Chronic heart failure (heart failure), as a progressive clinical syndrome, has become the most important cardiovascular disease of the 21st century and the final battleground for the treatment of heart disease. For more than half a century, as research has progressed, the understanding of the occurrence and development of heart failure has fundamentally changed, and it has been recognized that the goal of heart failure treatment is not only to improve symptoms and quality of life, but more importantly to repair the biological properties of the failing myocardium and to interrupt the vicious cycle of neuroendocrine and cytokine activation and myocardial remodeling, thus ushering in a new era in the biological treatment of heart failure. In the new century, with the increasing evidence of evidence-based medicine, the recommendations and guidelines of the American College of Cardiology/American Heart Association (ACC/AHA), the European Society of Cardiology (ESC) and China on the diagnosis and treatment of heart failure have emerged and updated, and heart failure has entered the era of standardized and individualized evidence-based treatment. Now we mainly review the new advances in the diagnosis and treatment of chronic heart failure in recent years.
1 New diagnostic advances
1.1 Device examination
1.1.1 Echocardiography: According to the 2009 ACC/AHA guidelines, echocardiography is the most useful diagnostic tool for heart failure and can quantitatively answer the following three key questions: (1) Is the left ventricular ejection fraction (LVEF) decreased? (2) Is there an abnormal left ventricular structure? (3) Are there other structural cardiac abnormalities that could explain the patient’s clinical presentation? The guidelines recommend that any patient with a suspected or diagnosed heart failure must undergo at least one comprehensive echocardiographic evaluation. In addition, the results of the first echocardiogram can be used as a baseline reference for later evaluation of the patient’s change in condition, the process of ventricular remodeling, and the effectiveness of clinical treatment.
1.1.2 Electrocardiogram: Heart failure is often complicated by conduction abnormalities, resulting in atrioventricular, interventricular and/or intraventricular motion asynchrony, which severely affects left ventricular systolic function. ECG can be used to diagnose cardiac asynchrony: atrioventricular asynchrony is manifested by prolonged P-R interval, which reduces left ventricular filling; right and left interventricular asynchrony is manifested by left bundle branch conduction block, which causes right ventricular contraction earlier than left ventricle; intraventricular conduction block is manifested by prolonged QRS time limit (>120 ms) on ECG.
1.2 Laboratory tests
1.2.1 B-type brain natriuretic peptide: Both B-type brain natriuretic peptide (BNP) and its N-terminal precursor (NT-proBNP) are myocardial stress markers, and their role in the diagnosis of chronic heart failure has been recognized by guidelines. Plasma BNP can be used to identify cardiogenic and pulmonary dyspnea. most patients with dyspnea due to heart failure have BNP above 400 ng/L, and the diagnosis of heart failure is not supported by BNP <100 ns/L. NT-proBNP has a longer and more stable half-life than BNP and reflects newly synthesized BNP over a brief period of time. NT-proBNP <300 ng/L can exclude The sensitivity and specificity of NT-pmBNP 1200 ng/L for the diagnosis of heart failure were 85% and 88%, respectively. In addition, studies such as the STARS-BNP have shown that BNP levels are superior to discharge and outcome monitoring in assessing the prognosis of patients with heart failure. It is important to note that the cut point for "abnormally high" BNP and NT-proBNP may differ significantly in different populations.
1.2.2 Resistin: A cysteine-rich secreted protein that is an adipocytokine along with lipocalin, Frankel et al. measured plasma concentrations of resistin and lipocalin in 2739 participants in the Framingham Offspring Study to evaluate their association with new-onset heart failure. . After correcting for age, sex, blood pressure, diabetes, smoking, coronary artery disease, valvular heart disease, and left ventricular hypertrophy, the hazard ratios for new-onset heart failure were 2.89 and 4.01 for the middle and upper third of the resistance hormone concentrations, respectively, using the lowest 1/3 of the resistance hormone concentration as a reference. after further correcting for differences in body mass index, insulin resistance, c-reactive protein, and BNP, the hazard ratios remained as high as For each standard deviation increase (7.45 pg/ml) in the concentration of resistin, the risk of new heart failure increased by 26%. Lipocalin concentrations were not associated with new heart failure. This study suggests that plasma resistin levels may predict the risk of new heart failure.
1.2.3 and peptide (copepdin): The level of pressin has been shown to correlate with the severity of heart failure. However, copeptin is very unstable, clears rapidly, and is very difficult to detect. Copepdin is the C-terminal part of the peptide fragment of the pressin hormone pro, which is stable and can be measured quickly and reliably, and therefore can be used as an alternative marker to pressin. neuhold et al. conducted a long-term observation of 786 patients with different degrees of chronic heart failure, aiming to evaluate the predictive value of copepdin in patients with heart failure, and to compare it with the recognized heart failure markers BNP and NT-pmBNP. The results of the study showed that in patients with cardiac function classes II and III, and peptidein was the most powerful single predictor of death. In patients with cardiac function class IV, blood sodium levels were the best predictor of death, and weptin independently enhanced the predictive ability, while BNP lacked this potency.
2 New advances in treatment
2.1 Drug therapy
2.1.1 Declining status of digoxin: Digoxin has been clinically used for more than 200 years and has been used as the basic drug for the treatment of chronic heart failure. However, the results of the DIG study confirmed that digoxin neither reduced nor increased mortality compared with placebo, but was superior to placebo in reducing heart failure hospitalization rates. Based on this, the new guidelines lower the recommendation level for digoxin from the previous Class I to Class IIa recommendation only for patients with persistent symptomatic heart failure who are already on angiotensin-converting enzyme inhibitor (ACEI) [or angiotensin II receptor antagonist (ARB)], beta-blocker and diuretic therapy. Early and routine application is not advocated and is not recommended for NYHA class I patients.
2.1.2 ARB is a good alternative to ACEI: ARB has only been formally approved for the treatment of heart failure since the 21st century, so there is less evidence-based medical evidence compared to ACEI. In recent years, with the accumulation of ELITEII, OPTIMAAL and VALIANT studies, especially the results of the late CHARM and other trials, the status of ARBs in the treatment of heart failure has been improved, especially the evidence that candesartan and valsartan reduce mortality and disability is more clear. The newly published HEAAL study showed that crosartan 150 mg daily (high-dose group) was more effective than 50 mg daily (low-dose group) in the treatment of heart failure.
It is important to note that since there are no clinical studies confirming the superiority of ARB over ACEI in the treatment of heart failure, or at best comparable efficacy to ACEI, current guidelines continue to recommend ARB as an alternative to ACEI when ACEI is not tolerated due to cough or angioedema, or for patients with symptomatic heart failure despite the use of ACEI and β-blockers.
2.1.3 Recombinant human brain natriuretic peptide: recombinant human brain natriuretic peptide (rh-BNP) has pro-sodium, diuretic and tube-dilating effects, and can significantly improve hemodynamics, and is the only new drug approved for heart failure treatment at home and abroad in the past 2O years. The FUSION-I study initially showed that nesiritide improved symptoms and hemodynamic status in patients with chronic decompensated heart failure, but the subsequent FUSION-II study using nesiritide sequential therapy for chronic decompensated heart failure yielded neutral results, suggesting that sequential therapy with rh-BNP may not be suitable for patients with chronic heart failure. heart failure patients. Neurontin is a recombinant human brain natriuretic peptide developed independently in China, which is a national class I new drug. According to the results of the completed phase IV clinical study, Synbiotin is used to treat patients with acute heart failure and acute attacks of chronic heart failure, and has the effects of improving dyspnea and diuresis; it can also improve left ventricular ejection fraction (LVEF) and reduce NT-proBNP.
2.1.4 Statins: Recent studies have found that statins, in addition to their lipid-regulating effects, also have pleiotropic effects such as anti-inflammatory, antioxidant, protection of vascular endothelial function, and modulation of neurohumoral factors, which can reduce or delay the occurrence and progression of chronic heart failure.
A recent meta-analysis enrolled 13 clinical trials designed to assess the effect of statins on mortality in patients with heart failure. The analysis showed a 26% reduction in mortality in heart failure patients treated with statin therapy. Further stratified analyses also found significant benefits of statins in patients with heart failure of both ischemic and non-ischemic etiologies.
Although both in vitro studies and retrospective analyses suggest that adding a statin to basal therapy provides additional benefit in patients with chronic heart failure, the results of prospective clinical studies do not support this view.
The CORONA study was the first large clinical trial to evaluate the use of statins in patients with heart failure. The results showed that although resulvastatin significantly reduced LDL cholesterol and C-reactive protein levels in patients. However, there was no statistically significant difference in the incidence of the primary endpoint event between the resulvastatin and placebo groups, nor in the incidence of the secondary endpoints (all-cause death and coronary events). Similarly, the results of the GISSI-HF study were disappointing. The study optimized treatment in 4574 patients with NYHA class II to IV heart failure of all causes, to which resulvastatin 10 mg/d or placebo was added. Results after 3.9 years of follow-up showed no significant difference in the primary endpoint between those treated with resulvastatin or placebo, despite a significant reduction in LDL cholesterol from baseline, and no difference in all-cause mortality between the two groups.
This shows that there are still many pressing issues in the exploration of statins for the treatment of chronic heart failure that need to be clarified in large randomized controlled trials.
2.1.5 Other drugs: Other new drugs include the vasopressin receptor antagonist tolvaptan, the renin inhibitor aliskiren, the adenosine receptor antagonist KW3902, erythropoietin (EPO), recombinant human neurontin, and the new positive inotropic drug istaroxime. However, there is a lack of support from large-scale clinical trials, and further studies are still needed.
2.2 Non-pharmacological treatment
2.2.1 Cardiac resynchronization therapy (CRT): The newly published MADITCRT study explored the prophylactic use of CRT for heart failure. The study included 1820 patients with ischemic or nonischemic cardiomyopathy in cardiac function class I-II, randomized to receive CRT + buried cardioverter-defibrillator (ICD) or ICD alone, with the primary endpoint of death or nonfatal heart failure. During a mean follow-up period of 2.4 years, the CRT+ICD group had a significantly lower rate of primary endpoint events than the ICD-only group. In addition, there was a significant reduction in LV volume and a significant increase in LVEF in the CRT+ICD group, suggesting that CRT improves LV remodeling.
In addition, approximately 40% of patients with heart failure are clinically combined with atrial fibrillation. Recent studies have shown that heart failure patients with combined chronic atrial fibrillation still benefit from CRT, especially when paced with dual-chamber pacing versus single-chamber pacing of the right ventricle. Therefore, the latest ACC/AHA guidelines classify it as a Class IIa recommendation.
2.2.2 Partial left ventriculotomy: Partial left ventriculotomy, also known as ventricular decompensation, was originally promoted by Batista et al. for the treatment of end-stage dilated cardiomyopathy. Subsequent studies have found the procedure to be unsatisfactory, so the latest ACC/AHA guidelines suggest that it should not be used to treat patients with non-ischemic cardiomyopathy, but only for the treatment of ischemic heart failure due to coronary artery disease.
2.2.3 Cell transplantation: Since Soenpaa et al. first performed cardiomyocyte transplantation, a large number of studies have been conducted to investigate the appropriate cell type for transplantation, transplantation route, transplantation safety and efficacy. The recent BOOST Ⅱ, TOPCARE-CHF and SEISMIC studies have shown preliminary good results of stem cell application in heart failure treatment, but there are still many debates about the number, timing, route, site and other details of stem cell transplantation, and its indications, safety and long-term efficacy are still inconclusive.
3 Diastolic Heart Failure
3.1 New diagnostic advances: systolic heart failure must have systolic insufficiency (LVEF ≤ 40%), but diastolic heart failure is not always due to diastolic insufficiency, but can also be due to systolic insufficiency. That is, diastolic heart failure cannot be equated with diastolic insufficiency unless there is direct evidence of diastolic insufficiency. Therefore, the 2008 ESC guidelines recommend using “heart failure with preserved ejection fraction (HF-PEF)” instead of diastolic heart failure, while the 2009 ACC/AHA guidelines use “heart failure with normal ejection fraction (HF-NEF)” instead of diastolic heart failure. The 2007 Chinese Heart Failure Guidelines used the term diastolic heart failure instead of diastolic heart failure.
Echocardiography has an important role in the diagnosis of diastolic heart failure, and the 3 diagnostic criteria proposed by the European Society of Cardiology Ultrasound Section are as follows: (1) signs and/or symptoms of chronic heart failure; (2) normal or mildly impaired left ventricular systolic function (LVEFI >45% to 50%); and (3) evidence of diastolic insufficiency (poor left ventricular relaxation or diastolic restriction). The key to the diagnosis of diastolic insufficiency is the need to confirm the slowing of ventricular diastolic velocity. Early on, pulsed Doppler was mostly used to determine mitral flow velocity, and it is now believed that the use of tissue Doppler to determine early mitral annular diastolic velocity (E’) and late diastolic velocity (A’) can more accurately reflect diastolic insufficiency.
3.2 New Advances in Treatment
Although there is ample evidence from evidence-based medicine that the renin-angiotensin-aldosterone system blocker ACEI/ARB improves the prognosis of systolic heart failure; however, a series of studies in recent years has shown that patients with diastolic heart failure do not benefit from it. The earlier CHARM study confirmed that candesartan reduced mortality in patients with heart failure; however, analysis of a subgroup of patients with diastolic heart failure in this study did not confirm a benefit . The PEPCHF study of perindopril in the treatment of senile diastolic heart failure also yielded neutral results compared with placebo. More recently, the I-PRESERVE study, which had been highly anticipated, only confirmed that the efficacy of irbesartan in diastolic heart failure was not different compared with placebo. Therefore, the current treatment for diastolic heart failure focuses on eliminating or reducing diastolic dysfunction, such as ventricular hypertrophy, fibrosis, or ischemia. The second is to reduce pulmonary and systemic venous congestion, which is the main manifestation of diastolic insufficiency