Left Ventricular Infarct Size Research Articles

Myocardial strain combined with clinical risk factors in the prediction of in-hospital heart failure among patients with ST-segment elevation myocardial infarction

To investigate the predictive value of myocardial strain derived from cardiac magnetic resonance (CMR) combined with clinical indicators for in-hospital heart failure (HF) in STEMI patients. In all, 139 STEMI patients were included, with 28 in the heart failure group and 111 in the non-HF group, and clinical and laboratory data were collected. Left ventricular (LV) global radial strain (GRS), global longitudinal strain (GLS), global circumferential strain (GCS), left ventricular ejection fraction (LVEF), stroke volume (SV), and infarct size (IS) were assessed by CMR. The HF group had worse GRS, GLS, GCS, LVEF, SV, larger IS, longer symptom to balloon time (SBT) and higher levels of high-sensitivity C-reactive protein (hs-CRP) and neutrophil percentage (N%) than the non-HF group (P<0.05). There was a strong correlation between GRS and LVEF (r=0.741, P<0.001). After adjustment for CMR and clinical risk factors, GRS<15.6%, LVEF<37.7%, SBT>350 min, hs-CRP>11.45 mg/L, and N%>74% were independently associated with HF. Clinical model (SBT>350 min+hs-CRP>11.45 mg/L+N%>74%) were associated with a lower diagnostic accuracy for predicting in-hospital HF than GRS+clinical co-model and LVEF+clinical co-model (P<0.05), respectively. There was no significant difference in the area under the curve (AUC) between GRS+clinical co-model and LVEF+clinical co-model (P=0.620): AUC for clinical model=0.824, AUC for GRS+clinical co-model=0.895, and AUC for LVEF+clinical co-model=0.907. GRS may be effective in predicting in-hospital heart failure after STEMI compared to LVEF, a classical cardiac function parameter, and its combination with clinical risk factors, especially SBT, hs-CRP, and N%, may provide further evidence for early prognostic assessment.

Effect of long-term inorganic nitrate administration on myocardial ischemia-reperfusion injury in ovariectomized rats.

Introduction: Menopause is associated with reduced nitric oxide (NO) bioavailability and lower tolerance against myocardial ischemia-reperfusion (IR) injury. This study investigated whether long-term nitrate administration provides resistance against myocardial IR injury in ovariectomized (OVX) rats. Method: After ovariectomy, female rats were assigned to the OVX and the OVX + nitrate groups (n = 14/group); the latter group consumed nitrate (100mg/L) for 9months. At month 9, each group was divided into two subgroups (n = 7/subgroup), of which one subgroup was exposed to myocardial IR (IR+ hearts) and the other was not exposed (IR- hearts). The hearts of rats were isolated, and NO metabolite (NOx), oxidative stress indices, and mRNA expressions of endothelial (eNOS), inducible (iNOS), and neuronal (nNOS) NO synthases, as well as markers of apoptosis, were measured in the IR- and IR+ hearts. In the IR+ hearts, cardiac function indices (CFI) and the infarct size were also measured. Results: Nitrate increased catalase activity (97%) and eNOS expression (2.94-fold) in the IR- hearts. In the IR+ hearts, nitrate reduced left ventricular (LV) end-diastolic pressure (11.6%) and infarct size (26.2%) and increased recovery of LV developed pressure (44.0%) and peak rate of positive (28.9%) and negative (15.4%) changes in LV pressure. In addition, in the IR+ hearts, nitrate increased eNOS and B-cell lymphoma-2 (Bcl-2) as well as decreased iNOS, Bcl-2 associated X protein (Bax), caspase-3, caspase-8, caspase-9, and tumor necrosis factor-α (TNF-α) expression. Nitrate increased total antioxidant capacity (TAC) and catalase (CAT) activity and decreased malondialdehyde (MDA) levels at month nine in serum and IR+ hearts. Conclusion: The favorable effects of nitrate against IR injury were associated with higher eNOS and Bcl-2 expression, CAT activity, TAC, and lower iNOS, Bax, caspase-3, caspase-8, caspase-9 and TNF-α expression, and MDA in the heart tissue. Nitrate preconditioning alleviated IR-induced myocardial injury in OVX rats; this effect was associated with eNOS upregulation before IR and the blunting of OVX-induced eNOS downregulation, iNOS upregulation, apoptosis, and oxidative stress in heart tissue after IR.

Fractal analysis of left ventricular trabeculae in post-STEMI: from acute to chronic phase.

The temporal evolution of ventricular trabecular complexity and its correlation with major adverse cardiovascular events (MACE) remain indeterminate in patients presenting with acute ST elevation myocardial infarction (STEMI). This retrospective analysis enrolled patients undergoing primary percutaneous coronary intervention (pPCI) for acute STEMI, possessing cardiac magnetic resonance (CMR) data in the acute (within 7days), subacute (1month after pPCI), and chronic phases (6months after pPCI) from January 2015 to January 2020 at the three participating sites. Fractal dimensions (FD) were measured for the global, infarct, and remote regions of left ventricular trabeculae during each phase. The potential association of FD with MACE was analyzed using multivariate Cox regression. Among the 200 analyzed patients (182 men; median age, 61years; age range, 50-66years), 37 (18.5%) encountered MACE during a median follow-up of 31.2months. FD exhibited a gradual decrement (global FD at acute, subacute, and chronic phases: 1.253 ± 0.049, 1.239 ± 0.046, 1.230 ± 0.045, p < 0.0001), with a more pronounced decrease observed in patients subsequently experiencing MACE (p < 0.001). The global FD at the subacute phase correlated with MACE (hazard ratio 0.89 (0.82, 0.97), p = 0.01), and a global FD value below 1.26 was associated with a heightened risk. In patients post-STEMI, the global FD, serving as an indicator of left ventricular trabeculae complexity, independently demonstrated an association with subsequent major adverse cardiovascular events, beyond factors encompassing left ventricular ejection fraction, indexed left ventricular end-diastolic volume, infarct size, heart rate, NYHA class, and post-pPCI TIMI flow. In patients who have had an ST-segment elevation myocardial infarction, global fractal dimension, as a measure of left ventricular trabeculae complexity, provided independent association with subsequent major adverse cardiovascular event. • Global and regional FD decreased after STEMI, and more so in patients with subsequent MACE. • Lower global FD at the subacute phase and Δglobal FD from acute to subacute phase were associated with subsequent MACE besides clinical and CMR factors. • Global FD at the subacute phase independently correlated with MACE and global FD value below 1.26 was associated with higher risk.

Differences in left ventricular myocardial function and infarct size in female patients with ST elevation myocardial infarction and spontaneous coronary artery dissection.

Differences in pathophysiology, clinical presentation, and natural course of ST-elevation myocardial infarction in female patients due to either spontaneous dissection (SCAD-STEMI) or atherothrombotic occlusion (type 1 STEMI) have been discussed. Current knowledge on differences in left ventricular myocardial function and infarct size is limited. The aim of this study was to assess baseline clinical characteristics, imaging findings, and therapeutic approach and to compare differences in echocardiographic findings at baseline and 3-month follow-up in patients with SCAD-STEMI and type 1 STEMI. This was a prospective multicenter study of 32 female patients (18-55 years of age) presenting with either SCAD-STEMI due to left anterior descending coronary artery (LAD) dissection or type 1 STEMI due to atherothrombotic LAD occlusion. The two groups were similar in age, risk factors, comorbidities, and complications. SCAD-STEMI patients more often had Thrombolysis in Myocardial Infarction 3 flow, while type 1 STEMI patients were more often treated with percutaneous coronary intervention and dual antiplatelet therapy. Baseline mean left ventricular (LV) ejection fraction (LVEF) was similar in the two groups (48.0% vs. 48.6%, p = 0.881), but there was a significant difference at the 3-month follow-up, driven by an improvement in LVEF in SCAD-STEMI compared to type 1 STEMI patients (Δ LVEF 10.1 ± 5.3% vs. 1.8 ± 5.1%, p = 0.002). LV global longitudinal strain was slightly improved in both groups at follow-up; however, the improvement was not significantly different between groups (-4.6 ± 2.9% vs. -2.0 ± 2.8%, p = 0.055). The results suggest that female patients with SCAD-STEMI are more likely to experience improvement in LV systolic function than type 1 STEMI patients.

The paradox of the association between epicardial adipose tissue, infarct size and left ventricular remodelling after ST-segment elevation myocardial infarction: a CMR study

Abstract Background Epicardial adipose tissue (EAT) is a biologically active fat deposit contained below the visceral pericardium. In latest years, EAT has emerged as a predictor of atherosclerosis, coronary artery disease and adverse cardiovascular events. Nevertheless, EAT significance after ST-segment elevation myocardial infarction (STEMI) in acute phase and its association with left ventricular remodelling is unknown. Purpose We aimed to assess the association of cardiac magnetic resonance (CMR)-derived EAT with the extent of infarct size (IS), microvascular obstruction (MVO) and left ventricular remodelling in a homogeneous cohort of STEMI patients. Methods We prospectively included 255 patients discharged after a first reperfused, anterior STEMI. An early CMR (1-week after STEMI) was performed in all patients. EAT volume (mL/m2), left ventricular (LV) end-diastolic and end-systolic indexed volumes (LVEDiV and LVESiV, mL/m2), left ventricular ejection fraction (LVEF, %), infarct size (IS, % of LV mass) and microvascular obstruction (MVO, % of LV mass) were quantified. A subgroup of 195 patients underwent a follow-up (6-month) CMR. Patients were categorized as extensive EAT (&amp;gt;35 mL/m2) or non-extensive EAT (≤35 mL/m2) according to the upper tertile of this parameter. A specific analysis was performed in patients with extensive IS (&amp;gt;30% of LV mass). Results Patients with extensive EAT were older (62±12 vs. 57±13 years, p=0.004), had an increased prevalence of diabetes mellitus (31% vs. 16%, p=0.007) and depicted a worse baseline risk profile (GRACE risk score 138±37 vs. 126±36 points, p=0.02). At 1-week CMR, patients with extensive EAT displayed larger IS (31±17% vs 24±16%, p=0.001), more MVO (1.4 [0-6.2]% vs 0 [0-2.5]% of LV mass, p=0.022) and more myocardial oedema (39±16% vs 32±17% of LV mass, p=0.003). After adjustment for baseline characteristics, EAT was independently associated with IS (standardized beta coefficient=0.30, p&amp;lt;0.001). However, patients with extensive EAT did not show neither larger LV volumes nor more depressed LVEF (p&amp;gt;0.1 for all comparisons). In the extensive IS subgroup (n=69, 27%), patients with extensive EAT depicted less dilated ventricular volumes (LVEDiV 90±26 vs 111±40 mL/m2, p=0.011; LVESiV 51±26 vs 72±36 mL/m2, p=0.009) and higher LVEF (46±13 vs. 38±10%, p=0.007) at 6-month CMR. At 6-month CMR, in a propensity score-matched population (n=170, 85 with extensive EAT and 85 without extensive EAT), EAT was independently associated with more preserved LVEF, and less dilated LVEDiV and LVESiV only in the subgroup of patients with extensive IS (p&amp;lt;0.05 for all comparisons) (Figure 1). Conclusions EAT seems to exert a bimodal effect in patients with anterior STEMI. More extensive EAT is associated with more extensive infarct size in acute phase but, in patients with large IS, those with extensive EAT display less adverse remodelling during follow-up. This "paradox" of EAT after STEMI merits further investigation.Figure 1.

Time of day dependent symptom onset is not associated with left ventricular function and myocardial damage after ST-segment elevation myocardial infarction

Abstract Background Circadian processes are suggested to influence ischemic injury in ST-segment elevation myocardial infarction (STEMI). Observational data suspect a circadian dependence of the occurrence of microvascular obstruction (MVO) in patients with STEMI. However, these observations derive from a small sample size and circadian variations in left ventricular function and myocardial damage after STEMI are still a matter of controversy. Purpose We aimed to investigate the association of time of day dependent symptom onset with left ventricular ejection fraction (LVEF), infarct size (IS) and MVO in a large cohort of STEMI patients treated with primary percutaneous coronary intervention (PCI). Methods This observational study investigated acute STEMI patients treated with primary PCI. Cardiac magnetic resonance (CMR) imaging was performed within 1 week after the index event for the determination of left ventricular function and infarct characteristics. The time of symptom onset was used to discriminate patients according to LVEF, IS as well as MVO occurrence and extent over a 24 hours cycle to evaluate circadian behavior. Results In final analysis, 889 acute STEMI patients treated with primary PCI with a delay of 189 [120-315] minutes were included. Median age of the overall cohort was 57 [51-66] years and 17% were female. Median LVEF was 49 [42-55]%, IS assumed 15.5 [8.0-24.7]% of left ventricular myocardial mass (LVMM) and MVO occurred in 57% of STEMI patients. No hourly differences between symptom onset and MVO occurrence (p=0.108), MVO extent (p=0.735), LVEF (p=0.644) and IS (p=0.722) have been evaluated. When comparing 3 hourly segments of symptom onset, no variations in MVO occurrence (p=0.114), MVO extent (p=0.308), LVEF (p=0.547) and IS (p=0.405) were observed. Conclusions No circadian variations in symptom onset and the occurrence and extent of MVO, LVEF and IS were observed in this large cohort of STEMI patients treated with primary PCI. Further research is needed to investigate the complex interplay between circadian processes and ischemic injury in this patient population.

Stimulation of soluble guanylyl cyclase in erythrocytes induces export of cGMP and cardioprotection in type 2 diabetes

Abstract Background Red blood cells (RBCs) are known to export cardioprotective nitric oxide (NO) bioactivity. Although, RBCs contain a functional soluble guanylyl cyclase (sGC), the signalling behind the export of NO bioactivity remains unclear. Impairment of NO signalling in RBCs has been suggested to contribute to augmented cardiac ischemia-reperfusion injury in type 2 diabetes (T2D). We hypothesized that increased NO signaling by stimulation of sGC in RBCs protects from myocardial ischemia-reperfusion injury by release of a cardioprotective signal. Purpose To investigate whether stimulation of sGC, the intracellular NO receptor, in RBCs from T2D patients induces export of a cardioprotective factor and to determine its nature. Methods RBCs were collected from patients with T2D and from gender- and age-matched healthy subjects and incubated with different pharmacological compounds affecting the NO-signalling pathway. The RBCs or their supernatant were then administered to isolated Langendorff-perfused rat hearts subjected to 25 min global ischemia and 60 min reperfusion. Left ventricular developed pressure and infarct size were measured. ELISA and immunofluorescence were used to determine levels of cyclic guanosine monophosphate (cGMP) and substrate of protein kinase G activation. All animal experiments and procedures were performed according to the guidelines by the U.S National Institutes of Health (NIH publication no 85-23, revised 1996). The present study was performed following The Code of Ethics of the World Medical Association outlined in the Declaration of Helsinki of 1975 and revised in 1983 for experiments that involve human subjects. Results RBCs from T2D patients impaired post-ischemic cardiac function and increased infarct size compared to RBCs from healthy subjects, and these effects were prevented by pre-incubation of the RBCs with the sGC stimulator CYR715. Administration of the supernatant from RBCs incubated with the sGC stimulator resulted in similar cardioprotection, indicating release of a cardioprotective factor from the RBCs (Figure 1A and B). The cardioprotection was abolished by inhibition of transport of cGMP with MK571, an inhibitor of cyclic nucleotide transport. Extracellular cGMP levels in the supernatant from RBCs were increased following sGC stimulation, and administration of exogenous cGMP induced cardioprotection (Figure 1C and D). Expression of protein kinase G-dependent phosphorylated vasodilator-specific phosphoprotein in cardiomyocytes was increased following administration of supernatant from RBCs incubated with the sGC stimulator (Figure 1E). Conclusions This study shows that stimulation of sGC in RBCs leads to release of a cardioprotective mediator, identified as cGMP, that activates cardiac protein kinase G and protects from ischemia-reperfusion injury. It further identifies RBC sGC as a novel therapeutic target to prevent cardiovascular injury in T2D.Figure 1

Paracrine cardioprotective signaling by red blood cells through hypoxia-mediated activation of soluble guanylate cyclase and release of cyclic guanosine monophosphate

Abstract Background Red blood cells (RBCs) are known to regulate cardiovascular function under hypoxic conditions and to mediate cardioprotection via nitric oxide (NO)-like bioactivity. However, the molecular signalling behind this effect and the identity of any mediator released by the RBCs remain unknown. Previous studies revealed that NO activates soluble guanylate cyclase (sGC) and increases formation of the second messenger cyclic guanosine monophosphate (cGMP) in RBCs. The functional role of this signalling in RBCs during hypoxia/ischemia is still unclear. Aim To determine the functional role of the NO-sGC-cGMP signalling pathway in RBCs during hypoxia and myocardial ischemia. Method RBCs collected from wild-type and sGC knockout mice were exposed to 1% hypoxia or normoxia for 1 h. The RBCs or the extracellular supernatant were then administered to isolated Langendorff-perfused mouse hearts subjected to 40 min global ischemia and 60 min reperfusion. Afterwards, left ventricular developed pressure and infarct size were determined. Additional groups of mice and patients with mild hypertension were given oral nitrate (10mM in their drinking water) before the collection of RBCs to further increase NO signalling. Result Administration of RBCs or the extracellular supernatant collected from wild-type mouse RBCs exposed to hypoxia to isolated hearts subjected to ischemia-reperfusion improved post-ischemic cardiac function and reduced infarct size (Fig. 1A and B). By contrast, supernatant collected from hypoxic RBCs of sGC knockout mice failed to induce cardioprotection (Fig. 1C). The cardioprotection induced by hypoxic RBCs of wild-type mice was blocked by MK571, an inhibitor of cyclic nucleotide transport (Fig. 1D). Hypoxia increased extracellular export of hate cGMP from mouse RBCs (Fig. 1E), and exogenous cGMP resulted in similar cardioprotection induced by the supernatant. The cardioprotective effect of RBCs was blocked by an inhibitor of cardiac cGMP-dependent protein kinase G (PKG) (Fig. 1F) and was associated with increased cardiac PKG-dependent phosphorylation of vasodilator-stimulated phosphoprotein. Oral administration of nitrate to mice for 4 weeks to increase NO bioactivity further enhanced the cardioprotective effect of hypoxic RBCs. RBCs collected from patients randomized to a 5-week nitrate-rich diet induced cardioprotection in the isolated rat heart via an effect dependent on sGC activation in the RBCs (Fig 2). Conclusion RBCs generate and export cGMP as a physiological response to hypoxia mediating cardioprotection via a paracrine effect. This effect can be further augmented by a simple dietary intervention with nitrate suggesting preventive and therapeutic opportunities in ischemic heart disease.Figure 1Figure 2

Xin-Li formula attenuates heart failure induced by a combination of hyperlipidemia and myocardial infarction in rats via Treg immunomodulation and NLRP3 inflammasome inhibition.

Heart failure (HF) is a complex clinical syndrome that represents the end result of several pathophysiologic processes. Despite a dramatic evolution in diagnosis and management of HF, most patients eventually become resistant to therapy. Xin-Li Formula (XLF) is a Chinese medicine formula which shows great potential in the treatment of HF according to our previous studies. The present study was designed to investigate the effects of XLF on HF induced by a combination of hyperlipidemia and myocardial infarction (MI) in rats and reveal the underlying mechanism. A rat model of HF induced by hyperlipidemia and MI was established with intragastric administration of XLF and Perindopril. Invitro, CD4+ T cells from mouse spleen and LPS/ATP-stimulated THP-1 macrophages were employed. XLF was shown to have markedly protective effects on MI-induced HF with hyperlipidemia in rats, including improvement of left ventricular function, reduction of left ventricular fibrosis and infarct size. Moreover, XLF administration significantly increased the number of Foxp3+ Tregs, and inhibited mTOR phosphorylation and NLRP3 signaling pathway. Invitro, we found that XLF had induced Treg activation via the inhibition of mTOR phosphorylation in CD4+ T cells. Additionally, XLF inhibited NLRP3 inflammasome activation in LPS/ATP-stimulated THP-1 macrophages. Taken together, this study raises the exciting possibility that Xin-Li Formula may benefit HF patients due to its immunomodulatory and anti-inflammatory effects via Treg activation and NLRP3 inflammasome inhibition.

Peak early diastolic strain rate improves prediction of adverse cardiovascular outcomes in patients with ST-elevation myocardial infarction.

The prognostic role of diastolic dysfunction measured by the circumferential peak early diastolic strain rate (PEDSR) on ST-elevation myocardial infarction (STEMI) is not completely established. We aimed to investigate the prognostic value of diastolic function by measuring PEDSR within 1week after STEMI. The cardiac magnetic resonance (CMR) pictures of 420 subjects from a clinical registry study (NCT03768453) were analyzed and the composite major adverse cardiac events (MACEs) were followed up. The PEDSR of patients was significantly lower compared with that of control subjects (P < 0.001). Within the median follow-up period of 52months, PEDSR of patients who experienced MACEs deceased more significantly than that of patients without MACEs (P < 0.001). After adjusting with clinical or CMR indexes, per 0.1/s reduction of PEDSR increased the risks of MACEs to 1.402 or 1.376 fold and the risk of left ventricular (LV) remodeling to 1.503 or 1.369 fold. When PEDSR divided by best cutoff point, significantly higher risk of MACEs (P < 0.001) and more remarkable LV remodeling (P < 0.001) occurred in patients with PEDSR ≤ 0.485/s. Moreover, when adding the PEDSR to the conventional prognostic factors such as LV ejection fraction and infarction size, better prognostic risk classification models were created. Finally, aging, tobacco use, remarkable LV remodeling, and a low LV ejection fraction were factors related with the reduction of PEDSR. Diastolic dysfunction has an important prognostic effect on patients with STEMI. Measurement of the PEDSR in the acute phase could serve as an effective index to predict the long-term risk of MACEs and cardiac remodeling.

Long-term inorganic nitrate administration protects against myocardial ischemia-reperfusion injury in female rats

BackgroundThe favorable effects of nitrate against myocardial ischemia-reperfusion injury (MIRI) have primarily focused on male rats and in short term. Here we determine the impact of long-term nitrate intervention on baseline cardiac function and the resistance to MIRI in female rats.MethodsFemale Wistar rats were randomly divided into untreated and nitrate-treated (100 mg/L sodium nitrate in drinking water for 9 months) groups (n = 14/group). At intervention end, levels of serum progesterone, nitric oxide metabolites (NOx), heart NOx concentration, and mRNA expressions of NO synthase isoforms (NOS), i.e., endothelial (eNOS), neuronal (nNOS), and inducible (iNOS), were measured. Isolated hearts were exposed to ischemia, and cardiac function indices (CFI) recorded. When the ischemia-reperfusion (IR) period ended, infarct size, NO metabolites, eNOS, nNOS, and iNOS expression were measured.ResultsNitrate-treated rats had higher serum progesterone (29.8%, P = 0.013), NOx (31.6%, P = 0.035), and higher heart NOx (60.2%, P = 0.067), nitrite (131%, P = 0.018), and eNOS expression (200%, P = 0.005). Nitrate had no significant effects on baseline CFI but it increased recovery of left ventricular developed pressure (LVDP, 19%, P = 0.020), peak rate of positive (+ dp/dt, 16%, P = 0.006) and negative (–dp/dt, 14%, P = 0.014) changes in left ventricular pressure and decreased left ventricular end-diastolic pressure (LVEDP, 17%, P < 0.001) and infarct size (34%, P < 0.001). After the IR, the two groups had significantly different heart nitrite, nitrate, NOx, and eNOS and iNOS mRNA expressions.ConclusionsLong-term nitrate intervention increased the resistance to MIRI in female rats; this was associated with increased heart eNOS expression and circulating progesterone before ischemia and blunting ischemia-induced increased iNOS and decreased eNOS after MIRI.

Cardiomyocyte-targeting exosomes from sulforaphane-treated fibroblasts affords cardioprotection in infarcted rats

BackgroundExosomes (EXOs), tiny extracellular vesicles that facilitate cell–cell communication, are being explored as a heart failure treatment, although the features of the cell source restrict their efficacy. Fibroblasts the most prevalent non-myocyte heart cells, release poor cardioprotective EXOs. A noninvasive method for manufacturing fibroblast-derived exosomes (F-EXOs) that target cardiomyocytes and slow cardiac remodeling is expected. As a cardioprotective isothiocyanate, sulforaphane (SFN)-induced F-EXOs (SFN-F-EXOs) should recapitulate its anti-remodeling properties.MethodsExosomes from low-dose SFN (3 μM/7 days)-treated NIH/3T3 murine cells were examined for number, size, and protein composition. Fluorescence microscopy, RT-qPCR, and western blot assessed cell size, oxidative stress, AcH4 levels, hypertrophic gene expression, and caspase-3 activation in angiotensin II (AngII)-stressed HL-1 murine cardiomyocytes 12 h-treated with various EXOs. The uptake of fluorescently-labeled EXOs was also measured in cardiomyocytes. The cardiac function of infarcted male Wistar rats intramyocardially injected with different EXOs (1·1012) was examined by echocardiography. Left ventricular infarct size, hypertrophy, and capillary density were measured.ResultsSustained treatment of NIH/3T3 with non-toxic SFN concentration significantly enhances the release of CD81 + EXOs rich in TSG101 (Tumor susceptibility gene 101) and Hsp70 (Heat Shock Protein 70), and containing maspin, an endogenous histone deacetylase 1 inhibitor. SFN-F-EXOs counteract angiotensin II (AngII)-induced hypertrophy and apoptosis in murine HL-1 cardiomyocytes enhancing SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a) levels more effectively than F-EXOs. In stressed cardiomyocytes, SFN-F-EXOs boost AcH4 levels by 30% (p < 0.05) and significantly reduce oxidative stress more than F-EXOs. Fluorescence microscopy showed that mouse cardiomyocytes take in SFN-F-EXOs ~ threefold more than F-EXOs. Compared to vehicle-injected infarcted hearts, SFN-F-EXOs reduce hypertrophy, scar size, and improve contractility.ConclusionsLong-term low-dose SFN treatment of fibroblasts enhances the release of anti-remodeling cardiomyocyte-targeted F-EXOs, which effectively prevent the onset of HF. The proposed method opens a new avenue for large-scale production of cardioprotective exosomes for clinical application using allogeneic fibroblasts.

Myocardial infarction-induced disruption of blood-brain barrier in hypothalamic paraventricular nucleus is mediated by interleukin-17A signaling in rat

Increased inflammatory cytokines in the circulation act in the brain to promote neuroinflammation and sympathetic excitation in myocardial infarction-induced heart failure (HF). However, the mechanisms by which proinflammatory cytokines interrupt blood-brain barrier (BBB) to reach brain remain unclear. We recently reported that the levels of interleukin (IL)-17A, a key inflammatory mediator of immune responses, are significantly elevated in circulation and the brain in HF. IL-17A has been shown to disrupt the integrity of BBB in in vitro model and in vivo rodent model of experimental autoimmune encephalomyelitis. The present study sought to determine whether BBB in hypothalamic paraventricular nucleus (PVN), a key cardiovascular/autonomic region of the brain within the BBB, was damaged in HF and if so, whether IL-17A contributes to BBB disruption in this disease setting. Adult male Sprague Dawley rats underwent coronary artery ligation to induce HF or sham surgery (Sham). Some HF rats were pretreated with bilateral PVN microinjections of an IL-17 receptor A (IL-17RA) siRNA AAV virus or a scrambled siRNA control. The left ventricular function and infarction size were evaluated by echocardiography. Four weeks after coronary artery ligation, BBB permeability was assessed with fluorescein isothiocyanate (FITC, 10 kDa)-dextran extravasation and molecular measurements of its biomarkers. FITC was injected through left carotid artery at a rate of 300 μl/min (10 mg/ml, 3 ml/kg) and allowed to circulate for 30 min. We found that HF rats displayed noticeable FITC extravasation within the PVN area when compared with brain cortex after injections. FITC extravasation was not observed in the PVN and brain cortex in Sham rats. Compared with Sham rats, HF rats had significantly increased PVN mRNA expression of caveolin-1 (1.05± 0.13 vs 3.30 ± 0.48*, fold changes; *P&lt;0.05), a molecular marker of transcytosis, and decreased PVN mRNA levels of occludin and zonula occludens-1 (1.05± 0.14 vs 0.57 ± 0.13*; 1.05± 0.10 vs 0.54 ± 0.03*, respectively), two important tight junction-associated molecules. However, the mRNA expression of caveolin-1, occludin or zonula occludens-1 did not display significant difference in the brain cortex between HF and Sham rats. Pretreatment with IL-17RA siRNA, substantially reduced FITC extravasation within the PVN and reversed mRNA expression of caveolin-1 (1.08 ± 0.20 vs. 0.51 ± 0.09*), occludin (1.07 ± 0.15 vs. 1.86 ± 0.18*) or zonula occludens-1 (1.02 ± 0.08 vs.1.84 ± 0.24*) in HF rats when compared with HF rats pretreated with a scrambled siRNA control. These data indicated that BBB permeability is increased in the PVN in myocardial infarction-induced HF. The activated IL-17A/IL-17RA signaling in BBB endothelium in the PVN in HF may play an important role in disrupting BBB, probably by a molecular mechanism to augment transcellular transport and reduce tight junction protein expression. Supported by NIH grants R01 HL-139521 &amp; HL-155091 to SGW This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Left Atrial Remodeling Following ST-Segment-Elevation Myocardial Infarction Correlates With Infarct Size and Age Older Than 70 Years.

Background Following myocardial infarction, left ventricular remodeling (LVR) is associated with heart failure and cardiac death. At the same time, left atrial (LA) remodeling (LAR) is an essential part of the outcome of a wide spectrum of cardiac conditions. The authors sought to evaluate the correlates of LAR and its relationships with LVR after myocardial infarction. Methods and Results This is a retrospective analysis of 320 of 443 patients enrolled for study of LVR after ST-elevation myocardial infarction. Left ventricular (LV) volumes, infarct size and LA volume index were assessed by cardiac magnetic resonance imaging during index hospitalization (day 6 [interquartile range, 4-8]) and after a 3-month follow-up. LAR was studied using a linear mixed model for repeated measurements. Overall, there was a decrease in LA volume index between 6 days and 3 months (43.9±10.4 mL versus 42.8±11.1 mL, P=0.003). Patients with changes in LA volume index >8% over time were older, with greater body mass index, lower LV ejection fraction, and larger infarct size. Unadjusted predictors of LAR were age older than 70 years, infarct size, anterior infarction, time to reperfusion, history of hypertension, LV end-diastolic volume, and heart failure at day 6. Independent correlates were age older than 70 years (3.24±1.33, P=0.015) and infarct size (2.16±0.72 per 10% LV, P<0.001). LA remodeling was correlated with LV remodeling (r=0.372, P<0.001), but neither LA nor LV volumes at day 6 were related to LVR or LAR, respectively. Conclusions The authors found LA changes to occur in the months after myocardial infarction, with an overall decrease in LA volumes. While LAR coincided with LVR, the correlates for LAR were age older than 70 years and larger infarct size.

Microvascular obstruction identifies a subgroup of patients who benefit from stem cell therapy following ST-elevation myocardial infarction

Microvascular obstruction (MVO) is associated with greater infarct size, adverse left-ventricular (LV) remodeling and reduced ejection fraction following ST-elevation myocardial infarction (STEMI). We hypothesized that patients with MVO may constitute a subgroup of patients that would benefit from intracoronary stem cell delivery with bone marrow mononuclear cells (BMCs) given previous findings that BMCs tended to improve LV function only in patients with significant LV dysfunction. We analyzed the cardiac MRIs of 356 patients (303 M, 53 F) with anterior STEMIs who received autologous BMCs or placebo / control as part of 4 randomized clinical trials that included the Cardiovascular Cell Therapy Research Network (CCTRN) TIME trial and its pilot, the multicenter French BONAMI trial and SWISS-AMI trials. A total of 327 patients had paired imaging data at 1 year. All patients received 100 to 150 million intracoronary autologous BMCs or placebo / control 3 to 7 days following primary PCI and stenting. LV function, volumes, infarct size and MVO were assessed prior to infusion of BMCs and 1 year later. Patients with MVO (n = 210) had reduced LVEF and much greater infarct size and LV volumes compared to patients without MVO (n=146) (P < .01). At 12 months, patients with MVO who received BMCs had significantly greater recovery of LVEF compared to those patients with MVO who received placebo (absolute difference=2.7%; P < .05). Similarly, left-ventricular end-diastolic (LVEDVI) and end-systolic volume indices (LVESVI) demonstrated significantly less adverse remodeling in patients with MVO who received BMCs compared to placebo. In contrast, no improvement in LVEF or LV volumes was observed in those patients without MVO who received BMCs compared to placebo. The presence of MVO on cardiac MRI following STEMI identifies a subgroup of patients who benefit from intracoronary stem cell therapy.

Residual ST-segment elevation to predict long-term clinical and CMR-derived outcomes in STEMI

Residual ST-segment elevation after ST-segment elevation myocardial infarction (STEMI) has traditionally been considered a predictor of left ventricular (LV) dysfunction and ventricular aneurism. However, the implications in terms of long-term prognosis and cardiac magnetic resonance (CMR)-derived structural consequences are unclear. A total of 488 reperfused STEMI patients were prospectively included. The number of Q wave leads with residual ST-segment elevation > 1 mm (Q-STE) at pre-discharge ECG was assessed. LV ejection fraction (LVEF, %) and infarct size (IS, % of LV mass) were quantified in 319 patients at 6-month CMR. Major adverse cardiac events (MACE) were defined as all-cause death and/or re-admission for acute heart failure (HF), whichever occurred first. During a mean follow-up of 6.1 years, 92 MACE (18.9%), 39 deaths and 53 HF were recorded. After adjustment for baseline characteristics, Q-STE (per lead with > 1 mm) was independently associated with a higher risk of long-term MACE (HR 1.24 [1.07–1.44] per lead, p = 0.004), reduced (< 40%) LVEF (HR 1.36 [1.02–1.82] per lead, p = 0.04) and large (> 30% of LV mass) IS (HR 1.43 [1.11–1.85] per lead, p = 0.006) at 6-month CMR. Patients with Q-STE ≥ 2 leads (n = 172, 35.2%) displayed lower MACE-free survival, more depressed LVEF, and larger IS at 6-month CMR (p < 0.001 for all comparisons). Residual ST-segment elevation after STEMI represents a universally available tool that predicts worse long-term clinical and CMR-derived structural outcomes.

Adenosine as adjunctive therapy in acute coronary syndrome: a meta-analysis of randomized controlled trials.

Adenosine has been tested in several randomized controlled trials (RCTs) to minimize the incidence of coronary microvascular obstruction (CMVO). The aim of this study was to pool all the RCTs comparing intracoronary or intravenous adenosine versus placebo in patients with acute coronary syndrome (ACS) undergoing myocardial revascularization. PubMed and Scopus electronic databases were scanned for eligible studies up to 5th June 2022. A total of 26 RCTs with 5843 patients were included. Efficacy endpoints were major adverse cardiac events (MACE), all-cause death, non-fatal myocardial infarction, and heart failure. Atrioventricular blocks and ventricular fibrillation/sustained ventricular tachycardia (VF/SVT) were the safety endpoints. Myocardial blush grade, thrombolysis in myocardial infarction (TIMI) flow grade, left ventricular ejection fraction (LVEF), infarct size, and ST-segment resolution were also assessed. Adenosine administration was not associated with any clinical benefit in terms of MACE, all-cause death, non-fatal myocardial infarction, and heart failure. However, adenosine was associated with an increased rate of advanced atrioventricular blocks and of VF/SVT in studies with total mean ischaemic time>3h, compared to placebo. Remarkably, among patients undergoing percutaneous coronary intervention, adenosine was associated with reduced myocardial blush grade 0-1 and TIMI flow grade 0-2, compared to placebo. Furthermore, adenosine did not show favourable effects on LVEF and infarct size. Adenosine infusion, as adjunctive therapy in ACS, was associated with an increased risk of advanced atrioventricular blocks and increased rates of adenosine-triggered ventricular arrhythmias in patients with long ischaemic time, without providing any clinical benefit compared to placebo.

ATP-Sensitive Potassium Channel Opener Diazoxide Reduces Myocardial Stunning in a Porcine Regional With Subsequent Global Ischemia Model.

Background ATP-sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic opening of ATP potassium channels with diazoxide preserves myocardial function following prolonged global ischemia, making it an ideal candidate for use during cardiac surgery. We hypothesized that diazoxide would reduce myocardial stunning after regional ischemia with subsequent prolonged global ischemia, similar to the clinical situation of myocardial ischemia at the time of revascularization. Methods and Results Swine underwent left anterior descending occlusion (30 minutes), followed by 120 minutes global ischemia protected with hyperkalemic cardioplegia±diazoxide (N=6 each), every 20 minutes cardioplegia, then 60 minutes reperfusion. Cardiac output, time to wean from cardiopulmonary bypass, left ventricular (LV) function, caspase-3, and infarct size were compared. Six animals in the diazoxide group separated from bypass by 30 minutes, whereas only 4 animals in the cardioplegia group separated. Diazoxide was associated with shorter but not significant time to wean from bypass (17.5 versus 27.0 minutes; P=0.13), higher, but not significant, cardiac output during reperfusion (2.9 versus 1.5 L/min at 30 minutes; P=0.05), and significantly higher left ventricular ejection fraction at 30 minutes (42.5 versus 15.8%; P<0.01). Linear mixed regression modeling demonstrated greater left ventricular developed pressure (P<0.01) and maximum change in ventricular pressure during isovolumetric contraction (P<0.01) in the diazoxide group at 30 minutes of reperfusion. Conclusions Diazoxide reduces myocardial stunning and facilitates separation from cardiopulmonary bypass in a model that mimics the clinical setting of ongoing myocardial ischemia before revascularization. Diazoxide has the potential to reduce myocardial stunning in the clinical setting.

Abstract 10915: Microvascular Obstruction Identifies a Subgroup of Patients Who Benefit From Intracoronary Stem Cell Delivery Following ST-Elevation Myocardial Infarction

Aims: Microvascular obstruction (MVO) following ST-elevation myocardial infarction (STEMI) is associated with greater infarct size, adverse left-ventricular (LV) remodeling and reduced ejection fraction. We hypothesized that patients with MVO may constitute a subgroup of patients that would benefit from intracoronary stem cell delivery with bone marrow mononuclear cells (BMCs) given previous findings that BMCs tended to improve LV function only in patients with significant LV dysfunction. Methods and Results: We analyzed the cardiac MRIs of 356 patients (303 M, 53 F) with anterior STEMIs who received autologous BMCs as part of 3 clinical trials that included the Cardiovascular Cell Therapy Research Network (CCTRN) TIME trial and its pilot (n=157), the multi-center French BONAMI trial (n=91) and the SWISS-AMI trial (n=108). All patients received 100 - 150 million intracoronary autologous BMCs or placebo / control 3 - 7 days following primary PCI and stenting. LV function, volumes, infarct size and MVO were assessed prior to infusion of BMCs and 1 year later. Patients with MVO (n=210) had reduced LVEF and much greater infarct size and LV volumes compared to patients without MVO (n=146) (all p &lt; 0.01) (TABLE). At 12 months, patients with MVO who received BMCs had significantly greater recovery of LVEF compared to those patients with MVO who received placebo (absolute difference = 2.7 %; p &lt; 0.05). Similarly, the changes in left-ventricular end-diastolic (LVEDV) and end-systolic volumes (LVESV) were consistent with significantly less adverse remodeling in patients with MVO who received BMCs compared to placebo ( % change; LVEDV = -9.7%; p &lt; 0.05 and LVESVI = -14.7 %; p = 0.006). In contrast, patients without MVO experienced no benefit of BMC administration compared to placebo. Conclusion: The presence of MVO on cardiac MRI following STEMI identifies a subgroup of patients who may benefit from intracoronary stem cell delivery of BMCs.

Only Acute but Not Chronic Thrombocytopenia Protects Mice against Left Ventricular Dysfunction after Acute Myocardial Infarction.

Platelets are major players of thrombosis and inflammation after acute myocardial infarction (AMI). The impact of thrombocytopenia on platelet-induced cellular processes post AMI is not well defined. The left anterior descending artery was ligated in C57/Bl6 mice and in two thrombocytopenic mouse models to induce AMI. Platelets from STEMI patients and from C57/Bl6 mice displayed enhanced platelet activation after AMI. This allows platelets to migrate into the infarct but not into the remote zone of the left ventricle. Acute thrombocytopenia by antibody-induced platelet depletion resulted in reduced infarct size and improved cardiac function 24 h and 21 days post AMI. This was due to reduced platelet-mediated inflammation after 24 h and reduced scar formation after 21 days post AMI. The collagen composition and interstitial collagen content in the left ventricle were altered due to platelet interaction with cardiac fibroblasts. Acute inflammation was also significantly reduced in Mpl-/- mice with chronic thrombocytopenia, but cardiac remodeling was unaltered. Consequently, left ventricular function, infarct size and scar formation in Mpl-/- mice were comparable to controls. This study discovers a novel role for platelets in cardiac remodeling and reveals that acute but not chronic thrombocytopenia protects left ventricular function post AMI.