Question

10. What is a myocardial infarction? Explain the process of how a myocardial infarction in the left ventricle can lead to congestive heart failure?

Answer 1

A heart attack, or myocardial infarction (MI), is permanent damage to the heart muscle. "Myo" means muscle, "cardial" refers to the heart, and "infarction" means death of tissue due to lack of blood supply.

HF is defined as “a clinical syndrome resulting from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill or eject blood”[10]. This has been translated into several validated diagnostic criteria (e.g., the Framingham criteria[11] and the European Society of Cardiology criteria[12]), but the primary definition of HF as a clinical syndrome has led to differing clinical, imaging and biomarker definitions coexisting in clinical practice and research. Unlike MI, there is no “universal definition” and consequently, the diagnosis of HF is often heterogeneous between studies and over time[13].

Early studies of HF following MI used clinical criteria such as the Killip and New York Heart Association classifications[14,15]. While crude, Killip class has retained prognostic value in more recent cohorts such as the GRACE registry: Patients in Killip class I had an in-hospital mortality of 3%, rising to 20% for those in class III[16]. In the PPCI population, higher Killip class at presentation is an independent predictor of in-hospital and 6-mo mortality[17]. Clinical HF scores were refined by the development of echocardiography, which led to objective measurement of ejection fraction and ventricular volumes as an intrinsic part of a HF diagnosis[18].

The timing of HF following MI is important clinically, mechanistically and for research. Three key time periods need to be distinguished: HF at the index MI presentation, during the course of the first admission, and after discharge. The timing of HF is often not well-defined by research studies, making comparison between studies challenging. From a statistical perspective, older studies failed to treat HF as a time-dependent, evolving covariate whose incidence was modifiable by the up-front treatment, meaning that late-onset HF after MI is less well characterised than HF at presentation[19].

PATHOPHYSIOLOGY OF HF AFTER MI

Several overlapping mechanisms contribute to HF after MI (Figure ​(Figure1).1). HF during the index MI occurs due to a combination of myocardial stunning, myocyte necrosis, decompensation of pre-existing HF or acute mitral regurgitation due to papillary muscle dysfunction. HF during the hospitalisation may also be due to any of the above, compounded by fluid or contrast overload, renal dysfunction, or complications such as ventricular septal defect or cardiac tamponade. Late HF reflects the consequences of cardiomyocyte death and scar formation occurring alongside ventricular remodelling.

The cellular pathophysiology of MI has been clearly defined in animal models. Within 30 min of ischaemia, cardiomyocyte structural changes and oedema develop, leading to progressive cell death from three hours. Acute contractile dysfunction occurs due to oxidative stress and calcium overload, which is reversible if flow is restored[20]. Reperfusion itself causes a second wave of injury, by production of reactive oxygen species. Despite successful epicardial reperfusion, embolization of thrombotic debris, plugging by inflammatory cells and release of vasoactive mediators from damaged endothelium leads to ongoing microvascular dysfunction in up to 50% of patients[21].

Myocardial injury leads to activation of a stereotyped inflammatory cascade, comprised of early neutrophil ingress followed by monocyte-macrophage infiltration. Between days 3-5 following MI there is a transition from inflammation to repair, with activation of fibroblasts and progressive scar deposition[22]. Over time there is compensatory activation of the renin-angiotensin and sympathetic nervous systems and pathological remodelling, with changes to the ventricular geometry, wall thinning, ischaemic mitral regurgitation and further cardiomyocyte loss. The precise contribution of the different pathophysiological components (e.g., microvascular dysfunction, inflammation) to injury is likely to be heterogeneous, and understanding mechanistic pathways in specific patient subgroups will be key to identifying novel therapeutic strategies[23].

TEMPORAL TRENDS IN HF AFTER MI

HF after MI was first described as an adverse prognostic feature by Killip in the 1960s[14]. HF was associated with large infarcts and multivessel disease, and the presence of impaired ventricular function was linked to worsening mortality[24,25]. Prior to thrombolysis, the incidence of in-hospital HF after ST-elevation myocardial infarction (STEMI) was approximately 40%[15]. This appeared to reduce after the introduction of thrombolysis, with HF present in approximately 3% of patients at presentation and 17% during admission[26]. Successful reperfusion was associated with improved LV function and long-term survival[27]. HF during admission remained an adverse prognostic feature, with 1-year mortality rates approximately 5 fold higher in those with HF[28].

More recent studies have suggested a further reduction in HF rates with use of primary PCI. In an Italian cohort of 2089 MI patients treated exclusively by PPCI between 1995 and 2005, 17% presented in HF, but only a further 1% developed new onset HF during the hospital admission[29]. Similarly, in an analysis from the HORIZONS-AMI cohort of 3602 patients recruited between 2005-2007 treated with PPCI, 8.0% of patients were in Killip class II-IV at presentation. At 30 d, only 4.6% of patients had developed a clinical HF syndrome (defined by NYHA/Killip class), rising to 5.1% at 2 years[30].

These studies are not directly comparable, and reflect selected trial cohorts with a short duration of follow-up and differing methods of HF ascertainment. Several dedicated time trend analyses have now been performed. In Olmsted County, 1537 patients with an index MI between 1979 and 1994 were identified, spanning the introduction of thrombolysis in the late 1980s[31]. Over the study period the 5-year incidence of HF decreased from 40% to 33%. In a later study of 2596 MI patients between 1990 and 2010, there was increasing use of PPCI and a reduced risk of both early (0-7 d; HR = 0.67, 95%CI: 0.54-0.85) and late (8 d-5 years; HR = 0.63, 95%CI: 0.45-0.88) HF over time[32]. In patients with HF, mortality was higher for those with delayed vs early onset HF[33].

A reduction in post-MI HF has also been seen in other studies. In a sample of 2.8 million MI hospitalisations (in Medicare beneficiaries) between 1998-2010, there was a reduction in the incidence of subsequent HF hospitalisation from 16 to 14 per 100 person-years[34]. In a Danish cohort, the incidence of HF at 90 d post-MI reduced from 24% to 20% alongside a an increase in PCI from 2.5% to 38% between 1997 and 2010[35]. Similarly, in Western Australia there was a reduction in the prevalence of HF at 90 d from 28% to 17% between 1996 and 2007[36]. Finally, in the SWEDEHEART registry of 199851 patients admitted with an MI between 1996 and 2008, there was a reduction in the incidence of clinical HF (albeit measured during the index hospitalization) from 46% to 28% alongside increasing use of PPCI[37].

In contrast, data from Framingham Heart Study shows an increase in HF over time[38,39]. In 676 patients who developed a first MI between 1970 and 1999, both the 30-d and 5-year incidence of HF increased. At 5 years, the incidence of HF was 28% in 1970-1979 and 32% in 1990-1999, which remained significant after multivariate adjustment, with a risk ratio of 1.74 (95%CI: 1.07-2.84) for HF in 1990-1999 compared with 1970-1979[39]. Similarly, the Worcester Heart Attack Study showed an increasing incidence of HF between 1975 and 2001, and in the Alberta Elderly MI cohort, there was a 25% increase in the incidence of in-hospital HF between 1994-2000, from 31% to 39%[40,41].

In the face of conflicting data from a relatively small number of studies, it remains difficult to draw firm conclusions on the impact of PPCI on the incidence of HF. There are key differences between studies in the definition of HF and MI, the validation of these diagnoses, the timing of ascertainment and the duration of follow-up. While the majority appear to suggest that PPCI is associated with reduced HF incidence, for many the duration of follow-up is short. Some studies have not differentiated between incident and prevalent cases. Reconciling these differences will require further studies with long term follow-up. If increasing survival from MI is leading to a rise in HF, this may only be seen in updated analyses, as interventionalists take on increasingly frail and elderly patients who previously were not surviving[42].

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