Our study has several important findings. First, we define the natural history of LVEDP following reperfused STEMI for the first time. There is a very small reduction in LVEDP over the first few days after reperfusion, but this is of uncertain clinical significance. Second, STEMI patients with elevated LVEDP have higher rates of mortality and heart failure admissions. Third, even in patients with preserved LVEF or mild systolic dysfunction (i.e. LVEF > 40%) following STEMI, LVEDP remained a significant predictor of heart failure admissions and death. Fourth, the correlation between LVEDP and LVEF in STEMI patients, although statistically significant, was quite modest. Taken together, these findings suggest LVEDP could more accurately risk stratify patients after reperfused STEMI.
The management of STEMI has evolved over the decades since the TIMI II study. All patients in this trial had aspirin, heparin, rt-PA, beta blockers, nitrates and frusemide only. The guideline recommended STEMI management in the current era is either primary percutaneous coronary intervention (PCI) or early fibrinolysis followed by rescue or routine PCI. (13) The use of drug eluting stents for PCI, statins and dual anti-platelet therapy have further improved the prognosis of these patients. Similarly, availability of angiotensin converting enzyme inhibitors, angiotensin receptor blockers and mineralocorticoid antagonists have changed the dynamics of post myocardial infarction adverse remodelling and left ventricular dysfunction. (14) We restricted our analysis to the patients who had successful reperfusion with an open infarct-related artery i.e. TIMI flow grade 2 and 3 to ensure our analysis is as relevant as possible to the current clinical practice of early revascularisation.
The proposed mechanism of elevated LVEDP resulting in poor outcomes is adverse left ventricular remodelling (LVR) with subsequent left ventricular fibrosis (+/- dilatation), development of heart failure and scar-related ventricular arrhythmias. As per the Law of Laplace (left ventricular wall stress = (LVEDP x radius)/ (2 x wall thickness), the LVEDP contributes to wall stress, the primary driver of LVR following STEMI. (15) Thus, theoretically, interventions to reduce LVEDP, may in turn, reduce post-infarction remodelling, heart failure and mortality.
Our study adds to the existing literature showing that hemodynamic assessment provides important prognostic information in patients with STEMI. In the current era, several studies have evaluated the prognostic value of measuring LVEDP at primary PCI. Bagai et al. found in their cohort of 1909 patients undergoing primary PCI that the 90-day mortality after STEMI was higher (4.1% vs. 2.2%; P = 0.007) in patients who had an LVEDP above the median (> 22 mm Hg). (16) Similarly, Planer et al. showed that LVEDP was an independent determinant of adverse outcomes in multivariate analysis of 2797 patients undergoing primary PCI in the HORIZONS-AMI trial. Patients with LVEDP > 18 mm Hg (above the median) had increased risk of death at 30 days (hazard ratios 2.0; 95% confidence interval 1.20–3.33; P = 0.007) and 2 years (hazard ratios 1.57; 95% confidence interval 1.1 to 2.2; P = 0.009) compared to patients with LVEDP < 18 mmHg. (17) It is interesting to note that the median LVEDP in our cohort was the same as in the HORIZONS-AMI trial, suggesting modern medical therapy has done little to change the LVEDP acutely after STEMI.
A few hemodynamic risk stratification models of patients with STEMI have been proposed and LVEDP, when used in conjunction with other hemodynamic parameters, and left ventricular systolic function have demonstrated prognostic capacity in these models. Sola et al, in their single centre retrospective analysis of 219 STEMI patients, showed that a systolic blood pressure to LVEDP ratio ≤ 4 identified the group of STEMI patients at high risk of in-hospital death. (18) Similarly, in an analysis of 1283 STEMI patients, Ndrepepa et al. demonstrated that a lower LVEF/LVEDP ratio was independently associated with increased risk of cardiac mortality up to 8 years after primary PCI. (19) The LVEF/LVEDP ratio, but not LVEF or LVEDP alone, improved predictive accuracy of multivariable models with respect to long-term cardiac mortality.
Describing the natural history of LVEDP at baseline followed by a pre-discharge repeat cardiac catheterization is an interesting and unique finding of this study. It is interesting to note that despite successful reperfusion (TIMI flow grade ≥ 2) in this cohort, only a small proportion of patients had a significant decline in LVEDP from baseline to PHD catheterization. Thus, pharmacological and/or mechanical therapies to achieve early reduction of LVEDP may reduce subsequent heart failure and mortality.
Despite having adequate evidence-based anti-heart failure medications, post-myocardial infarction heart failure is still a clinical concern even when achieving the guideline-recommended door to balloon times in the contemporary management of STEMI in the developed world. (20, 21) This is related to ischemia and left ventricular loading resulting in adverse remodelling. Recently, there has been renewed interest in the early unloading of the left ventricle in the STEMI patients. (22, 23) The LVEDP, along with left ventricular end-systolic pressure, left ventricular volume and heart rate, are the drivers behind left ventricular loading and increased oxygen demand. This left ventricular loading correlates with the magnitude of myocardial injury in the STEMI patients and affects clinical outcomes. Satıroğlu et al. studied the acute impact of opening the infarct related artery in STEMI on left ventricular hemodynamic changes and compliance. (24) A total of 29 patients with anterior and inferior STEMI had aortic pressure and LVEDP measured before and after primary PCI in the cardiac catheterization laboratories. After successful reperfusion, the left ventricle compliance improved and LVEDP decreased by 6 ± 3 mmHg (p = 0.0005) and 5 ± 6 mmHg (p = 0.026) in inferior and anterior STEMI, respectively. This shows that opening the infarct related artery not only relieves ischemia but also has beneficial acute hemodynamic effects. Our study adds to the existing knowledge, showing that LVEDP continues to fall modestly over the next few days following reperfusion in STEMI.
Current guidelines focus on routine measurement of LVEF post myocardial infarction, due to its ease of measurement both at baseline and during follow up. Non-invasive parameters of diastolic function involving echocardiography have only a modest correlation with invasive LVEDP measurement. (25) Our study suggests that measuring LVEDP provides additional prognostic information in STEMI patients.
Despite the advancements in the management of patients with STEMI, elevated LVEDP has seldom been used as a treatment target. The elevated LVEDP in STEMI patients without cardiogenic shock can be safely reduced pharmacologically in the acute setting after primary PCI with a combination of nitrates and diuretics. (26) Thus, it is enticing to speculate that the early reduction in LVEDP in STEMI patients, specifically targeting those with the highest LVEDP, will reduce LVR and improve outcomes; however this hypothesis remains to be tested in prospective randomised controlled trials, such as the ongoing Reduction of End Diastolic Pressure in Acute Myocardial Infarction [REDPAMI] trial (registered at ANZCTR.org.au; registration number ACTRN12618000096257).
Our study has some important limitations. The TIMI II study recruited patients over 30 years ago and this is a post hoc analysis only. Therefore, it is subject to all the limitations of post-hoc analyses; however, we should point out that this relationship was hypothesised a priori and was not a result of data mining in this dataset. In recent decades, the treatment of STEMI has revolutionary changes, including primary PCI, dual antiplatelet therapy with potent P2Y12 inhibitors, routine use of angiotensin converting enzyme inhibitors (or angiotensin receptor blockers) and mineralocorticoid antagonist in left ventricular dysfunction and statins for dyslipidmia. Although the results from the TIMI II study could not reflect the current STEMI management it does highlight the natural history of elevated LVEDP and its effect on post myocardial infarction heart failure and mortality. It adds to our understanding the pathophysiology and can guide the future treatments, as improving post myocardial infarction heart failure outcomes is a big challenge for modern cardiovascular practice. (27) Thus, this analysis should be taken as hypothesis generating, and prospective randomized studies in this field are warranted especially as primary PCI outcomes have plateaued and we are now seeing an increase in survivors who develop heart failure post myocardial infarction.