This retrospective study leads to the following main findings. First, the current in-hospital CR incidence is 1.4% in STEMI patients but the real incidence is much higher considering the pre-hospitalization onset of CR since a high proportion of CR occurred within day-1 after STEMI. Second, the in-hospital and 60-day mortality of CR patients remains very high. Third, open-chest surgery, life support or device closure therapy are superior to medications to improve the prognosis of CR patients. Forth, the risk of CR is higher if STEMI patients are elderly, with large infarct size and high levels of inflammatory parameters. Finally, reperfusion post coronary artery occlusion completely eliminated onset of rupture in mice.
The overall incidence of CR reported in the literature prior to the pPCI era was 10–20%2, and the incidence of CR reported over the recent 10 years is around 1%1, 13, 14. In the current study, the in-hospital incidence of CR was 1.4% in STEMI patients. Practically, the true incidence of CR is difficult to reach, as indicated by our study revealing that 19/40 patients developed CR at admission. Such a high proportion of patients with early onset of CR highlights that CR remains a major challenge to modern cardiology and forms one of main reasons of sudden cardiac death post-MI. A further hurdle added to this challenge is the current very low autopsy rate. In a recent study, Chen et al analyzed 11,234 STEMI patients from the 7 major hospitals in China and found that the incidence of CR was between 1–4% among these hospitals15. Early reperfusion therapy could be the major factor responsible for the decline in the incidence of CR1. The results of mice experiment provides a strong experimental evidence for the overt reduction of rupture in the last few decades with the initially increasing and currently routine use of primary PCI. Although ACC/AHA10 and ESC 11 guidelines recommend reperfusion therapy within the first 12 hours after symptom onset in all STEMI patients, some STEMI patients could not receive reperfusion therapy due to various reasons including delay admission. Unfortunately, study has revealed that the proportion of patients in China who did not receive pPCI has not significantly improved over the last decade15. Low proportion of reperfusion therapy is likely one of the reasons for the onset of CR in-hospitalization.
Clinical reports prior to the reperfusion therapy era described the frequency of CR as two peaks: within 24 hours and during 6–14 days after STEMI with nearly even proportion 2, 16. In our population study, whilst the early peak of CR remains, the late peak of CR seems blunted. Based on the Becker classification of CR17, early CR is mainly type-I or type-II, whereas late rupture were type-III associated with significant wall thinning and ventricular remodeling. The clinicopathological features of early and late rupture are different18. Early phase rupture is characterized by an abrupt slit-like tear in the infarcted myocardium, while late phase rupture exhibits infarct expansion and wall thinning18.
While some studies indicated that reperfusion therapy could only decrease the incidence of late rupture while showing limited benefit on the early CR16, 19, it is generally agreed that early reperfusion is able to reduce the rupture incidence20. Although in this population study, 9 patients had early CR after pPCI, we cannot ignore the influence of reperfusion therapy. In the mice experiment, reperfusion therapy can decrease the CR incidence apparently. Whilst the mechanism for such an evident protection remains to be illustrated, considering that infarct size might be reduced by reperfusion after 1 h ischemia in mice study9, but not if ischemia last for 4 hours, it is clear that the protection associated with reperfusion not only to cardiomyocytes, but also to non-cardiomyocyte matrix tissues within the ischemic zone, is important. It remains to be tested whether mice with MI might develop CR under simulated hemodynamic, physical or psychological stressors.
Our study showed that the mortality of CR remained to be very high (64% within hospital and 72% within 60 days) relative to the earlier reports showing 100% mortality for FWR2 and approximately 90% for VSR without treatment21, albeit the mortality of patients underwent surgery for correction of VSR varied between 20–60%12,22. Management of CR patients is complex and might require a variety of therapeutic approaches, including pharmacologic (include ACEI, β-blocker, intravenous nitrates, and hydralazine) and device-based therapies to achieve afterload reduction and hemodynamic stabilization. Whilst medical therapy and non-pharmacologic methods may only stabilize CR patients, the treatment of choice is closure of rupture site by surgical and catheter-based means23, 24. The outcome of operated CR patients is closely related to their hemodynamic state prior to the surgery. Emergency surgery for CR has been limited in our hospital due to the fact that patients with CR are often in extremis prior the surgery and many died suddenly. On the other hand, currently the percutaneous devices to primarily close VSR are only applicable to selected cases with simple defects (e.g. VSR less than 15 mm in diameter) with the optimal time approximately 3 weeks following MI. In our cohort, only 2 out of 25 CR patients were suitable for percutaneous closure at 3 weeks after rupture occurred and they both survived over 60 days. Unfortunately, we experienced a high percentage of CR patients who refused further treatment because of reasons including critical conditions or high expenses.
In the current study, we revealed several independent risk factors of CR including female gender, old age, lower MI or angina history or higher heart rate, findings similar to earlier reports2, 5, 25, 26. Our study also added mechanistic insight by showing that both infarct size and the extent of inflammation are underlying factors for the onset of CR. The enzymatic index of infarct size, peak CK-MB27, was one of the independent risk factors of CR in patients with STEMI. However, caution is required since many patients died before they arrived hospital with their infarct size was difficult to assess due to lack of serial measure of CM-MB and hence such relationship between infarct size and the risk of early onset of CR remains elusive. CRP is a non-specific and commonly used biomarker for inflammatory response. Hepatic production of CRP is increased upon stimulation by various cytokines derived from innate immune response evoked by myocardial ischemia and infarction28. We also observed a significant correlation between peak levels of CK-MB and CRP, implying a causative relation of the scale of infarct mass and subsequent inflammatory response. Indeed, others have also reported association of CRP levels and indexed infarct size29, 30. Previous studies have shown that higher levels of CRP are associated with adverse prognosis in MI patients31 including CR. Further support of inflammatory mechanism comes from our finding of higher inflammatory cell counts in CR relative to non-CR patients.
We found that the majority of CR patients (68%) arrived hospital within 24 hours after symptom onset, a proportion higher than that of non-CR STEMI patients, albeit by logistic regression analysis excluded the time from symptom onset to hospital as an independent risk factor. The likely reason for the early admission of CR versus non-CR patients is due to the severity of symptom per se in patients with CR forcing them to seek medical assistance. Meanwhile, the rural location of residence of patients is an independent risk factor of CR. The possible explanation is that excessive time was required to arrive central hospitals to those patients who live in remote regions, and that common knowledge of MI was insufficient to those patients. Relevant to this is the limited availability of PCI especially pPCI in rural hospitals.
A significant body of knowledge has been generated by preclinical studies on the mechanism and therapeutic intervention of CR. With the demonstration of the mouse as the only laboratory species that develop CR post transmural MI like human patients32, numerous studies have been conducted in mice9, 33. Mechanistically, rupture event occurred in mice within a single onset peak timing (days 4–5) and there was no early onset of rupture within the first 48 hrs. This differs from human patients with MI showing that significant percentage of CR occurred within the first 24 hours and that following reperfusion and other therapies, the previously reported second peak of CR events was largely diminished CR in the mouse model typically occurs during 3–5 days after STEMI exhibiting wall thinning and dilatation by histopathology32, simulating the human type-III rupture. In the mouse model of MI, the infarct size and scale of inflammatory response are pivotal determinants of CR, observations in keeping with the findings from the present study9, 34. Furthermore, mice with an old age had a higher risk of CR than young counterparts and that such difference was associated with more severe cardiac inflammation35. Regional inflammation results in accumulation of proteinases, particularly matrix metalloproteinase-9, responsible for the breakdown of existing collagen networks leading to reduced tensile strength of the infarcted wall36–38. Therapeutically, studies on mice have revealed successful inhibition of CR by anti-inflammatory therapies39, reperfusion or use of some currently routine medications like anti-platelet drugs, ARB or ACEI33. Collectively, our findings on patients with CR are supported in part by studies in the mouse model of CR regarding significance of infarct size, age35, inflammation37, 39 and histopathology of type-III CR9, 32. Unlike human patients, CR in the mouse never occurs in the first day after MI and such species difference is interesting albeit unknown in the mechanism. Further research is required to illustrate the mechanism of early CR and test therapeutic interventions.
Our study has a few limitations that are worth to be discussed. This was a retrospective observational study consisting data from a single center, and hence had a limited number of CR cases. Some of laboratory or angiographic data were unable to obtain in those patients who had CR at admission. Furthermore, the diagnosis of CR was based on echocardiographic images and clinical characteristics, but without pathologic (autopsy) validation.