Treatment of dilated cardiomyopathy with Qili Qiangxin Capsule combined with Sacubitril Valsartan in one case

Tong Li, Cuiying Zhang

1 First Clinical Medical College of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province,China;

2 First Department of Cardiovascular Medicine, Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, China

Abstract

Key words: Dilated cardiomyopathy; Sacubitril Valsartan; Qili Qiangxin Capsule

Introduction

Dilated cardiomyopathy (DCM) is a primary cardiomyopathy of unknown cause.This disease is characterized by enlargement of left and/or right ventricles,accompanied by ventricular systolic hypofunction and/or congestive heart failure.The prevalence of the disease is relatively common, with the incidence of 13-84/100,000 in China.The disease condition is progressively aggravated,and the affected patient may die at any stage of the disease.At present, clinical comprehensive treatment including beta-receptor antagonist, angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor antagonist (ARB)is mainly used to slow down ventricular remodeling,alleviate myocardial damage and delay the development of lesions[1].However, some patients still have poor prognosis.Qili Qiangxin Capsule is a Chinese patent medicine targeted for heart failure based on collateral disease theory of traditional Chinese medicine[2].This medicine has the merits of tonifying qi and warming yang,promoting blood circulation and dredging collaterals,inducing diuresis and alleviating edema.It has a good curative effect for patients with heart failure syndrome caused by deficiency of yang-qi and stagnation of collaterals and blood stasis.Sacubitril Valsartan is the first angiotensin receptor-enkephalin inhibitor, which can improve cardiac systolic and diastolic function, reverse ventricular remodeling and elevate left ventricular ejection fraction (LVEF)[3].This patient was treated with Qili Qiangxin Capsule combined with Sacubitril Valsartan and achieved good curative effect.The case report is as follows.

Summary of Medical Records

The patient, a 22-year-old woman, was hospitalized on February 01, 2018.Complaint: Paroxysmal shortness of breath, edema of both lower limbs for 1 month,aggravation with cough and sputum for 1 week.History:Before January, the patient began to suffer from shortness of breath during supine rest at night, alleviated shortness of breath in high pillow or sitting position, affecting sleep,concomitant pitting edema of lower limbs, no fever, chills,dizziness, headache, abdominal pain, abdominal distension or other symptoms.Then she visited the local hospital and underwent relevant examinations.B-type brain natriuretic peptide showed 1646 pg/ml, electrocardiogram showed myocardial ischemia, echocardiography showed abnormal segmental motion of left ventricular wall and bilateral enlargement.For suspecting heart failure, the patient was given symptomatic and supportive treatment, including digoxin (cardiotonic), spironolactone (diuresis), betareceptor blocker (inhibiting sympathetic excitation),and benazepril (reversing ventricular remodeling), but the treatment was ineffective.1 week ago, the patient developed sudden aggravation of shortness of breath,dyspnea, especially during slight movement and in supine position, accompanied with cough, expectoration, white foam sputum, and fatigue when resting.Then she came to the First Affiliated Hospital of Shaanxi University of Chinese Medicine.Ultrasonic cardiogram showed heart enlargement, restriction of left ventricular diastolic function, decrease of left ventricular systolic function,mild reflux of mitral valve, a small amount of pericardial effusion (left ventricular end-diastolic diameter: 57 mm, left atrial anteroposterior diameter: 55 mm, right ventricular anteroposterior diameter: 27 mm, right atrial transverse diameter: 54 mm, EF: 30%).The outpatient was admitted to the hospital with the diagnosis of “Class IV Cardiac Function of Dilated Cardiomyopathy”.Admission symptoms: shortness of breath, dyspnea, limited lying time, cough, sputum, fatigue, no fever, no nausea and vomiting, poor appetite, bad night rest, no abnormal stool and urine.Physical examination: body temperature 36.4℃, pulse 103 beats per minute, breathing 24 breaths per minute, blood pressure 124/84 mmHg, young women, clear consciousness, poor mental state, cyanosis of lips, jugular vein enlargement, chest symmetry and no deformity, consistent bilateral breathing movement,dullness to percussion in bilateral lungs, rough breathing sound in bilateral lungs, moist rales in base of bilateral lungs, no protuberance in precordial region, apical enlargement to the left lower part, heart rate 103 beats per minute, rhythm, blunt heart sounds, diastolic galloping rhythm heard in mitral stethoscope, systolic murmurs of grade 2/6 heard in apex, and no pathological murmurs heard in remaining valve stethoscope.Moderate pitting edema in both The lower extremities, and obvious edema on both feet.Pale tongue, white and greasy fur, deep and thin pulse.Auxiliary examination: ECG: sinus rhythm,ventricular rate 110 beats per minute, myocardial ischemia;B-type brain natriuretic peptide (BNP) 2249 pg/ml, NT-proBNP 614 pg/ml; no abnormalities in myocardial enzymes, blood routine, urine routine, fecal routine, liver function, kidney function, electrolyte, blood lipid, and fasting blood glucose.Chest X-ray: The texture of both lungs became thicker.Heart shadow enlarged to both sides,which accorded with cardiomyopathy.Western medicine diagnosis: dilated cardiomyopathy, cardiac function of grade IV; Chinese medicine diagnosis: chest arthralgia (Qi deficiency, blood stasis and water obstruction syndrome).After admission, the patient was given oxygen inhalation in western medicine treatment, including the mixture of sodium nitroprusside 50 mg and 50 ml 5% glucose injection injected by light-avoiding micro-pump to reduce the pre-and post-cardiac load, metoprolol succinate sustained-release tablets 23.75 mg once a day to inhibit sympathetic nerve, furosemide tablets 20 mg once a day and spironolactone 20 mg once a day to induce diuresis and alleviate pre-cardiac load, Sacubitril Valsartan Sodium Tablets 50 mg twice a day to correct heart failure and inhibit ventricular remodeling.Coenzyme Q10 capsules 20 mg 3 times a day, trimetazidine hydrochloride tablets 20 mg 3 times a day, isosorbide mononitrate sustainedrelease capsules 50 mg once a day, intravenous infusion of levocarnitine 6 g and 250 ml 0.9% sodium chloride was given to nourish myocardium, protect heart, properly supplement potassium vitamin and maintain electrolyte balance.In Chinese medicine treatment, the mixture of 60 ml Shenmai injection and 100 ml 5% glucose injection was given intravenously and three Qili Qiangxin Capsules were taken orally three times a day.On day 6 after admission, shortness of breath, dyspnea, cough and phlegm were relieved obviously.The patient could rest in lying position.Blood pressure was 112/76 mmHg, heart rate was 83 beats/min, jugular vein was not filled, and edema of both lower limbs was obviously relieved.On day 14 after admission, the patient had no shortness of breath, dyspnea, cough and sputum, and her fatigue was significantly alleviated.She showed good appetite, may rest at night and had no abnormal stool and urine.Blood pressure was 110/78 mmHg, heart rate was 77 beats/min, no lip cyanosis, no filling of jugular vein, resonance to percussion in bilateral lungs, clear breathing sound in bilateral lungs, no moist rales, grade 2/6 systolic murmur heard in the apex, no edema in bilateral lower limbs or both feet, pale tongue, thin and white coating, deep and fine pulse.The NT-proBNP 403.05 pg/ml was reexamined.The electrocardiogram showed that the flattened T-wave was rised, suggesting that heart failure had been corrected.The dosage of Sacubitril Valsartan Sodium Tablets was adjusted to 100 mg twice a day, and metoprolol succinate sustained-release tablets were increased to 47.5 mg once a day.The patient was definitely diagnosed and her symptoms were improved.She was ordered to discharge and continued to take medicine after discharge: coenzyme Q10 20 mg 3 times a day, trimetazidine hydrochloride tablets 20 mg 3 times a day, metoprolol succinate 47.5 mg once a day, spironolactone tablets 20 mg once a day,furosemide tablets 20 mg once a day, Sacubitril Valsartan 100 mg twice a day, three Qili Qiangxin Capsules 3 times a day.

On March 05, 2018, in the patient’s first visit after discharge, there was no obvious shortness of breath or dyspnea observed, she could lie at night and her daily activities were not restricted, without cough, sputum,general fatigue or edema of both lower limbs, showing dim tongue, thin white coating, deep fine pulse, 110/72 mmHg of blood pressure, 68 beats/min of heart rate.Chest X-ray reexamination showed that the heart shadow was larger (smaller than before), which was consistent with the manifestation of dilated heart disease.Color Doppler echocardiography showed that left ventricular diastolic function was normal, systolic function LVEF was decreased by 39%, mitral regurgitation was moderate,tricuspid regurgitation was mild.Compared with the admission data on February 01, 2018, the patient had no obvious symptoms of heart failure, grade II of cardiac function, decreased heart volume, increased left ventricular ejection fraction, normal blood pressure and heart rate.The dosage of metoprolol succinate was increased to 95 mg once a day, Sacubitril Valsartan to 200 mg twice a day,and Qili Qiangxin Capsules maintained be given 3 times a day.The other medicine remains unchanged.

On June 25, 2018, in the patient’s third visit, she showed stable symptoms, no shortness of breath, no edema of lower limbs, dim tongue, thin white coating, deep fine pulse, 114/70 mmHg of blood pressure and 74 beats/min of heart rate.Color Doppler echocardiography showed changes in myocardial involvement, left ventricular enlargement with minor mitral regurgitation, left ventricular systolic function LVEF was decreased by 45%,coronary vein sinus widened (persistent left superior vena cava).Echocardiography showed improvement of myocardial ischemia, and trimetazidine hydrochloride was discontinued.NT-proBNP 334.04 pg/ml was reexamined,the dosage of metoprolol succinate was increased to 190 mg once a day and Sacubitril Valsartan to 200 mg twice a day, which reached the maximum tolerable dose of the patient.The patients’ liver function, kidney function,blood potassium, blood pressure and heart rate were monitored regularly.Qili Qiangxin Capsules were still taken orally, three capsules, three times a day, while the rest drugs remained unchanged.

On January 08, 2019, in the fifth visit of the patient, she had no obvious shortness of breath or edema of both lower limbs, showing pale red tongue, thin white coating,deep fine pulse.Blood pressure was 116/76 mmHg, heart rate was 72 beats/min.Color Doppler echocardiography showed that the left ventricle was enlarged, left ventricular anterior septum and anterior wall motion decreased, leftventricular wall motion was uncoordinated, left superior chamber persisted, tricuspid regurgitation was mild (left ventricular end-diastolic diameter: 56 mm, left atrial anterior and posterior diameter: 36 mm, right ventricular anterior and posterior diameter: 21 mm, right atrial transverse diameter: 37 mm, EF: 51%).NT-proBNP 74 pg/ml was reexamined.Up to now, the patient’s condition maintained stable and she continued the medication with some adjustment.

Discussion

Dilated cardiomyopathy has no specific name in the theory of traditional Chinese medicine.According to clinical manifestations, it can be classified as “chest pain”, “edema”,“palpitation”, “asthma syndrome” and “heart distention”.The disease is prevalent in young and middle-aged people,and its lesion is located in the heart and often involves the lungs, spleen, liver, kidney and other organs[4].It is a series of symptoms of heart loss and nourishment caused by the lack of innate endowment, acquired loss of nutrition,chronic illness, deficiency of Yang Qi, unstable external defense, warm heat and toxic pathogens accumulated in heart, and heart-Yin depletion.The main pathogenesis is the mixture of deficiency and excess, deficiency of yangqi as the basis, phlegm and retained fluid, blood stasis and water dampness as the root cause.According to the different stages and clinical manifestations of the disease,this disease can be divided into three stages[5]: in the early stage, the deficiency of cardiopulmonary qi is dominant,phlegm and blood stasis is relatively mild, mainly manifested as panic, shortness of breath and fatigue; in the middle stage, the deficiency of heart and kidney yang can cause palpitation, fatigue, fear of cold, cold limbs, edema and other symptoms; in the late stage, the deficiency of yin and yang is dominant, and the patients appear mental fatigue, dyspnea, palpitation, deep and weak pulse.The disease is based on deficiency and excess, and is treated according to syndrome differentiation of qi, blood and body fluid.Clinically, they are divided into Qi deficiency and blood stasis type, Qi-Yin deficiency and blood stasis type, Qi deficiency and blood stasis and water stasis type,Yang deficiency and blood stasis and water stasis type[6].According to the symptoms and signs of the patients, the patients are mostly affected due to ordinary deficiency,combined with inappropriate regulation and nourishment,insufficient Yang Qi and nourishment in the heart, poor blood circulation, obstruction of the heart vein, stasis and water stoppage, and chest obstruction, and the treatment is suitable for warming yang and invigorating qi, activating blood circulation and dredging collaterals,and reducing edema.Qili Qiangxin Capsule is the first compound Chinese patent medicine to treat chronic heart failure established under the guidance of collateral disease theory in China[7].In the theory of TCM meridian, the pathogenesis of chronic heart failure is explored from the aspects of qi, blood and water.Qi, blood and water are cemented to each other, blood stasis can not only directly block the veins, leading to obstacles in water circulation, but also block the movement of Yingwei Qi,thus aggravating the dysfunction of Yingwei Qi; water pathological changes also block Yingwei Qi, causing abnormal blood flow and blood stasis; Qi, blood and water are mutually harmful, forming a vicious pathological cycle, and eventually leading to the accumulation of heart collaterals.This is consistent with the theory of neuroendocrine system in western medicine, long-term over-activation directly damages the heart and blood vessels, leads to myocardial hypertrophy and deterioration of cardiac function, and further aggravates the activation of neuroendocrine system, thus forming a vicious cycle process[8].Aiming at the pathogenic characteristics of chronic heart failure such as deficiency of Qi and yang,stagnation of collateral stasis and masses developed with obstruction of collaterals, this paper puts forward the treatment principle of “treating qi, blood and water together, dividing and dispelling” guided by the theory of collaterals, and determines the treatment method of “benefiting qi and warming yang, promoting blood circulation and dredging collaterals, inducing diuresis and eliminating edema”.Furthermore, an innovative prescription of Qili Qiangxin Capsule is developed.It mainly consists of Safflower, Salvia miltiorrhiza, Astragalus membranaceus, Cinnamon twig, Ginseng, Alisma orientalis, Aconite, Cortex periplocae, Dried orange peel,Radix polygonati officinalis and Pepperweed seed.Among them, Astragalus membranaceus and Aconite are the monarch drugs.Astragalus membranaceus is beneficial to Qi deficiency and Yang deficiency, and also promotes diuresis to remove edema[9].Aconite contribute to tonify qi to warm yang, consolidate super ficies and arrest sweating,and the combination of the two is especially suitable for those who are weak in Qi and Yang and have hidrosis.In addition, Ginseng, Salvia miltiorrhiza and Pepperweed seed are used.Ginseng reinforces vital energy, and stimulates the menstrual flow, the combination of Ginseng that tonifies vital Qi and Astragalus membranaceus that partially supplements Wei Qi can supplement qi and lift yang, consolidate superficials and relieve depletion[10];Salvia miltiorrhiza promotes blood circulation to remove blood stasis; Pepperweed seed purges lung and circulates water, three drugs are used as courtier drugs.The adjuvant drugs include Safflower to activate blood circulation and dissipate blood stasis, dried orange peel to regulate Qi and dampness, Alisma orientalis and Cortex periplocae to slightly induce diuresis, and Radix polygonati officinalis to nourish yin and maintain healthy qi.The conductant drug Cinnamomum cassia twig warms yang and converts qi.All drugs are used to treat dilated cardiomyopathy by warming Yang Qi, activating blood circulation,promoting water retention and detumescence.Modern pharmacology believes that Salvia miltiorrhiza can dilate coronary artery and increase coronary artery blood flow[11]; Ginseng can dilate blood vessels, enhance myocardial contractility, cardiac output and anti-ischemic ability of myocardium will also be enhanced; Pepperweed seed can reduce phlebitis and reduce cardiac load[12]; Astragalus membranaceus can reduce renin and angiotensin in patients, reverse ventricular remodeling, and reduce oxygen radical damage of cardiac myocytes, increase their oxygen tolerance[13].Therefore, Qili Qiangxin Capsule can improve the cardiac function of patients with chronic heart failure and prevent chronic heart failure, which is closely related to its effects of enhancing myocardial contractility, inducing diuresis, inhibiting the over-activation of neuroendocrine system such as RASS,inhibiting inflammation, myocardial fibrosis, apoptosis and autophagy, improving myocardial energy metabolism,promoting angiogenesis and improving endothelial function[14].Other studies have shown that Qili Qiangxin Capsule does not cause electrolyte disturbance, it can reduce the occurrence of arrhythmia without significant impact on liver function, renal function and myocardial enzymes[15].It is also the only recommended Chinese patent medicine in China’s guidelines for the diagnosis and treatment of heart failure.In this study, this patient was treated with western medicine and Qili Qiangxin Capsule.It can warm yang and invigorate qi, activate blood circulation and relieve edema, treat both symptoms and symptoms, and has a good effect.

At present, there is no specific treatment for dilated cardiomyopathy in western medicine.Early drug intervention is still the basic treatment of dilated cardiomyopathy, including the use of ACEI or ARB,beta receptor blockers, aldosterone receptor antagonists,diuretics, vasoactive drugs and other drugs[16].The main purpose is to slow down ventricular remodeling and further myocardial damage, and delay the development of lesions.ACEI or ARB, beta receptor blocker and aldosterone receptor antagonist are called “golden triangle”drugs for heart failure.They should be used as early as possible without contraindication.Starting from a low level, the dosage should be gradually increased to reach the maximum dose that different patients can tolerate.However, in the actual use process, most patients are difficult to receive the target dose due to various adverse reactions, and the 5-year mortality rate is still over 50%[17].In recent years, new angiotensin receptor enkephalin inhibitor (ARNI) has emerged, forming a “new golden triangle” based on ARNI with beta receptor blockers and aldosterone receptor antagonists.Sacubitril Valsartan is the first angiotensin receptor brain natriuretic peptide inhibitor in the world, and has the drug properties of both Sacubitril and Valsartan[18].Damage of cardiac myocytes in patients with heart failure causes changes in size, shape and function of cardiac myocytes, resulting in overactivation of RASS and sympathetic nervous system, ventricular remodeling and hemodynamic changes.While RASS and sympathetic nervous system are activated, natriuretic peptide system is also activated.Natriuretic peptide has the functions of dilating blood vessels, lowering blood pressure, lowering sympathetic nerve activity, lowering vasopressin, reducing aldosterone, inducing diuresis and inhibiting ventricular remodeling[19].Natriuretic peptide metabolism is mainly through two processes: self-receptor mediated scavenging and enkephalin degradation.Sacubitril is a precursor drug, which is metabolized into active NEPI (neutral endopeptidase inhibitor) in vivo.It can inhibit enkephalin, enhance the effects of natriuretic peptide, bradykinin, adrenomedullin, angiotensin I/II and other vasoactive activities.However, the emergence of NEPI also increases the concentration of angiotensin I, II and endothelin-1, which counteracted each other.Therefore, the use of enkephalin inhibitors alone has little effect on heart failure and offsets its potential benefits.To inhibit enkephalin, RASS must be blocked in order to avoid the elevation of angiotensin I, II and endothelin-1.Valsartan is the AT1 R (angiotensin I receptor) blocker,which can block the RASS system.Therefore, ARNI has dual effects of ARB and NEPI, which can inhibit both RASS and regulate natriuretic peptide system, and inhibit ventricular remodeling[20].In addition, PARADIGMHF study showed that, compared with traditional golden triangle drug ACEI, Sacubitril Valsartan could reduce the risk of cardiovascular death, hospitalization risk and allcause death risk of heart failure.It can also improve the common daily activity limitation and almost all physical and social activity items in the total score of the Kansas Cardiomyopathy Questionnaire (KCCQ) in patients with heart failure.The greatest improvement is observed in sexual relations.At the same time, the adverse reactions such as renal function damage, hyperkalemia and cough in the Sacubitril Valsartan are scarcely seen[21].This study provides high-level evidence-based support for ARNI’s position in the guidelines.The new edition of heart failure guidelines in Europe and the United States strongly recommends ARNI for the treatment of heart failure patients with symptomatic decreased ejection fraction.The latest guidelines for diagnosis and treatment of heart failure in China also recommend that ARNI should be used instead of ACEI/ARB in order to further reduce the incidence and mortality of heart failure patients with NYHA cardiac function of II-III grade and declined symptomatic ejection fraction if they can tolerate ACEI/ARB.

The initial treatment of this patient was formulated based on the traditional “golden triangle” drug of ACEI or ARB, beta receptor blocker and aldosterone receptor antagonist, and the curative effect was not satisfactory.According to the guideline of medication for heart failure,the “new golden triangle” was applied, taking ARNI as the cornerstone and supplementing beta receptor blocker and aldosterone receptor antagonist.Combined with Qili Qiangxin Capsule, both symptoms and root causes were addressed, and the curative effect was very good.