China’s fight against new-onset heart failure after acute myocardial infarction: a major stage victory

Heart failure (HF) may complicate acute coronary syndrome (ACS) and is associated with a high burden of both short- and long-term morbidity and mortality[1–2]. Patients with ACS can initially present with a wide variety of clinical signs and symptoms, and rapid diagnosis is mandatory as prevention is the primary goal. Acute decompensation of chronic HF or de novo HF complicating ACS can be challenging, as patients may present with atypical symptoms, electrocardiogram findings may be confounded by pre-existing abnormalities, and biomarkers of myocardial injury such as cardiac troponins may also be elevated in patients with chronic or acute HF, independent of ACS[3]. This can delay straightforward diagnosis and timely treatment of ACS, increasing the risk of other in-hospital morbidity (such as renal dysfunction, respiratory failure, or pulmonary infections) as well as in-hospital mortality[4]. Timely recognition of ACS as a cause of acute HF and well-coordinated management of both conditions is, therefore, of paramount importance[3,5]. In the context of acute myocardial infarction, healthcare providers must rapidly decide whether immediate invasive management is needed. Left ventricular dysfunction, pulmonary congestion, or both may develop due to neurohormonal activation, inflammation, and myocardial stunning. ST-elevation myocardial infarction (STEMI) requires prompt primary percutaneous coronary intervention (PPCI), or fibrinolysis if PPCI cannot be performed within 120 minutes. Early reperfusion therapy helps minimize infarct size and enables the best possible preservation of left ventricular function[5]. In all patients with ACS, a combination of antiplatelet and anticoagulant therapy should be administered. Stunned myocardium can improve following revascularization and healing from ischemic myocardial damage is associated with cellular migration and scar formation. HF symptoms are often preceded by cardiac remodeling, which was originally defined only by left ventricular dysfunction and dilatation, but was later shown to be also associated with typical cellular and molecular alterations in the residual intact myocardium, and is accompanied by adaptive changes of the peripheral cardiovascular system[6]. The pharmacological management of acute HF should follow current guidelines[7–8], and includes immediate relief of pain and anxiety, along with the use of diuretics according to individual requirements. Other key treatments include renin-angiotensin-aldosterone system (RAAS) inhibitors such as angiotensin-converting enzyme inhibitors or angiotensin-1-receptor blockers, β-blockers, and mineralocorticoid receptor antagonists. Of note, the recent Prospective ARNI versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events after Myocardial Infarction (PARADISE-MI) Study reported that the angiotensin receptor/neprilysin inhibitor (ARNI) sacubitril/valsartan did not significantly reduce the composite primary outcome of cardiovascular death, hospitalization for HF, or outpatient HF when compared with ramipril. However, the secondary endpoint, comprising cardiovascular death, total HF hospitalizations, myocardial infarction, or stroke, was nominally reduced[9]. Despite a similar lack of statistically significant beneficial effects in two other pivotal trials (dapagliflozin in patients with acute myocardial infarction [DAPA-MI] and empagliflozin in patients with acute myocardial infarction [EMPA-MI]) with respect to the risk of first hospitalization for HF or all-cause death, the potential of ARNI and sodium-glucose cotransporter 2 (SGLT2) inhibitors in the management of de novo HF following ACS remains promising. A lower overall risk of HF-related morbidity and mortality among all study participants hospitalized for ACS, many of whom recovered due to prompt revascularization, may help explain the smaller than anticipated difference in primary outcome events between study arms in recent trials. This underscores, however, that acute HF in ACS can be considered a causally treatable condition, provided reperfusion therapy is administered early. Future study is needed to better define the role of ARNI and SGLT2 inhibitors in the treatment of de novo HF following ACS. Of note, a recent editorial proposed that landmark analysis might be an appropriate method to clarify whether beneficial effects of these newer drugs on the time to first HF hospitalization or death after ACS occur in patients, who are a priori at risk for HF or those, who have pre-existing chronic HF, rather than reflecting a modification of the pathophysiological pathways leading to HF[10]. Finally, new compounds (e.g., anti-inflammatory) that specifically target infarct size or healing processes are currently under development[11]. Future prospective research that specifically targets de novo HF in the context of ACS is needed to generate more evidence for the optimal pharmacological management of these patients. Data from the nationwide Swedish coronary care unit registry Swedish web-system for enhancement and development of evidence-based care in heart disease evaluated according to recommended therapies (SWEDEHEART) and the American 2024 Heart Disease and Stroke Statistics suggest that the incidence of acute HF following ACS is declining, likely due to earlier revascularization, effective HF pharmacotherapies, and improved secondary prevention measures[12–13]. However, given the global burden of ACS, the absolute number of patients with acute HF complicating ACS is anticipated to remain high, and an urgent need remains for further research in different world regions, ethnicities, and healthcare settings. Closing these knowledge gaps is key to enable tailored strategies for further improvement of healthcare delivery in patients, in whom ACS is complicated by acute HF. China, home to a fifth of the world’s population, is undergoing rapid demographic and epidemiological transitions that have led to an increase in the prevalence and incidence of cardiovascular diseases, including ACS. Following marked increases in incidence and prevalence rates since 1990, cardiovascular diseases became the leading cause of death in China by 2017[14]. A retrospective analysis, covering the period between 2001 and 2011, indicated that while PPCI for STEMI became a clinical standard in many other countries, the proportion of patients receiving timely reperfusion therapy in China was still below 30%[15]. At this time, the infrastructure for early diagnosis and timely treatment of ACS were less well developed in China. Although most hospitals were equipped with transport and treatment capabilities, delays in patient transportation and treatment procedures were not uncommon, due to logistic problems. In addition, marked regional variations existed in the allocation of healthcare resources, and the capacity of medical services varied in different regions of this large country, depending also on the level of economic development of different regions[16]. Starting in 2011, hospital-based chest pain centers were established throughout China, marking a significant step in improving care for patients with chest pain. In 2016, the National Chest Pain Centers Program (NPCPC) was founded as a nationwide collaborative initiative to enhance healthcare in individuals with chest pain. By December 2021, 5,107 hospitals across all 31 provinces in China had already joined the NPCPC program. Importantly, participating hospitals were requested to systematically feed patient-related data into a centralized web-based platform, the Chinese Cardiovascular Association Database-Chest Pain Center (CCA Database-CPC). This database collects structured information on demographic characteristics, risk factors, comorbidity profile, laboratory and technical findings, clinical features, and outcomes. It serves dual purposes: enabling quality control and benchmarking in routine healthcare and supporting research initiatives. In this issue of Cardiology Plus, Xie et al.[17] report on a retrospective analysis, which makes use of the CCA Database-CPC to describe the incidence, clinical characteristics, related factors, and prognostic significance of de novo in-hospital HF after STEMI in contemporary China. The analysis was based on data collected over a 2-year period (from January 2020 to December 2021) from all patients hospitalized with ACS, who had a discharge diagnosis of STEMI and no previous history of HF. Information regarding all-cause mortality at 7 and 30 days after the onset of symptoms was obtained from another database (Chinese Center for Disease Control and Prevention), if not available from the CCA Database-CPC. The analysis involved 373,835 STEMI patients with a mean age of 62 years, who were categorized as having either de novo HF or no HF. Overall, in-hospital de novo HF was observed in 10.6% of the total cohort. These individuals tended to be older, were more frequently female (one in four participants), and had a higher burden of comorbidities. They were also less likely to receive reperfusion therapy or had a longer delay of reperfusion, resulting in a more than twofold increase in the risk of all-cause mortality at both 7 and 30 days. Besides older age, female sex, lacking or delayed reperfusion, and a greater comorbidity burden, elevated levels of cardiac troponin were identified as contributing factors. This work highlights a major stage victory in China’s fight against the deleterious sequels of acute HF complicating ACS and makes a relevant contribution to filling some of the above-mentioned knowledge gaps. The major strengths of this study include the comprehensive and structured collection of patient data on demographic and clinical characteristics, diagnostic and other procedural details, mode, frequency, and timelines of treatments applied as well as on clinical outcome data in a uniform database. A further strength is the huge patient number. In addition, data were collected by more than 5,000 hospitals across all the provinces of the People’s Republic of China, and are, therefore, likely to be representative of China’s population as a whole. Over the time period covered by the analysis, 60% of this STEMI cohort underwent PPCI, with a mean door-to-balloon time well within the desirable time frame of 120 minutes, and around 70% of the patients experienced any reperfusion measure. Thus, important progress has been made over a relatively short time period, which is an outstanding achievement given the complex geographic situation in this large multi-ethnic country. Information on the incidence rates of de novo HF in ACS is scarce in the literature. Goodwin et al.[4] performed a pooled analysis of four large anticoagulant or antiplatelet drug trials conducted between 2006 and 2011, involving more than 48,000 individuals with acute myocardial infarction. The authors categorized 11% of the cohort as presenting with acute HF, a finding consistent with similar reports from previous registry trials involving both STEMI and non-STEMI populations[18–20]. The analysis revealed that patients with a history of pre-existing HF were more likely to experience acute worsening compared to the subgroup with incident de novo HF (40% vs. only 7%). Furthermore, patients with acute HF complicating ACS had a higher risk of 1-year all-cause mortality. The adjusted hazard ratio for mortality was 2.02 (95% confidence interval [95% CI]: 1.31–1.66) for those with worsening chronic HF and 1.47 (95% CI: 1.15–1.88) for those with de novo HF. Compared with individuals without HF during the index hospitalization, who more frequently presented with non-STEMI, patients with acute HF generally experienced higher rates of rehospitalization for HF and other major adverse cardiovascular outcome events (MACE)[4]. Although both trials are not strictly comparable, since Xie et al.[17] focused exclusively on patients with an established diagnosis of STEMI at discharge, excluded those with a HF history, and limited their report to the first month after the onset of ACS symptoms, both studies concur in underscoring that patients who develop HF in the context of ACS represent an especially vulnerable subgroup. Furthermore, they demonstrate the imperative need for improved immediate treatment, encompassing both interventional and medical therapies, and careful long-term follow-up and disease management to optimize outcomes for this high-risk population. Remarkably, and in line with the further increase in mortality risk between 7 and 30 days observed by Xie et al.,[17] Goodwin et al.[4] also reported that patients with de novo HF had the highest 30-day mortality risk compared with subgroups with no HF or worsening chronic HF. This elevated risk may be attributed, at least in part, to delayed initiation of appropriate HF therapies, since physicians may have been reluctant to implement guideline-recommended treatments[4]. In early experimental trials, we were able to introduce the principal concept that RAAS inhibition enables reduction in infarct size after coronary occlusion[21]. Correspondingly, the current study highlights that, despite the availability of today’s standard medications, such as RAAS inhibitors, β-blockers, and lipid-lowering drugs, these therapies were prescribed at discharge at lower rates for individuals hospitalized with ACS and de novo HF. This underscores the critical need for the timely optimization of life-saving pharmacotherapies, particularly in the vulnerable subgroup of patients with acute HF complicating ACS. In the past, numerous trials showed that in STEMI patients earlier reperfusion is associated with a lower incidence of de-novo HF, and that, vice versa, HF incidence rates increase incrementally with longer door-to-balloon time (reviewed in more detail by Tannu et al.)[2]. Likewise, findings from the Danish trial in acute myocardial infarction-2 (DANAMI-2) Trial showed that impaired coronary flow after PPCI, the prevalence of left ventricular systolic dysfunction and longer-term mortality risk all increased with longer symptom-to-balloon times[22]. Although no randomized trials exist to guide the management of STEMI patients presenting more than 12 hours after symptom onset, guidelines recommend coronary angioplasty even in patients with delayed STEMI presentation (>12 hours) with acute HF[5]. The findings of Xie et al.[17] corroborate all the previous observations, reinforcing the benefit of revascularization, even hours after the onset of symptoms. Their results demonstrate a clear advantage of revascularization compared with non-reperfusion strategies, particularly given the rising mortality risk associated with delays in initiating medical management. In addition, the study highlights the negative impact of a high heart rate and low blood pressure, calling for immediate medical treatment when acute HF complicates ACS. We are eagerly awaiting additional information on the incidence of worsening pre-existing HF in the context of ACS, the rates of repeat hospitalizations, MACE, and chronic HF beyond the first 30 days, as well as 1-year all-cause and cardiovascular mortality risk within each subgroup, and on positive changes of all these results with further evolution of the Chinese healthcare system. The comprehensive CCA Database-CPC, in combination with the death registry of the Chinese Center for Disease Control and Prevention, represents a most valuable source of evidence regarding suitable means to best possibly cope with the growing challenges of cardiovascular disease in a rapidly changing healthcare landscape in future China. The current higher rate of de novo HF and worse outcomes in female participants are likely to have a multifactorial background, in line with a previous study addressing this issue in Chinese women with ACS, regardless of the presence of HF[23]. Female patients were not only older than men but were also less likely to receive evidence-based acute treatments for ACS, including early dual antiplatelet therapy, heparins during hospitalization, and reperfusion therapy for STEMI. This calls for targeted quality improvement programs to reduce sex-related disparities in quality of care and outcomes. The observation that patients with a revascularization history had a decreased risk of developing de novo HF may suggest that better a priori information about ischemic heart disease could have prompted patients to seek medical help earlier and highlights the need for continued population-wide knowledge campaigns regarding various cardiovascular diseases and their prevention and sequels. Xie et al.[17] are right to conclude that, given the current incidence rates of de novo HF, further efforts are mandatory that make reperfusion therapies available to all patients with STEMI in contemporary China. Reducing the time to reperfusion and minimizing the risk of incident acute HF are essential goals. The excellent infrastructure of the chest pain centers, together with the growing efficiency of regional cooperative rescue systems and awareness programs, will help spread knowledge on warning symptoms preceding a heart attack, improve the recognition of ACS by patients themselves, and remind everyone that ischemic heart disease has become the number one killer in China, regardless of sex. Given the nationwide organization of the NPCPC and impressive quality improvements in cardiovascular medicine, the future of China’s ongoing fight against HF complicating ACS looks bright. AUTHOR CONTRIBUTIONS CEA and GE jointly conceived and planned this editorial. CEA took the lead in writing the manuscript, to which GE contributed significant intellectual content. CONFLICT OF INTEREST STATEMENT The authors declare that they have no conflict of interest with regard to the content of this manuscript. DATA SHARING STATEMENT Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.