Clinical research progress of ischemic heart failure and prospect of traditional Chinese medicine

Man-Ke Guan,Jia-Yuan Hu,Xiao-Yu Zhang,Yang Sun,Hong-Cai Shang,* The Key Laboratory of Chinese Internal Medicine of the Ministry of Education, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China. School of Medical Information Engineering, Guangzhou University of Chinese medicine.Guangzhou,China.

Background

Heart failure (HF) is the end stage of heart disease. The systolic and (or) diastolic dysfunction of the heart results in increased intracardiac pressure and decreased cardiac output. HF is mainly manifested in the combined symptoms of pulmonary congestion and vena cava congestion. The global incidence of heart failure continues to grow every year.In developed countries,the proportion of adults suffering from the disease is 1%-2%.The 12-month all-cause mortality rate of hospitalized patients is 17%and the 12-month rehospitalization rate is 44% [1].HF is an important factor to induce the death of patients with cardiovascular diseases.

Ischemic heart failure (IHF) is the most common type of HF in the world [2]. In the 2016 ESC guidelines,IHF was classified as HF with left ventricular ejection fraction (LVEF) < 40% with long-term myocardial ischemic changes.This article will discuss the progress of clinical research and prospect of TCM in the context of the mainstream definition of IHF.

Biomarkers

B-type natriuretic peptide(BNP)

BNP as a natural hormone synthesized by cardiac myocytes, can effectively regulate cardiac function and can be used as a quantitative marker of HF. Several studies have pointed out that BNP and its precursor NT-proBNP were significantly elevated in IHF patients as an index of cardiac stress response [3,4], which indicated BNP, NT-proBNP were important factors to support the diagnosis of IHF. However, according to recent experiment conducted by Zheng et al, early NT-proBNP levels were shown as a decreasing tendency in patients with acute IHF, and NT-proBNP levels in patients with IHF were much lower than those non-IHF patients [5].Further design is needed to explore the reasons for the inconsistency with previous reports, but both results suggest that BNP levels can help reduce the rate of missed diagnosis of ischemic etiology.

Cardiac troponin(cTn)

cTn is a regulatory protein of myocardial muscle contraction,including cTnT,cTnI and cTnC,respectively.Its concentration is positively correlated with the number of myocardial cell necrosis.Because of the low detection sensitivity of conventional cTNT, high-sensitivity cardiac troponin (hs-cTn) can be used for detection. Studies has testified that hs-cTn levels in IHF patients are higher than non-ischemic [6], so hs-cTn could be used in clinical practice as a marker for the diagnosis of IHF.

Growth differentiation factor-15(GDF-15)

GDF-15 is a characteristic factor in response to stress injury. The level of serum GDF-15 can be significantly increased in HF patients [7]. A clinical controlled trial found that serum GDF-15 levels in patients with ischemic cardiomyopathy were significantly higher than those in patients with dilated cardiomyopathy [8]. The result shows that the level of GDF-15 can provide a reference for judging the cause of HF,which is convenient for early diagnosis of IHF.

Cystatin C

Cystatin C is a protein that is primarily used as a marker of renal function.Clinical trial has proved that cystatin C levels can reflect mild or subclinical renal dysfunction in IHF patients and can be used to assess glomerular filtration function at an early stage [9]. Thus, serum cystatin C has diagnostic reference value in evaluating the short-term prognosis of IHF.

Western medicine treatment

Medication

The medication of IHF is basically similar to other types of HF conventional treatment (Table 1), but there are characteristic points mainly based on Heart failure with reduced ejection fraction (HFrEF) in specific selection and use.

β-receptor blockerβ-receptor blocker is recognized as complementary agent to angiotensin converting enzyme inhibitor (ACEI) and can be used in patients with HFrEF who still have symptoms after ACEI. Studies have indicated that because of the β-receptor blocker can slow heart rate and improve arrhythmia, the use of β-receptor blocker in HFrEF patients with sinus rhythm can reduce all-cause mortality[10].

Aldosterone receptor antagonistSpironolactone and eplerenone are the first and second generation aldosterone receptor antagonist.A clinical study by Zannad et al have suggested that eplerenone or spironolactone could be used to treat all HFrEF patients, including IHF patients,as well as HF patients who used ACEI and β-receptor blocker but still had symptoms and whose LVEF was less than 35%. The use of aldosterone receptor antagonist effectively reduced the rehospitalization rate and mortality rate[11].

Angiotensin receptor enkephalinase inhibitor(ARNI)

The popular drug entresto, which has been studied in recent years, is a new compound that binds to an angiotensin receptor blocker (valsartan) and a enkephalinase inhibitor (Shakuba) to act at both targets.ARNI can be used in place of ACEI or ARB to further reduce morbidity and mortality in patients who are able to tolerate ACEI or ARB or all HFrEF [12]. The long-term safety of the drug remains to be confirmed.

Positive inotropic drugsPositive inotropic drugs can enhance myocardial contraction and myocardial perfusion,improve cardiac function and reduce mortality.The result of COSMIC-HF study has pointed that cardiac myosin activator, as a new positive inotropic drug, can improve LVEF,reduce heart rate and NT-pro BNP levels in HFrEF patients,and has safety and tolerance[13].It may provide a new option for the treatment of IHF in the future.

OtherTrimetazidine, a commonly used drug for clinical treatment of IHF, can enhance myocardial contractility and improve left ventricular function. Current research has certified that trimetazidine can only be used in the treatment of IHF, and has no significant effect on outcomes of non-IHF[14].

Revascularization

Coronary artery bypass grafting (CABG)CABG is an important program to alleviate myocardial ischemia and coronary heart disease, and its effect has been confirmed by international research. STICH study is a controlled trial for patients with severe IHF, suggesting that the physiological benefits of CABG include effective reduction of ischemic heart events [15]. Control experiment conducted by O’Conno et al. has shown that the use of CABG for revascularization compared with drug therapy can effectively improve the 1-, 5-, and 10-year survival rates of IHF[16].The value of CABG in treating IHF should be more concerned.

Percutaneous coronary intervention (PCI)PCI can achieve complete or incomplete revascularization of patients with multivessel disease in IHF. Clinical controlled study has revealed that the PCI group had a significant advantage in the incidence of major adverse cardiac events and hospitalization time in 30 days compared with the CABG group [17]. Currently, there is no more valid evidence for the clinical study of PCI for IHF, but it will still be one of the research directions of revascularization therapy for IHF in the future.

Gene therapyAt present, gene therapy is still in a stage with large number of clinical researches.Although the use of experience of gene therapy is insufficient, the clinical safety is good [18]. CUPID study has indicated that high dose AAV1 or SERCA2a treatment group had the lowest late mortality rate and 82% reduction in various presupposed cardiovascular events, such as myocardial ischemia, worsening of HF and mortality[19]. In the future, gene therapy may play an important role in the treatment of IHF.

TCM treatmen

Traditional Chinese medicine believes that IHF is a secondary disease of blood stasis due to deficiency of qi and blood, poor blood circulation, and damage of heart’s vessel caused by invasion of pathogenic toxins [20].In recent years, the trials of Chinese medicine for IHF have been widely carried out in China.A cross-sectional study has been proposed, according to the progress of the disease, IHF mainly manifested as qi deficiency，blood stasis, deficiency of Yang, water overflowing and yin deficiency [21]. Following is an introduction to the clinical researches of TCM therapy of IHF combined with syndrome differentiation and treatment.

Qi deficiency and blood stasis

IHF begins with the damage of heart vessel due to deficiency of qi and blood, then the blockage of qi-blood leads to chest stuffiness and pains. It initially manifests the pathological characteristics of qi deficiency and blood stasis as well as intermingled deficiency and excess.Qishen Yiqi dripping pill are a kind of Chinese patent medicine，which is made from the active ingredients of astragalus, salvia, pseudo-ginseng and rosewood. It has the effects of benefiting qi and invigorating pulse，and activating blood analgesia. IHF patients who use this medicine to treat qi deficiency and blood stasis syndrome can improve Multiple outcome indicators including the 6-minute walking test,BNP level and others[22].Qishen Yiqi dripping pill also can improve the left ventricular function and protect cardiomyocytes[23].Heart-protecting musk pills and Dan Hong injection also play important roles in the treatment of IHF with qi deficiency and blood stasis syndrome[24,25].

Heart-kidney yang deficiency

Qian Jin Fang said that heart belongs to fire, kidney belongs to water, and water and fire should be mutually beneficial. Therefore, the pathological process of IHF is most closely related to the kidney besides the heart [21].Shenfu injection is a mixture made by extracting effective ingredients from red ginseng and aconite by modern technological means. It has the functions of supplementing qi and restoring yang, and warming yang to transform qi.The combination of Shenfu injection and conventional western medicine in the treatment of IHF with heart-kidney yang deficiency syndrome can enhance myocardial contractility, reduce myocardial oxygen consumption, protect myocardium and restore vascular function,and effectively improve the therapeutic effect of IHF[26].In addition,Qiliqiangxin capsule has also gained good results in clinical trials[27].

Deficiency of qi and retention of fluid

The patients’heart Yang is damaged,resulting in inability to promote blood circulation and blockage of blood vessels,so that body fluid stagnate and overflow,or even rush to the heart [28]. lingguizhugan decoction contains seven traditional Chinese medicines:astragalus, poria cocos，white atractylodes rhizome，codonopsis pilosula，cassia twig，salvia and liquorice. It has the functions of supplementing qi and warming yang,as well as activating blood and promoting urination. lingguizhugan decoction combined with western medicine in the treatment of IHF patients with excessive fluid rushing to the heart can improve the total effective rate of treatment and cardiac function. It can also reduce NT-proBNP level,hospitalization time and re-hospitalization rate [29].In clinic,modified Yangxin decoction combined with western medicine is also used to treat IHF with retention of fluid and has achieved good effect[30].

Deficiency of both qi and yin

IHF patients have a long course of illness,which leads to the loss of heart blood,qi and yin.In the later stage,it can be manifested as deficiency of both qi and yin. Sheng Mai injection mainly includes ginseng, ophiopogon japonicus and schisandra, which can supplement qi and remove blood stasis,as well as nourish yin and body fluid.Combined with Western medicine,it can effectively dilate coronary artery, improve blood pressure and peripheral circulation, increase cardiac output and myocardial contractility,and reduce myocardial oxygen consumption.So as to shorten the treatment cycle and significantly improve the total effective rate [31]. In addition, the clinical study of Sen-Mei injection in the treatment of IHF also reached the expected effect[20].

Discussion and conclusion

With the deepening understanding of IHF, people have strengthened the study of effective biochemical indicators.Although it is still difficult to differentiate ischemic and non-ischemic causes, it is helpful to improve the clinical efficacy and prognosis. The clinical application of conventional western medicine treatment is still the focus of research.People have refined the use of traditional HF drugs, developed new drugs such as ARNI to adapt different clinical situations, and strengthened the targeted treatment of IHF. In addition to drug therapy, researches on revascularization for IHF also show great potential,and these applications need more support from clinical data.

In the treatment of TCM, the quantity and quality of researches of decoctions are relatively small, while the oral preparations have many kinds, but the effect is not outstanding enough. TCM injection is more suitable for the treatment of IHF because of its nature,clear type and standardized dosage form. Most of them can achieve good curative effect and have high clinical recognition.In a word, the treatment of IHF with traditional Chinese medicine focuses on the overall syndrome differentiation.It has broad prospects in promoting the recovery of various organs, reducing the combined use of drugs and reducing adverse reactions. However, it has not yet formed a clear norm and required more high-quality clinical evidence to support the improvement of treatment programs.

1. Ponikowski P,Voors AA,Anker SD,et al.2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail 2016, 18:891-975.

2. Vahanian A. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008.Eur Heart J 2008,10:933-989.

3. Drexler B,Heinisch C,Balmelli C,et al.Quantifying Cardiac Hemodynamic Stress and Cardiomyocyte Damage in Ischemic and Nonischemic Acute Heart Failure.Circ Heart Fail 2012,5:17-24.

4. Miller ML,Hartman KA,Burritt MF,et al.Troponin,B-type natriuretic peptides and outcomes in severe heart failure: Differences between ischemic and dilated cardiomyopathies. Clin Cardiol 2010, 30:245-250.

5. Zheng YR, Ye LF, Cen XJ, et al. Low NT-proBNP levels: an early sign for the diagnosis of ischemic heart failure.Int J Cardiol 2016,228:666.

6. Bakal RB, Hatipoglu S, Kahveci G, et al.Determinants of high sensitivity troponin T concentration in chronic stable patients with heart failure: Ischemic heart failure versus non-ischemic dilated cardiomyopathy.Cardiol J 2014,21:67-75.

7. Liu H, Li Y. Research Progress of GDF-15 in Common Cardiovasular Diseases.Chin J Microcirc 2017:68-71.

8. Li SX, Lv Y, Li T. The research of early diagnosis value on the heart failure patients by copeptin，GDF-1 5 and NT-proBNP. J North Sichuan Med College 2017,32:112-5.

9. Li HY. Relationship between serum cystatin C and cardiac function in patients with chronic ischemic heart failure.Guide of China Med 2014:131-132.

10. Kotecha D, Flather MD, Altman D, et al. Heart Rate and Rhythm and the Benefit of Beta-Blockers in Patients With Heart Failure.J Am Coll Cardiol 2017,69:2885-2896.

11. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms.N Engl J Med 2011,364:11-21.

12. Xu DL, Bai YJ. Interpretation of 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure.Chin Gen Pract 2017,20:3579-3583.

13. Teerlink J R, Felker G M, McMurray J J, et al.Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure(COSMIC-HF):a phase 2, pharmacokinetic, randomised, placebo-controlled trial.Lancet 2016,388:2895-2903.

14. Winter JL, Castro PF, Quintana JC, et al. Effects of trimetazidine in nonischemic heart failure: a randomized study.J Card Fail 2014,20:149-154.

15. Carson P, Wertheimer J, Miller A, et al. The STICH trial(Surgical Treatment for Ischemic Heart Failure):mode-of-death results. Jacc Heart Fail 2013, 1:400-408.

16. Christopher MO’Connor,Velazquez EJ,Gardner LH,et al. Comparison of coronary artery bypass grafting versus medical therapy on long-term outcome in patients with ischemic cardiomyopathy (a 25-year experience from the Duke Cardiovascular Disease Databank).Am J Cardiol 2002,90:101-107.

17. Buszman P, Iwona Szkróbka, Gruszka A, et al.Comparison of effectiveness of coronary artery bypass grafting versus percutaneous coronary intervention in patients with ischemic cardiomyopathy.Am J Cardiol 2007,99:36-41.

18. Penny WF, Hammond HK. Randomized Clinical Trials of Gene Transfer for Heart Failure with Reduced Ejection Fraction.Hum Gene Ther 2017,28:378-384.

19. Jessup M, Greenberg B, Mancini D, et al. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): A Phase 2 Trial of Intracoronary Gene Therapy of Sarcoplasmic Reticulum Ca2+-ATPase in Patients with Advanced Heart Failure. Circ 2011, 124:304-313.

20. Huang BF. Clinical observation of Sen-Mei injection combined with metoprolol in the treatment of ischemic cardiomyopathy with heart failure.Xinxueguanbing Fangzhi Zhishi 2018:42-44.

21. Zhou YP, Hu YH, Wu HQ, et al. Association between Ischemic Heart Failure in TCM Syndromes and Cardiac Function. Chin J Integr Med Cardio/Cerebrovasc Dis 2008,6:1389-1391.

22. Hou YZ, Wang S, Zhao ZQ, et al. Clinical assessment of complementary treatment with Qishen Yiqi dripping pills on ischemic heart failure: study protocol for a randomized, double-blind,multicenter,placebo-controlled trial(CACT-IHF).Trials 2013,14:138-138.

23. Sun LX, Ji YP, Su J, et al. Effect of Qishen Yiqi dripping pills in Treating Coronary Heart Disease with Ischemic Heart Failure. Prevention and Treatment of Cardio-Cerebral-Vascular Disease 2018,18:65-66,68.

24. Li MJ. Clinical efficacy and safety of heart-protecting musk pills combined with levocarnitine oral liquid in the treatment of elderly patients with ischemic cardiomyopathy and heart failure. International Medicine and Health Guidance News 2017,23:3231.

25. Chen JF,Xue SJ,Duan KD,et al.Clinical Controlled Study on Danhong Injection in the Treatment to Acute Heart Failure Caused by Ischemic Cardiomyopathy.World Chin Med 2017:116-118.

26. Yang HQ, Gu HQ, Gong SJ. Impact of Shenfu injection combined with recombinant human brain natriuretic peptide on cardiac function, plasma BNP and hs-CRP in Ischemic cardiomyopathy heart failure.J Bethune Military Medical College 2017:707-709.

27. Gao YZ, Wang HB, Miao B, et al. Clinical observation of Qiliqiangxin capsule combined with trimetazidine in the treatment of heart failure in ischemic cardiomyopathy. Mod J Integr Tradi Chin Western Med 2016:845-847.

28. He QY. Discussion on the treatment of refractory heart failure based on the theory of ‘unsmooth blood circulation results in water retention in Synopsis of Golden Chamber China J Tradi Chin Medi and Pharm 2015,30:120-122.

29. Sui SH, Cai XF. Effect of Lingguizhugan decoction and trimetazidine on cardiac function in patients with chronic heart failure in ischemic cardiomyopathy.Mod J Integr Tradi Chin Western Med 2017, 26:2214-2216.

30. Chen B, Ming XH, Zhang Y. Clinical observation of modified Yangxin decoction on heart failure in ischemic cardiomyopathy. Chin Health Care Nutr 2016,26:320-321.

31. Yang BG, Wang QK, Yin GL. 40 Cases of heart failure in ischemic heart disease treated by Sheng Mai injection and sodium nitroprusside. J Clin Med Literature（Electronic Edition）2018,18:134+256.