by mitral regurgitation. However, their results indicated a negative outcome, suggesting that beta-blockers might actually be harmful to patients with mitral regurgitation.
I took metoprolol from September 2016 until I stopped in January 2017, for a total of 20 weeks. This timeframe coincided closely with when the rats in the experimental group began to show mortality. The paper noted that, in the later stages of the experiment, the authors stopped administering beta-blockers to some of the rats, which is similar to my situation of discontinuing the medication. The survival rate of the rats that had their beta-blockers withdrawn was better than that of those that continued receiving them. Since the experiment only ran for 36 weeks, I was curious whether the authors had any later data, so I contacted Min Pu to inquire.
Min Pu et al’s experiment suggested that my heart failure was caused by the long-term use of metoprolol . However, the specific molecular mechanism by which beta-blockers led to my heart failure is still unclear, as there are no relevant studies to explain it.
On April 18, 2017, after taking an ACE inhibitor, Benazepril, my ejection fraction quickly improved from 35% to 61%. This indicated that the heart failure caused by long-term use of metoprolol in a patient with mitral regurgitation was quite different. Simply following standard heart failure treatments was enough to reverse the ejection fraction.
At that time, Sacubitril were discovered to be effective in improving heart failure. However, Sacubitril/Valsartan (Entresto) had not yet been launched in China. In May 2017, I purchased racecadotril, which is also a neprilysin inhibitor. I took both medications together for the next six months. After my ejection fraction improved, my condition significantly increased compared to before, but I remained in a pathological state. Although I could walk a few hundred meters in six minutes, walking for half an hour would leave me extremely fatigued. Lifting anything over five kilograms would cause discomfort in my heart, so I had to be very careful about the weight of items around me. An echocardiogram indicated diastolic dysfunction.
I underwent a lot of tests and found that I had mild hemolysis (lactate dehydrogenase over 500). I speculated that one mechanism by which metoprolol caused my heart failure could be its effect on cardiac hemodynamics, leading to increased peak blood flow velocity within the heart. Mitral regurgitation also alters cardiac hemodynamics; the combination of the two could compress red blood cells under abnormal blood flow conditions, even damaging them, which might explain my mild hemolysis. Damaged red blood cells can directly harm the vascular endothelium. I found reports suggesting that captopril could mitigate the impact of mitral regurgitation on left ventricular remodeling, possibly by stabilizing red blood cells. Based on this speculation, I purchased some captopril at the end of 2017, and my symptoms improved significantly, allowing me to walk for an hour outside. After my post-recovery symptoms improved, I stopped taking racecadotril, and I didn’t notice any significant changes after discontinuing it, leading me to mistakenly conclude that neprilysin inhibitors might not have a major effect on me.
By the summer of 2018, I began extensively researching related information, hypothesizing other mechanisms by which metoprolol could cause heart failure in patients with mitral regurgitation. First, we need to understand how metoprolol affects the heart, and the following diagram roughly describes the relevant molecular mechanisms.
The mechanism of beta-blockers https://www.tldrpharmacy.com/content/pharmacology-101-an-overview-of-beta-blockers
I speculated that after long-term use of metoprolol, under conditions of mitral regurgitation, the pathways marked in red might undergo some persistent changes, and these changes could be the main reason for my ongoing symptoms. By the summer of 2018, although I had made significant improvements compared to a year earlier, my outings were still limited to within an hour. Beyond that time, I would experience abnormal symptoms, and attempting to lift anything over five kilograms would cause discomfort. However, even if my speculation was correct, finding the relevant medication was another challenge. I screened a large number of drugs from clinical trials and discovered in the fall of 2018 that the mechanism of Neucardin (recombinant human Neuregulin-1, developed by Shanghai Zesheng) aligned well with my needs.
However, Neucardin was a heart failure medication still undergoing clinical trials, and it had been in development for nearly ten years without being launched. I assessed that it would be difficult for this drug to reach the market within a few years, and since my ejection fraction had already returned to normal, I didn’t meet the eligibility criteria to participate in the trials. So, I began searching for various ways to obtain the medication.
At the end of 2018, I suddenly discovered that Sacubitril/Valsartan was available for purchase. Numerous papers indicated that neprilysin inhibitors were effective for all types of heart failure, so I resumed taking Sacubitril/Valsartan regularly, which led to some improvement. Later, I also took Empagliflozin, whose effects in heart failure was also proven.
In early 2019, I managed to acquire a dose of Neucardin. After the injection, my heart function showed a dramatic improvement almost immediately. Most notably, previously, if I attempted to lift anything over five kilograms, I would experience discomfort in my heart. After the injection, I could lift a 20-kilogram suitcase without any issues. My outings returned to normal, without the one-hour limitation. Moreover, this improvement was very rapid; I noticed effects the same evening after the injection, and by the next day, I felt significantly better. This clear improvement indicated that Neucardin could indeed reverse the myocardial damage caused by Metoprolol for patients with mitral regurgitation.
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