SuperMap algorithm: an efficient, safe and accurate modality for mapping and eliminating challenging cardiac arrhythmias.

Even with the development of advanced catheter-based mapping systems, there remain several challenges in the electrophysiological evaluation and elimination of atrial arrhythmias. For instance, atrial tachycardias with irregular rates cannot be reliably mapped by systems that require stability in order to sequentially gather data points to be organized thereafter. Separately, these arrhythmias often arise following initial ablation for atrial fibrillation, posing logistic challenges. Here, we present the available literature summarizing the use of a non-contact mapping catheter, the AcQMap catheter, in conjunction with SuperMap, an algorithm that compiles a large number of non-contact data points from multiple catheter positions within the atria. These studies demonstrate the efficiency, safety and accuracy of this technology.

Irregular heart rhythms (arrhythmias) are often treatable with medications, but sometimes require expert evaluation in a cardiac electrophysiology laboratory. They are often studied and treated using thin, flexible catheters which enter the body through blood vessels in the leg and reach the internal walls of the heart. Time, expertise and specialized equipment are necessary to identify characteristics specific to each patient's arrhythmia. For each arrhythmia, a unique electrical blueprint is created before trying to eliminate it. The fleeting nature of certain arrhythmias can make it difficult to generate these blueprints, and many take a lot of time to accurately identify, leading to procedural challenges. Here we evaluate studies discussing the use of a new catheter (AcQMap) and its accompanying strategy for identifying arrhythmias. Unlike traditional catheters that require direct contact with the internal walls of the heart, the AcQMap catheter floats within these blood-filled chambers and does not touch the walls when obtaining data points. Instead, using ultrasound waves and electrical signals, it can generate data points to create blueprints. This technology also uses a new algorithm that enables the catheter to move freely within the heart, obtaining numerous data points and grouping them together to create maps efficiently and safely, even for fleeting or challenging arrhythmias.

Role of Guideline Directed Medical Therapy Doses and Optimization in Patients Hospitalized With Decompensated Systolic Heart Failure.

Despite significant advances in evidence-based treatments for heart failure with reduced ejection fraction (HFrEF), the use of guideline directed medical therapy (GDMT) at recommended doses remains suboptimal. We examine the usage and modification of inpatient GDMT and its effect on outcomes in patients hospitalized with a diagnosis of acute on chronic HFrEF between 2013 and 2018. Overall use and modification of GDMT, which included heart failure appropriate beta-blockers (BB), renin-angiotensin system inhibitors (RASi) and aldosterone blockers (MRA) during the hospitalization were collected. Target dosages were based on guideline recommendations. Primary endpoints included 30-day hospitalization-free survival and 1-year survival. Among 1,655 patients, discharge use of BB, RASi, and MRA was 73.4%, 55.9% and 13.8%, respectively. Upon discharge, ≥50% target dose of BB, RASi, and MRA was used in 25.3%, 15.6%, and 13.7%, respectively. In multivariable analyses, there was a statistically significant improvement in 1-year survival and 30-day hospitalization-free survival in patients discharged on increasing number of medication classes optimized at ≥50% target dose (per extra medication, HR 0.74, 0.64-0.86, p <0.001, and HR 0.73, 0.62-0.86, p = 0.0002), respectively. Initiation and/or uptitration of BB and RASi was associated with improved 30-day hospitalization-free survival and 1-year survival, (HR 0.73 (0.57-0.92), p = 0.0087; HR 0.62 (0.46-0.82), p <0.001) for BB and (HR 0.77 (0.62-0.95), p <0.001; HR 0.62 (0.48-0.80), p <0.001) for RASi, respectively. In conclusion, inpatient optimization of GDMT in acute HFrEF is feasible and associated with improved 30-day hospitalization-free survival and 1-year survival.

Management of ST Elevation Myocardial Infarction (STEMI) in Different Settings.

ST-segment elevation myocardial infarction (STEMI) is a life-threatening condition that requires emergent, complex, well-coordinated treatment. Although the primary goal of treatment is simple to describe-reperfusion as quickly as possible-the management process is complicated and is affected by multiple factors including location, patient, and practitioner characteristics. Hence, this narrative review will discuss the recommended management and treatment strategies of STEMI in the circumstances.

Severe pulmonary hypertension in aging female apolipoprotein E-deficient mice is rescued by estrogen replacement therapy.

BACKGROUND: Apolipoprotein E (ApoE) is a multifunctional protein, and its deficiency leads to the development of atherosclerosis in mice. Patients with pulmonary hypertension (PH) have reduced expression of ApoE in lung tissue. ApoE is known to inhibit endothelial and smooth muscle cell proliferation and has anti-inflammatory and anti-platelet aggregation properties. Young ApoE-deficient mice have been shown to develop PH on high fat diet. The combined role of female sex and aging in the development of PH has not been investigated before. Here, we investigated the development of PH in young and middle-aged (MA) female ApoE-deficient mice and explored the role of exogenous estrogen (E2) replacement therapy for the aging females. METHODS: Wild type (WT) and ApoE-deficient female mice (Young and MA) were injected with a single intraperitoneal dose of monocrotaline (MCT, 60 mg/kg). Some ApoE-deficient MA female mice that received MCT were also treated with subcutaneous E2 pellets (0.03 mg/kg/day) from day 21 to 30 after MCT injection. Direct cardiac catheterization was performed terminally to record right ventricular systolic pressure (RVSP). Right ventricular (RV), left ventricular (LV), and interventricular septum (IVS) were dissected and weighed. Lung sections were examined using trichrome and immunofluorescence staining. Western blot analyses of lung and RV lysates were performed. RESULTS: In WT female mice, the severity of PH was similar between young and MA mice as RVSP was not significantly different (RVSP = 38.2 ± 1.2 in young vs. 40.5 ± 8.3 mmHg in MA, p < 0.05). In ApoE-deficient mice, MA females developed significantly severe PH (RVSP = 63 ± 10 mmHg) compared to young females (RVSP; 36 ± 3 mmHg, p < 0.05 vs. MA female). ApoE-deficient MA females also developed more severe RV hypertrophy compared to young females (RV hypertrophy index (RV/[LV + IVS]) = 0.53 ± 0.06 vs. 0.33 ± 0.01, p < 0.05). ApoE-deficient MA female mice manifested increased peripheral pulmonary artery muscularization and pulmonary fibrosis. E2 treatment of MA female ApoE-deficient mice resulted in a significant decrease in RVSP, reversal of pulmonary vascular remodeling, and RV hypertrophy. In MA female ApoE-deficient mice with PH, only the expression of ERß in the lungs, but not in RV, was significantly downregulated, and it was restored by E2 treatment. The expression of ERα was not affected in either lungs or RV by PH. GPR30 was only detected in the RV, and it was not affected by PH in MA female ApoE-deficient mice. CONCLUSIONS: Our results suggest that only aging female ApoE-deficient but not WT mice develop severe PH compared to younger females. Exogenous estrogen therapy rescued PH and RV hypertrophy in aging female ApoE-deficient mice possibly through restoration of lung ERß.

Construction of two novel reciprocal conplastic rat strains and characterization of cardiac mitochondria.

Because of the lack of appropriate animal models, the potentially causal contributions of inherited mitochondrial genomic factors to complex traits are less well studied compared with inherited nuclear genomic factors. We previously detected variations between the mitochondrial DNA (mtDNA) of the Dahl salt-sensitive (S) rat and the spontaneously hypertensive rat (SHR). Specifically, multiple variations were detected in mitochondrial genes coding for subunits of proteins essential for electron transport, in mitochondrial reactive oxygen species production, and within the D-loop region. To evaluate the effects of these mtDNA variations in the absence of the corresponding nuclear genomic factors as confounding variables, novel reciprocal strains of S and SHR were constructed and characterized. When compared with that of the S rat, the heart tissue from the S.SHR(mt) conplastic strain wherein the mtDNA of the S rat was substituted with that of the SHR had a significant increase in mtDNA copy number and decrease in mitochondrial reactive oxygen species production. A corresponding increase in aerobic treadmill running capacity and a significant increase in survival that was not related to changes in blood pressure were observed in the S.SHR(mt) rats compared with the S rat. The reciprocal SHR.S(mt) rats did not differ from the SHR in any phenotype tested, suggesting lower penetrance of the S mtDNA on the nuclear genomic background of the SHR. These novel conplastic strains serve as invaluable tools to further dissect the relationship between heart function, aerobic fitness, cardiovascular disease progression, and mortality.

Pregnancy is associated with decreased cardiac proteasome activity and oxidative stress in mice.

During pregnancy, the heart develops physiological hypertrophy. Proteasomal degradation has been shown to be altered in various models of pathological cardiac hypertrophy. Since the molecular signature of pregnancy-induced heart hypertrophy differs significantly from that of pathological heart hypertrophy, we investigated whether the cardiac proteasomal proteolytic pathway is affected by pregnancy in mice. We measured the proteasome activity, expression of proteasome subunits, ubiquitination levels and reactive oxygen production in the hearts of four groups of female mice: i) non pregnant (NP) at diestrus stage, ii) late pregnant (LP), iii) one day post-partum (PP1) and iv) 7 days post-partum (PP7). The activities of the 26 S proteasome subunits ß1 (caspase-like), and ß2 (trypsin-like) were significantly decreased in LP (ß1∶83.26 ± 1.96%; ß2∶74.74 ± 1.7%, normalized to NP) whereas ß5 (chymotrypsin-like) activity was not altered by pregnancy but significantly decreased 1 day post-partum. Interestingly, all three proteolytic activities of the proteasome were restored to normal levels 7 days post-partum. The decrease in proteasome activity in LP was not due to the surge of estrogen as estrogen treatment of ovariectomized mice did not alter the 26 S proteasome activity. The transcript and protein levels of RPN2 and RPT4 (subunits of 19 S), ß2 and α7 (subunits of 20 S) as well as PA28α and ß5i (protein only) were not significantly different among the four groups. High resolution confocal microscopy revealed that nuclear localization of both core (20S) and RPT4 in LP is increased ∼2-fold and is fully reversed in PP7. Pregnancy was also associated with decreased production of reactive oxygen species and ubiquitinated protein levels, while the de-ubiquitination activity was not altered by pregnancy or parturition. These results indicate that late pregnancy is associated with decreased ubiquitin-proteasome proteolytic activity and oxidative stress.

Genistein, a soy phytoestrogen, reverses severe pulmonary hypertension and prevents right heart failure in rats.

Pretreatment with a phytoestrogen genistein has been shown to attenuate the development of pulmonary hypertension (PH). Because PH is not always diagnosed early, we examined whether genistein could also reverse preexisting established PH and prevent associated right heart failure (RHF). PH was induced in male rats by 60 mg/kg of monocrotaline. After 21 days, when PH was well established, rats received daily injection of genistein (1 mg/kg per day) for 10 days or were left untreated to develop RHF by day 30. Effects of genistein on human pulmonary artery smooth muscle cell and endothelial cell proliferation and neonatal rat ventricular myocyte hypertrophy were assessed in vitro. Severe PH was evident 21 days after monocrotaline, as peak systolic right ventricular pressure increased to 66.35±1.03 mm Hg and right ventricular ejection fraction reduced to 41.99±1.27%. PH progressed to RHF by day 30 (right ventricular pressure, 72.41±1.87 mm Hg; RV ejection fraction, 29.25±0.88%), and mortality was ≈75% in RHF rats. Genistein therapy resulted in significant improvement in lung and heart function as right ventricular pressure was significantly reduced to 43.34±4.08 mm Hg and right ventricular ejection fraction was fully restored to 65.67±1.08% similar to control. Genistein reversed PH-induced pulmonary vascular remodeling in vivo and inhibited human pulmonary artery smooth muscle cell proliferation by ≈50% in vitro likely through estrogen receptor-ß. Genistein also reversed right ventricular hypertrophy (right ventricular hypertrophy index, 0.35±0.029 versus 0.70±0.080 in RHF), inhibited neonatal rat ventricular myocyte hypertrophy, and restored PH-induced loss of capillaries in the right ventricle. These improvements in cardiopulmonary function and structure resulted in 100% survival by day 30. Genistein restored PH-induced downregulation of estrogen receptor-ß expression in the right ventricle and lung. In conclusion, genistein therapy not only rescues preexisting severe PH but also prevents the progression of severe PH to RHF.

Intralipid, a clinically safe compound, protects the heart against ischemia-reperfusion injury more efficiently than cyclosporine-A.

BACKGROUND: We have recently shown that postischemic administration of intralipid protects the heart against ischemia-reperfusion injury. Here we compared the cardioprotective effects of intralipid with cyclosporine-A, a potent inhibitor of the mitochondrial permeability transition pore opening. METHODS: In vivo rat hearts or isolated Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion with intralipid (0.5%, 1% and 2% ex-vivo, and 20% in vivo), cyclosporine-A (0.2 µM, 0.8 µM, and 1.5 µM ex- vivo and 10 mg/kg in vivo), or vehicle. The hemodynamic function, infarct size, calcium retention capacity, mitochondrial superoxide production, and phosphorylation levels of protein kinase B (Akt)/glycogen synthase kinase-3ß (GSK-3ß) were measured. The values are mean ± SEM. RESULTS: Administration of intralipid at reperfusion significantly reduced myocardial infarct size compared with cyclosporine-A in vivo (infarct size/area at risk)%: 22.9 ± 2.5% vs. 35.2 ± 3.5%; P = 0.030, n = 7/group). Postischemic administration of intralipid at its optimal dose (1%) was more effective than cyclosporine-A (0.8 µM) in protecting the ex vivo heart against ischemia-reperfusion injury, as the rate pressure product at the end of reperfusion was significantly higher (mmHg · beats/min: 12,740 ± 675 [n = 7] vs. 9,203 ± 10,781 [n = 5], P = 0.024), and the infarct size was markedly smaller (17.3 ± 2.9 [n = 7] vs. 29.2 ± 2.7 [n = 5], P = 0.014). Intralipid was as efficient as cyclosporine-A in inhibiting the mitochondrial permeability transition pore opening (calcium retention capacity = 280 ± 8.2 vs. 260.3 ± 2.9 nmol/mg mitochondria protein in cyclosporine-A, P = 0.454, n = 6) and in reducing cardiac mitochondrial superoxide production. Unlike intralipid, which increased phosphorylation of Akt (6-fold) and GSK-3ß (5-fold), cyclosporine-A had no effect on the activation of these prosurvival kinases. CONCLUSIONS: Although intralipid inhibits the opening of the mitochondrial permeability transition pore as efficiently as cyclosporine-A, intralipid is more effective in reducing the infarct size and improving the cardiac functional recovery.

Reverse right ventricular structural and extracellular matrix remodeling by estrogen in severe pulmonary hypertension.

Chronic pulmonary hypertension (PH) leads to right-ventricular failure (RVF) characterized by RV remodeling. Ventricular remodeling is emerging as an important process during heart failure and recovery. Remodeling in RVF induced by PH is not fully understood. Recently we discovered that estrogen (E2) therapy can rescue severe preexisting PH. Here, we focused on whether E2 (42.5 µg·kg(-1)·day(-1), 10 days) can reverse adverse RV structural and extracellular matrix (ECM) remodeling induced by PH using monocrotaline (MCT, 60 mg/kg). RV fibrosis was evident in RVF males. Intact females developed less severe RV remodeling compared with males and ovariectomized (OVX) females. Novel ECM-degrading disintegrin-metalloproteinases ADAM15 and ADAM17 transcripts were elevated ∼2-fold in all RVF animals. E2 therapy reversed RV remodeling in all groups. In vitro, E2 directly inhibited ANG II-induced expression of fibrosis markers as well as the metalloproteinases in cultured cardiac fibroblasts. Estrogen receptor-ß agonist diarylpropionitrile (DPN) but not estrogen receptor-α agonist 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) was as effective as E2 in inhibiting expression of these genes. Expression of ECM-interacting cardiac fetal-gene osteopontin (OPN) also increased ∼9-fold in RVF males. Intact females were partially protected from OPN upregulation (∼2-fold) but OVX females were not. E2 reversed OPN upregulation in all groups. Upregulation of OPN was also reversed in vitro by E2. Plasma OPN was elevated in RVF (∼1.5-fold) and decreased to control levels in the E2 group. RVF resulted in elevated Akt phosphorylation, but not ERK, in the RV, and E2 therapy restored Akt phosphorylation. In conclusion, E2 therapy reverses adverse RV remodeling associated with PH by reversing fibrosis and upregulation of novel ECM enzymes ADAM15, ADAM17, and OPN. These effects are likely mediated through estrogen receptor-ß.

Spontaneous ventricular fibrillation in right ventricular failure secondary to chronic pulmonary hypertension.

BACKGROUND: Right ventricular failure (RVF) in pulmonary hypertension (PH) is associated with increased incidence of sudden death by a poorly explored mechanism. We test the hypothesis that PH promotes spontaneous ventricular fibrillation (VF) during a critical post-PH onset period characterized by a sudden increase in mortality. METHODS AND RESULTS: Rats received either a single subcutaneous dose of monocrotaline (MCT, 60 mg/kg) to induce PH-associated RVF (PH, n=24) or saline (control, n=17). Activation pattern of the RV-epicardial surface was mapped using voltage-sensitive dye in isolated Langendorff-perfused hearts along with single glass-microelectrode and ECG-recordings. MCT-injected rats developed severe PH by day 21 and progressed to RVF by approximately day 30. Rats manifested increased mortality, and ≈30% rats died suddenly and precipitously during 23-32 days after MCT. This fatal period was associated with the initiation of spontaneous VF by a focal mechanism in the RV, which was subsequently maintained by both focal and incomplete reentrant wave fronts. Microelectrode recordings from the RV-epicardium at the onset of focal activity showed early afterdepolarization-mediated triggered activity that led to VF. The onset of the RV cellular triggered beats preceded left ventricular depolarizations by 23±8 ms. The RV but not the left ventricular cardiomyocytes isolated during this fatal period manifested significant action potential duration prolongation, dispersion, and an increased susceptibility to depolarization-induced repetitive activity. No spontaneous VF was observed in any of the control hearts. RVF was associated with significantly reduced RV ejection fraction (P<0.001), RV hypertrophy (P<0.001), and RV fibrosis (P<0.01). The hemodynamic function of the LV and its structure were preserved. CONCLUSIONS: PH-induced RVF is associated with a distinct phase of increased mortality characterized by spontaneous VF arising from the RV by an early afterdepolarization-mediated triggered activity.