Cardiac rupture – the most serious complication of Takotsubo syndrome

Background The most serious complication of the acute Takotsubo phase is a myocardial perforation, which is rare, but it usually results in the death of the patient. Methods In the years 2008–2020, 265 patients were added to the Podlasie Takotsubo Registry. Cardiac rupture was observed in five patients (1.89%), referred to as the Takotsubo syndrome with complications of cardiac rupture (TS+CR) group. The control group consisted of 50 consecutive patients with uncomplicated TS. The diagnosis of TS was based on the Mayo Clinic Criteria. Results Cardiac rupture was observed in women with TS aged 74–88 years. Patients with TS and CR were older (82.20 vs. 64.84; p=0.011), than the control group, and had higher troponin, creatine kinase, aspartate aminotransferase, and blood glucose levels (168.40 vs. 120.67; p=0.010). The TS+CR group demonstrated a higher heart rate (95.75 vs. 68.38; p<0.0001) and the Global Registry of Acute Coronary Events (GRACE) scores (186.20 vs. 121.24; p<0.0001) than the control group. In patients with CR, ST segment elevation was recorded significantly more often in the III, V4, V5 and V6 leads. Left ventricular free wall rupture was noted in four patients, and in one case, rupture of the ventricular septum. In a multivariate logistic regression, the factors that increase the risk of CR in TS were high GRACE scores, and the presence of ST segment elevation in lead III. Conclusions Cardiac rupture in TS is rare but is the most severe mechanical complication and is associated with a very high risk of death. The main risk factors for left ventricular perforation are female gender, older age, a higher concentration of cardiac enzymes, higher GRACE scores, and ST elevations shown using electrocardiogram (ECG). FUNDunding Acknowledgement Type of funding sources: None.

Successful surgical repair of left ventricular pseudoaneurysm in a patient with subacute ST-elevation myocardial infarction

We report a successful surgical repair of left ventricular pseudoaneurysm in a patient with subacute ST-elevation myocardial infarction (STEMI). In the case of expansion of the infarct related ventricular wall, early (within 24 hours) or late (3-5 days after STEMI) cardiac rupture should be always borne in mind in order to proceed to life saving prompt surgical repair.

Secreted Frizzled-Related Protein 5 Protects Against Cardiac Rupture and Improves Cardiac Function Through Inhibiting Mitochondrial Dysfunction

Background: Secreted frizzled-related protein 5 (Sfrp5) has been suggested to be a protective regulatory protein in coronary heart disease. However, the role of Sfrp5 in regulating ischemic injury and its consequences is not known. The aim of our study was to explore the effects of Sfrp5 on hearts after myocardial infarction (MI) and to investigate the underlying mechanisms.Methods and Results: We found that Sfrp5 was downregulated over time in the heart tissue of MI mice. To further elucidate the role of Sfrp5 during MI, we established a cardiac overexpression of an Sfrp5 mouse model using the cardiotropic adeno-associated virus serotype 9 (AAV9). Overexpression of Sfrp5 significantly reduced infarct size as demonstrated by a decrease in mortality owing to cardiac rupture. Moreover, cardiac overexpression of Sfrp5 increased left ventricular function and mitochondrial biogenesis, decreased cardiomyocyte apoptosis, suppressed inflammation reaction, inhibited oxidative stress, and ameliorated cardiac remodeling as demonstrated by left ventricular ejection fraction, mitochondrial morphology, heart weight, NADH oxidase activity levels, and myocardial fibrosis at 2 weeks post-MI. At the molecular level, overexpression of Sfrp5 significantly increased the expression of p-AMPKThr172 protein with higher expression of mitochondrial fusion protein (MFN1 and MFN2) and lower expression of mitochondrial fission protein (p-Drp1Ser616/Mid49/MFF/Fis-1). In isolated neonatal rat cardiac myocytes, Sfrp5 treatment attenuated hypoxia-induced mitochondrial dysfunction. Inhibition of AMPK activity with compound C abrogated this benefit.Conclusions: Sfrp5 overexpression inhibits ischemic injury, reduces risk of cardiac rupture, ameliorates post-MI remodeling, and decreases the progression to heart failure via disrupting mitochondrial dysfunction and partly through normalizing the AMPK activity.

Excessive Hypoxia‐Inducible Factor‐1α Expression Induces Cardiac Rupture via p53‐Dependent Apoptosis After Myocardial Infarction

Background Apoptosis plays a pivotal role in cardiac rupture after myocardial infarction (MI), and p53 is a key molecule in apoptosis during cardiac rupture. Hif‐1α (hypoxia‐inducible factor‐1α), upregulated under hypoxia, is a known p53 inducer. However, the role of Hif‐1α in the regulatory mechanisms underlying p53 upregulation, apoptosis, and cardiac rupture after MI is unclear. Methods and Results We induced MI in mice by ligating the left anterior descending artery. Hif‐1α and p53 expressions were upregulated in the border zone at day 5 after MI, accompanied by apoptosis. In rat neonatal cardiomyocytes, treatment with cobalt chloride (500 μmol/L), which mimics severe hypoxia by inhibiting PHD (prolyl hydroxylase domain‐containing protein), increased Hif‐1α and p53, accompanied by myocyte death with caspase‐3 cleavage. Silencing Hif‐1α or p53 inhibited caspase‐3 cleavage, and completely prevented myocyte death under PHD inhibition. In cardiac‐specific Hif‐1α hetero‐knockout mice, expression of p53 and cleavage of caspase‐3 and poly (ADP‐ribose) polymerase were reduced, and apoptosis was suppressed on day 5. Furthermore, the cleavage of caspase‐8 and IL‐1β (interleukin‐1β) was also suppressed in hetero knockout mice, accompanied by reduced macrophage infiltration and matrix metalloproteinase/tissue inhibitor of metalloproteinase activation. Although there was no intergroup difference in infarct size, the cardiac rupture and survival rates were significantly improved in the hetero knockout mice until day 10 after MI. Conclusions Hif‐1α plays a pivotal role in apoptosis, inflammation, and cardiac rupture after MI, in which p53 is a critical mediator, and may be a prospective therapeutic target for preventing cardiac rupture.

Cardiac Fibrosis and Fibroblasts

Cardiac fibrosis is the excess deposition of extracellular matrix (ECM), such as collagen. Myofibroblasts are major players in the production of collagen, and are differentiated primarily from resident fibroblasts. Collagen can compensate for the dead cells produced by injury. The appropriate production of collagen is beneficial for preserving the structural integrity of the heart, and protects the heart from cardiac rupture. However, excessive deposition of collagen causes cardiac dysfunction. Recent studies have demonstrated that myofibroblasts can change their phenotypes. In addition, myofibroblasts are found to have functions other than ECM production. Myofibroblasts have macrophage-like functions, in which they engulf dead cells and secrete anti-inflammatory cytokines. Research into fibroblasts has been delayed due to the lack of selective markers for the identification of fibroblasts. In recent years, it has become possible to genetically label fibroblasts and perform sequencing at single-cell levels. Based on new technologies, the origins of fibroblasts and myofibroblasts, time-dependent changes in fibroblast states after injury, and fibroblast heterogeneity have been demonstrated. In this paper, recent advances in fibroblast and myofibroblast research are reviewed.

Cardiac Rupture—The Most Serious Complication of Takotsubo Syndrome: A Series of Five Cases and a Systematic Review

Background: The most serious complication of the acute Takotsubo phase is a myocardial perforation, which is rare, but it usually results in the death of the patient. Methods: In the years 2008–2020, 265 patients were added to the Podlasie Takotsubo Registry. Cardiac rupture was observed in five patients (1.89%), referred to as the Takotsubo syndrome with complications of cardiac rupture (TS+CR) group. The control group consisted of 50 consecutive patients with uncomplicated TS. The diagnosis of TS was based on the Mayo Clinic Criteria. Results: Cardiac rupture was observed in women with TS aged 74–88 years. Patients with TS and CR were older (82.20 vs. 64.84; p = 0.011), than the control group, and had higher troponin, creatine kinase, aspartate aminotransferase, and blood glucose levels (168.40 vs. 120.67; p = 0.010). The TS+CR group demonstrated a higher heart rate (95.75 vs. 68.38; p < 0.0001) and the Global Registry of Acute Coronary Events (GRACE) scores (186.20 vs. 121.24; p < 0.0001) than the control group. In patients with CR, ST segment elevation was recorded significantly more often in the III, V4, V5 and V6 leads. Left ventricular free wall rupture was noted in four patients, and in one case, rupture of the ventricular septum. In a multivariate logistic regression, the factors that increase the risk of CR in TS were high GRACE scores, and the presence of ST segment elevation in lead III. Conclusions: Cardiac rupture in TS is rare but is the most severe mechanical complication and is associated with a very high risk of death. The main risk factors for left ventricular perforation are female gender, older age, a higher concentration of cardiac enzymes, higher GRACE scores, and ST elevations shown using electrocardiogram (ECG).