Improves LV Systolic Function Research Articles

Late Gadolinium Enhancement Predicts Improvement in Global Longitudinal Strain after Aortic Valve Replacement in Aortic Stenosis

Myocardial fibrosis, as detected by late gadolinium enhancement (LGE) magnetic resonance imaging (MRI), is related to mortality after aortic valve replacement (AVR). This study aimed to determine whether LGEMRI predicts improvement in global longitudinal strain (GLS) after AVR in patients with severe aortic stenosis (AS). Twenty-nine patients with severe AS who were scheduled to undergo AVR were enrolled. Two-dimensional echocardiography and contrast-enhanced MRI were performed before AVR. GLS and LGEcore (g: > 5 SD of normal area), LGEgray (g: 2–5 SD), and LGEcore+gray (g) were measured. One year after AVR, GLS were examined by echocardiography to assess improvement in LV function. Preoperatively, GLS correlated with LGEcore (g) (r2 = 0.14, p < 0.05), LGEgray (g) (r2 = 0.32, p < 0.01) and LGEcore+gray (g) (r2 = 0.36, p < 0.01). LGEcore was significantly lower in patients with improved GLS after AVR (GLS1year ≥ −19.9%) compared to those with no improvement (1.34 g vs. 4.70 g, p < 0.01). LGE predicts improvement in LV systolic function after AVR.

P5575Acute left ventricular mechanics changes after TAVR: the afterload concept revisited

Abstract Background Recent studies have emphasized the prognostic value of mild left ventricular ejection fraction (LVEF) impairment in severe aortic stenosis. However, despite adaptive mechanisms to pressure overload, subtle impaired systolic function could be worsened by increased afterload and partly reversible immediately after its correction. Objectives The aim was to evaluate the short terms effects of transcatheter aortic valve replacement (TAVR) on LV systolic function assessed by global longitudinal strain (GLS). We hypothesized that abrupt decrease of LV afterload after TAVR could lead to immediate improvement of LV systolic function. Methods Patients referred to our Department for TAVR were included from January 2018 to July 2018 in this observational prospective single center study. Transthoracic echocardiography (TTE) was performed immediately before and 1–5 days after TAVR by the same operator and reviewed in a blind fashion. Results 35 symptomatic patients with severe aortic stenosis referred for TAVR (age 84±5 y, 18 male, NYHA 2–3, orifice area 0.7±0.2 cm2, LVEF 66±13%, GLS −15.1±4.7%) were included. Only 9/35 (26%) had a LVEF ≤60%. Overall, no significant change in LVEF (65±14%; p=0.55) or GLS (−16.1±4.8%; p=0.11) occurred immediately after TAVR despite a dramatic decrease in transoartic mean pressure gradient (44±15 mm Hg versus 6±3 mmHg; p&lt;0.0001). However in the subgroup of patients with LVEF ≤60%, a significant increase in GLS after TAVR was observed (−9.6±4.1% versus −12.1±3.3%; p=0.0039). Improvement in GLS according to the LVEF Conclusion Following TAVR, an early improvement in LV systolic function assessed by GLS was observed only in patients with pre-existing mild LV systolic dysfunction. Further studies should evaluate whether this improvement is associated with better long term outcome.

Acute left ventricular mechanics changes after TAVR: The afterload concept revisited

Recent studies have emphasized the prognostic value of mild left ventricular ejection fraction (LVEF) impairment in severe aortic stenosis. However, despite adaptive mechanisms to pressure overload, subtle impaired systolic function could be worsened by increased after load and partly reversible immediately after its correction. The aim was to evaluate the short terms effects of transcatheter aortic valve replacement (TAVR) on LV systolic function assessed by global longitudinal strain (GLS). We hypothesized that abrupt decrease of LV after load after TAVR could lead to immediate improvement of LV systolic function. Patients referred to our Department for TAVR were included from January 2018 to July 2018 in this observational prospective single center study. Transthoracic echocardiography (TTE) was performed immediately before and 1–5 days after TAVR by the same operator and reviewed in a blind fashion. Thirty-five symptomatic patients with severe aortic stenosis referred for TAVR (age 84 ± 5 y, 18 male, NYHA 2-3, orifice area 0.7 ± 0.2 cm 2 , LVEF 66 ± 13%, GLS - 15.1 ± 4.7%) were included. Only 9/35 (26%) had a LVEF ≤ 60%. Overall, no significant change in LVEF (65 ± 14%; P = 0.55) or GLS (−16.1 ± 4.8%; P = 0.11) occurred immediately after TAVR despite a dramatic decrease in transoartic mean pressure gradient (44 ± 15 mm Hg versus 6 ± 3 mmHg; P < 0.0001). However in the subgroup of patients with LVEF ≤ 60%, a significant increase in GLS after TAVR was observed (−9.6 ± 4.1% versus −12.1 ± 3.3%; P = 0.0039). Following TAVR, an early improvement in LV systolic function assessed by GLS was observed only in patients with pre-existing mild LV systolic dysfunction. Further studies should evaluate whether this improvement is associated with better long term outcome.

THE SGLT2 INHIBITOR EMPAGLIFLOZIN IMPROVES DIASTOLIC FUNCTION IN A HEART FAILURE MODEL MEDIATED VIA ENHANCED MYOCARDIAL KETONE METABOLISM

The SGTL2 inhibitor empagliflozin (Empa) reduces HF. We have recently demonstrated 1) the mechanism is due to a switch in myocardial metabolism towards ketone bodies (KB) consumption; and 2) KB infusion improves LV systolic function in a porcine HF model. However, there is no information about the

Abstract 17367: Infusion of the Ketone Body β-Hydroxybutyrate Improves Left Ventricular Systolic Function in an Animal Model of Heart Failure With Reduced Ejection Fraction

Introduction: In vitro, ketone bodies (KB) are the most energetically efficient fuel for myocardium. Ex vivo, KB infusion in the perfusion medium of working rat hearts increases the heat of combustion (produced energy) by 31%. However, there is no report about the in vivo effects of KB on LV function. We hypothesized that KB infusion in HFREF would improve energy production and thus LV systolic function. Methods: HFREF was induced in 15 pigs by 2-hour balloon occlusion of LAD: proximal LAD (n=8, severe HREF) and mid LAD (n=7, moderate HFREF). At 2 months, LV systolic function was evaluated during saline infusion and during infusion of the KB β-hydroxybutyrate. Severe HFREF animals underwent cardiac MRI for baseline LVEF, feature tracking strains, and contractile reserve (ΔLVEF under dobutamine 5μg/kg/min). Moderate HFREF pigs underwent invasive hemodynamic assessment (dP/dt) and 3D-echocadiography (3D-LVEF and 3D-strains). Simultaneous sampling from coronary artery and coronary sinus was performed to measure myocardial fuel consumption. Results: Proximal and mid LAD occlusion resulted in severe and moderate LV systolic dysfunction, respectively. In the severe HFREF, ketone infusion improved baseline LVEF, feature-tracking strains (both longitudinal and circumferencial strain), and contractile reserve. In the moderate HFREF, ketone infusion improved 3D-LVEF, 3D-strains and dP/dt (Table). Ketone infusion switched myocardial metabolism from glucose to ketone consumption. Conclusions: Continuous infusion of the KB hydroxybutyrate improves LV systolic function independent of LV systolic dysfunction severity via a shift in myocardial fuel metabolism away from glucose oxidation (energy inefficient) toward a more energy-efficient fuel like KB. This effect can explain the mechanism of action of the benefits of SGLT2 inhibitors in heart failure, as empagliflozin-induced mild kyperketonemia may increase LV systolic function and thus improve patient outcomes.

Increased Prevalence of Cardiac Allograft Donors with Improved LV Systolic Function Utilizing an Out-of-Hospital Treatment and Recovery Center

Background Published data from UNOS demonstrated that donor hearts with transient LV dysfunction can be used without increasing the risk of poor transplant outcomes, but account for less than 3% of allocated donors. Our organ procurement organization (OPO) utilizes a centralized treatment and recovery facility allowing for aggressive protocol driven management and frequent assessment of organ function early after brain death declaration. Methods We retrospectively reviewed our OPO experience with cardiac allograft donors from 2013-2017. Clinical data (patient demographics, cause of death, medical management, biomarkers, and serial echocardiographic imaging) were extracted from the OPO EMR for all 168 allocated cardiac donors during this time period. Improved LV systolic function was defined as an initial LVEF ≤40% which later improved to ≥50% consistent with the definition used in the prior UNOS analysis. Results We found that 23% (38/168) of allocated cardiac allografts from our OPO had transient LV dysfunction with an EF ≤40% on the initial echocardiogram. This rate was consistent over the years examined. Moreover 55% of donors had an initial echocardiogram with an EF of less than 50%. Comparison of donors with an initial EF ≤40% to donors with normal LV function on initial examination revealed minimal differences. There was no difference in the average age or sex between the two groups. No differences were found in the dose of vasopressors used either at the time of arrival to the facility or at organ harvest. The average amount of blood transfused was not different between the two groups. Although peak ALT was significantly higher in donors with transient LV dysfunction (402 vs 175 Units/L), there was no differences found in peak AST, troponin, lactate, or creatinine. Conclusion We found a markedly higher percentage of cardiac donors with transient LV dysfunction in allografts coming from our OPO facility compared to the UNOS database. The extent to which this reflects increased recognition versus increased organ yield is unknown at this time. These donors did not differ significantly from donors with normal LV function on initial examination. Coupled with prior data that showed equivalent outcomes in donors with recovered LV function, these data suggest that additional efforts to recover cardiac allografts initially found to have LV dysfunction could be an important means of increasing the donor pool and further work is ongoing to understand the most important factors in the recovery process.

Cardiac Involvement in Duchenne Muscular Dystrophy and Related Dystrophinopathies.

Dystrophinopathies include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), X-linked dilated cardiomyopathy (XLCM), and facioscapulohumeral muscular dystrophy (FSHD). DMD/BMD are X-linked recessive disorders, related to the synthesis of dystrophin. Most of DMD after the third decade of their age develop cardiomyopathy that remains silent, due to relative physical inactivity. Cardiac disease in female carriers presents with hypertrophy, arrhythmias or dilated cardiomyopathy, clinically overt by increasing age.In ECG, DMD presents increased R/S ratio in the right precordial leads, deep Q waves in the lateral leads, conduction abnormalities, and arrhythmias. Echocardiography, although widely available and inexpensive, is highly depended on the acoustic window and operator's experience. Tissue Doppler can be used to identify early changes of cardiomyopathy and detect progressive cardiac damage. CMR, a noninvasive, nonradiating technique, by evaluation of cardiac volumes, mass, ejection fraction, inflammation, and fibrosis, is ideal for early diagnosis. Subepicardial fibrosis in the inferolateral wall is the typical CMR lesion in DMD/BMD.Early initiation of angiotensin converting enzyme inhibitors (ACEI) treatment, such as perindopril, was associated with lower mortality in DMD with normal LV ejection fraction at study entry. Other studies documented that a beta-blocker (BB), in addition to ACEI, improves LV systolic function in MD. These encouraging results recommend initiation of ACEI and/or BB early after diagnosis of the muscular dystrophy, especially in DMD.

192 - Acute Hemodynamic Changes with Resynchronization in Patients with Continuous Flow Mechanical Circulatory Support: A Pilot Study

Introduction: Both cardiac resynchronization therapy (CRT) and durable mechanical circulatory support (MCS) improve survival and symptoms in chronic systolic heart failure. However, the benefit of these therapies together has not been demonstrated in clinical studies. Acute hemodynamic studies of CRT in MCS have not been reported. Methods: We identified 7 patients with previously implanted CRT devices who underwent implantation of continuous flow MCS devices. CRT had been turned off at the time of MCS implant. Patients were studied 7 to 24 months after MCS. Pacing parameters were measured. When LV pacing was possible and tolerated, patients underwent routine right heart catheterization without resynchronization and after 15 minutes of resynchronization. Pump speed was unchanged pre- and post-resynchronization. Results: Last LV threshold prior to implantation ranged from 0.5 V at 0.5 ms to 2.63 V at 1 ms. One patient was unable to tolerate LV pacing after MCS due to diaphragmatic stimulation. In another patient, LV pacing threshold increased beyond the capability of device. Five patients with FDA approved MCS devices (two HeartMate II, three HVAD) were studied.Tabled 1MCSMCS + CRTAbsolute Difference% ChangeP-valueRA pressure (mmHg)12.0011.4-0.6-2.560.43PA pressure (mmHg)23.822.8-1-3.980.14PCWP (mmHg)1715.66-1.4-6.250.11Estimated pump flow (L/min)4.884.45-0.375-5.220.41Thermal Dilution CO (L/min)5.2746.5041.2320.650.05 Open table in a new tab Tabled 1MCSMCS + CRTAbsolute DifferenceP-valueRVPacing (V)0.780.960.180.35Sensing (mV)13.269.88-1.940.24RAPacing (V)0.9171.460.5420.42Sensing (mV)3.232.82-0.410.73 Open table in a new tab Cardiac index by thermodilution increased in five of five patients. No adverse effects to resynchronization were noted. Improvement in right atrial and pulmonary capillary wedge pressures was observed but was not statistically significant. There was a trend toward worsening right-sided pacing parameters. Conclusions: Acute hemodynamic studies suggest a potential benefit to CRT in patients with MCS. The increase in overall cardiac output in the setting of unchanged pump flow is likely due to improved LV systolic function and increased flow across the aortic valve. Changes in CRT device function after MCS may require system revision after MCS.

Low-Level Laser Application in the Early Myocardial Infarction Stage Has No Beneficial Role in Heart Failure.

Low-level laser therapy (LLLT) has been targeted as a promising approach that can mitigate post-infarction cardiac remodeling. There is some interesting evidence showing that the beneficial role of the LLLT could persist long-term even after the end of the application, but it remains to be systematically evaluated. Therefore, the present study aimed to test the hypothesis that LLLT beneficial effects in the early post-infarction cardiac remodeling could remain in overt heart failure even with the disruption of irradiations. Female Wistar rats were subjected to the coronary occlusion to induce myocardial infarction or Sham operation. A single LLLT application was carried out after 60 s and 3 days post-coronary occlusion, respectively. Echocardiography was performed 3 days and at the end of the experiment (5 weeks) to evaluate cardiac function. After the last echocardiographic examination, LV hemodynamic evaluation was performed at baseline and on sudden afterload increases. Compared with the Sham group, infarcted rats showed increased systolic and diastolic internal diameter as well as a depressed shortening fraction of LV. The only benefit of the LLLT was a higher shortening fraction after 3 days of infarction. However, treated-LLLT rats show a lower shortening fraction in the 5th week of study when compared with Sham and non-irradiated rats. A worsening of cardiac function was confirmed in the hemodynamic analysis as evidenced by the higher LV end-diastolic pressure and lower +dP/dt and −dP/dt with five weeks of study. Cardiac functional reserve was also impaired by infarction as evidenced by an attenuated response of stroke work index and cardiac output to a sudden afterload stress, without LLLT repercussions. No significant differences were found in the myocardial expression of Akt1/VEGF pathway. Collectively, these findings illustrate that LLLT improves LV systolic function in the early post-infarction cardiac remodeling. However, this beneficial effect may be dependent on the maintenance of phototherapy. Long-term studies with LLLT application are needed to establish whether these effects ultimately translate into improved cardiac remodeling.

Long-term low dose dietary resveratrol supplement reduces cardiovascular structural and functional deterioration in chronic heart failure in rats.

A short-term exposure to resveratrol at high dosages exerts a remarkable cardioprotective effect. Whether a long-term exposure to resveratrol at low dosages that can be obtained through consumption of a resveratrol-rich diet is beneficial to heart diseases is unknown. We tested the effects of a resveratrol-enriched diet on cardiovascular remodeling of chronic heart failure (CHF) in rats resulting from permanent ligation of left coronary artery. Two weeks after surgery, rats were started on either a resveratrol-enriched (R; 5 mg/kg per day; n = 23) or normal (Control; n = 23) diet for next 10 months. Serial echocardiography in Control showed a significant decline in LV ejection fraction, increases in LV end-systolic and end-diastolic volumes, and expansion in myocardial infarct from pre-treatment values. In R, compared with Control, there were substantial improvements in those parameters. End-point LV pressure-volume loop analysis showed a significantly improved LV systolic function and AV-coupling, an index of energy transfer efficacy between the heart and aortic tree, in R compared with Control (p < 0.05). Aortic pulse wave velocity, a measure of arterial stiffness, was significantly lower in R (389 ± 15 cm/s; p < 0.05) compared with Control (489 ± 38 cm/s). These results demonstrated that long-term dietary resveratrol supplement reduces cardiovascular structural and functional deterioration in CHF.

Abstract 12984: Long-term Therapy With Elamipretide Normalizes Protein Levels of the Signal Transducer and Activator of Transcription 3 (STAT3) in Mitochondria of Left Ventricular Myocardium of Dogs With Chronic Heart Failure

Introduction: The signal transducer and activator of transcription 3 (STAT3) has recently been identified in mitochondria (MITO) of cardiomyocytes (mSTAT3). In STAT3-/- cells, the activities of MITO complexes I and II of the electron transport chain (ETC) were significantly reduced suggesting that mSTAT3 is required for optimal ETC function. In the heart, mSTAT3 activity is modulated by the heat shock protein H11 kinase (H11K) previously shown to be reduced in MITO of dogs with HF. We showed that long-term (3 months) therapy with elamipretide (ELA, Bendavia TM ), a novel MITO-targeting peptide, improves LV systolic function and to normalize MITO respiration, rate of ATP synthesis and H11K levels in MITO of LV cardiomyocytes of dogs with heart failure (HF). Hypothesis: This study tested the hypothesis that the level of mSTAT3 is reduced in LV myocardium of dogs with HF and that long-term therapy with ELA restores levels of mSTAT3. Methods: LV tissue was obtained from 14 dogs with microembolization-induced HF (LV ejection fraction ~30%) randomized to 3 months therapy with subcutaneous injections of ELA (0.5 mg/kg once daily, n=7) or saline (Control, n=7). LV tissue from 6 normal dogs was used for comparison. Protein levels of mSTAT3 and porin; the latter a MITO protein unchanged in HF (internal control), were determined in isolated MITO fractions from LV tissue using by Western blotting coupled with chemiluminescence. Protein band intensities were quantified in densitometric units (du). Results: Protein levels of porin was similar in all 3 study groups (NL:0.24±0.01; Control: 0.22±0.01; ELA: 0.23±0.01 du). Levels of mSTAT3 were 0.82±0.05 du in NL, decreased to 0.29±0.03 du in Controls (p&lt;0.05 vs. NL) and were partially restored by ELA (0.53±0.05, p&lt;0.05 vs. Control). Levels of mSTAT3 normalized to porin were 3.6±0.3 du in NL, decreased to 1.3±0.1 in Controls (p&lt;0.05 vs. NL) and were restored to near normal levels following treatment with ELA (2.3±0.2, p&lt;0.05 vs. Control). Conclusions: mSTAT3 level is reduced in MITO of from LV myocardium of HF dogs and restored after chronic therapy with ELA. Normalization of mSTAT3 by ELA likely contributed to the observed improvement in MITO function following therapy with ELA in dogs with chronic HF.

Abstract 12949: Elamipretide ( Bendavia TM ) Restores 4-Hydroxy-2-Nonenal Protein Adducts and Aldehyde Dehydrogenase-2 Activity and mRNA Expression in Left Ventricular Myocardium of Dogs With Advanced Heart Failure

Background: 4-hydroxy-2-nonenal (4HNE), a reactive aldehyde, is generated in the failing heart and contributes to cardiomyocyte injury and death. Aldehyde dehydrogenase-2 (ALDH2) plays a key role in detoxifying mitochondrial (MITO) reactive aldehydes. We showed that chronic therapy with elamipretide (ELA), a novel MITO targeting peptide, improves LV systolic function, normalizes MITO function and reduces the burden of reactive oxygen species (ROS) in LV of dogs with microembolization-induced heart failure (HF). Hypothesis: This study tested the hypothesis that chronic therapy with ELA normalizes protein levels of 4-HNE-adducts and ALDH2 activity and expression in LV myocardium of HF dogs (LV ejection fraction ~30%). Methods: LV tissue from 14 HF dogs randomized to 3 months therapy with subcutaneous injections of ELA (0.5 mg/kg once daily, n=7) or subcutaneous injections of saline (control, CTR, n=7) and tissue from 6 normal (NL) dogs was used in the study. Level of 4-HNE-protein adducts was quantified using an Elisa kit. ALDH2 activity was assayed spectrophotometrically in LV MITO fractions by monitoring NADH formation from NAD to NADH at 340 nm. Protein levels of ALDH2 and porin (an internal loading control) were determined by Western blotting and band intensity quantified in densitometric units (du). mRNA expression of ALDH2 and GAPDH was measured in using real-time PCR. Results: Data are shown in the table. Levels of 4HNE-protein adducts were significantly increased and ALDH2 activity, mRNA expression and protein levels significantly decreased in CTR compared to NL dogs. ELA normalized 4-HNE levels, ALDH2 activity and expression. There were no differences in the level of porin or GAPDH among the 3 study groups. Conclusions: Chronic therapy with ELA normalizes ALDH2 and 4-HNE levels in LV myocardium of HF dogs. By limiting myocardial ROS burden, ELA contributes to cardiac end-organ protection and hence, to overall improvement in global LV function.

Human relaxin gene expression delivered by bioreducible dendrimer polymer for post-infarct cardiac remodeling in rats

In consensus, myocardial infarction (MI) is defined as irreversible cell death secondary to prolonged ischemia in heart. The aim of our study was to evaluate the therapeutic potential of anti-fibrotic human Relaxin-expressing plasmid DNA with hypoxia response element (HRE) 12 copies (HR1) delivered by a dendrimer type PAM-ABP polymer G0 (HR1/G0) after MI on functional, hemodynamic, geometric, and cardiac extracellular matrix (ECM) remodeling in rats. HR1/G0 demonstrated significantly improved LV systolic function, hemodynamic parameters, and geometry on 1 wk and 4 wks after MI in rats, compared with I/R group. The resolution of regional wall motional abnormalities and the increased blood flow of infarct-related coronary artery supported functional improvements of HR1/G0. Furthermore, HR1/G0 polyplex showed favorable post-infarct cardiac ECM remodeling reflected on the favorable cardiac ECM compositions. Overall, this is the first study, which presented an advanced platform for the gene therapy that reverses adverse cardiac remodeling after MI with a HR1 gene delivered by a bioreducible dendrimer polymer in the cardiac ECM.

(362) - Vepoloxamer (Purified Sodium-Free Poloxamer-188) Improves LV Systolic Function in Dogs with Advanced Heart Failure and Protects Failing Cardiomyocytes from Calcium Overload

(362) - Vepoloxamer (Purified Sodium-Free Poloxamer-188) Improves LV Systolic Function in Dogs with Advanced Heart Failure and Protects Failing Cardiomyocytes from Calcium Overload

Progenitor Hematopoietic Cells Implantation Improves Functional Capacity of End Stage Coronary Artery Disease Patients with Advanced Heart Failure.

Background. Proangiogenic Hematopoietic Cells (PHC) which comprise diverse mixture of cell types are able to secrete proangiogenic factors and interesting candidate for cell therapy. The aim of this study was to seek for benefit in implantation of PHC on functional improvement in end stage coronary artery disease patients with advanced heart failure. Methods. Patients with symptomatic heart failure despite guideline directed medical therapy and LVEF less than 35% were included. Peripheral blood mononuclear cells were isolated, cultivated for 5 days, and then harvested. Flow cytometry and cell surface markers were used to characterize PHC. The PHC were delivered retrogradely via sinus coronarius. Echocardiography, myocardial perfusion, and clinical and functional data were analyzed up to 1-year observation. Results. Of 30 patients (56.4 ± 7.40 yo) preimplant NT proBNP level is 5124.5 ± 4682.50 pmol/L. Harvested cells characterized with CD133, CD34, CD45, and KDR showed 0.87 ± 0.41, 0.63 ± 0.66, 99.00 ± 2.60, and 3.22 ± 3.79%, respectively. LVEF was improved (22 ± 5.68 versus 26.8 ± 7.93, p < 0.001) during short and long term observation. Myocardial perfusion significantly improved 6 months after treatment. NYHA Class and six-minute walk test are improved during short term and long term follow-up. Conclusion. Expanded peripheral blood PHC implantation using retrograde delivery approach improved LV systolic function, myocardial perfusion, and functional capacity.

Regression of left ventricular hypertrabeculation is associated with improvement in systolic function and favorable prognosis in adult patients with non-ischemic cardiomyopathy

BackgroundWe sometimes experience regression of left ventricular hypertrabeculation (LVHT), which is compatible with the diagnosis of LV non-compaction cardiomyopathy (LVNC) in adult patients. However, little is known about the association between LVHT regression and LV systolic function in adult patients. MethodsWe prospectively examined 23 consecutive adult patients who fulfilled the echocardiographic criteria for LVNC. LV reverse remodeling (RR) was defined as an absolute increase in LV ejection fraction of >10% at 6 months follow-up. LVHT area was calculated by subtraction from the outer edge to the inner edge of the LVHT at end-systole. ResultsThe mean follow-up period was 61 months. LVRR was observed in 9 patients (39%). The changes in the mean LVHT area showed significant correlation with the changes in LV ejection fraction (r=−0.78, p<0.0001). Cardiac death occurred in 7 patients (50%) without LVRR, but no patients with LVRR died (log-rank, p=0.003). Furthermore, composite of cardiac death and hospitalization for heart failure occurred in 10 patients (71%) without LVRR, whereas there was one patient with LVRR (log-rank, p<0.001). ConclusionsRegression of LVHT is associated with improvement in LV systolic function. LVRR might be associated with a favorable prognosis in patients with LVHT.

Abstract 18986: Unopposed TNF/TNFR1 Signaling Prevents Therapeutic Benefit From Cardiac Stem Cell Therapy After Reperfused Myocardial Infarction in Mice

Despite expansion of resident cardiac stem cells (CSCs) after myocardial infarction (MI), the heart is unable to regenerate, suggesting that local factors inhibit CSC function. Tumor necrosis factor-α (TNF), increased in infarcted and failing hearts, is one candidate inhibitory factor; its effects are specific to its two receptors (TNFRs). We hypothesized that TNF/TNFR signaling in CSCs modulates the efficacy of CSC therapy after reperfused MI in mice. Magnetically sorted, c-kit enriched, Lin– CSCs were isolated from wild-type (WT), TNFR1-/-, and TNFR2-/- mice, expanded, and 1 x 105 CSCs were administered via intramyocardial injection in the border zone 48 h after 60 min ischemia in WT C57BL/6 mice (n = 13-18/group). Five weeks after CSC therapy, as compared with PBS-injected MI mice, WT CSC transplantation significantly (p&lt;0.05) improved LV systolic function (ESV 50 ± 14 vs 63 ± 23 μL; EF 31 ± 11 vs 24 ± 9%). Analogous to WT CSCs, TNFR1-/- CSCs also significantly improved LV systolic function (ESV 44 ± 5 uL; EF 35 ± 3%). In contrast, TNFR2-/- CSC transplanted MI hearts exhibited greater LV systolic dysfunction (ESV 62 ± 5 uL; EF 29 ± 4%) as compared with both WT and TNFR1-/- CSC injected hearts, and were comparable to PBS-injected MI hearts. There was signficantly reduced border zone (BZ) fibrosis in both WT (7.6 ± 3.2%) and TNFR1-/- CSC (7.2 ± 1.9%) injected hearts as compared with either PBS-injected MI hearts (11.6 ± 2.8%), or TNFR2-/- CSC injected MI hearts (15.7 ± 4.0%). Analogous to fibrotic change, cardiomyocyte hypertrophy in post-MI hearts was significantly decreased after cell transplantation with either WT CSCs (322 ± 56 μm2) or TNFR1-/- CSCs (244 ± 29 μm2), as compared with PBS-injected MI hearts (423 ± 56 μm2), with more robust improvements in hypertrophy in the TNFR1-/- CSC MI hearts. In contrast, cardiomyocyte size after TNFR2-/- CSC transplantation (389 ± 58 μm2) was comparable to PBS injected hearts, and significantly greater than either WT or TNFR1-/- CSC injected MI hearts. We conclude that myocardial TNF diminishes the efficacy of CSC therapy via TNFR1 signaling, especially when unopposed by concomitant TNFR2 signaling. Selective TNFR1 blockade, or TNFR2 agonism, at the time of cell transplantation may improve the functional outcomes of CSC therapy after MI.

Long-term physiological T3 supplementation in hypertensive heart disease in rats.

Animal studies suggest that hypertension leads to cardiac tissue hypothyroidism, a condition that can by itself lead to heart failure. We have previously shown that short-term thyroid hormone treatment in Spontaneously Hypertensive Heart Failure (SHHF) rats near heart failure is beneficial. This study tested the hypothesis that therapeutic, long-term T3 treatment in SHHF rats can prevent or attenuate cardiac dysfunction. Female SHHF rats were treated orally with a physiological T3 dose (0.04 μg/ml) from 12 to 24 mo of age. Age-matched female SHHF and Wistar-Kyoto rats served as hypertensive and normotensive controls, respectively. SHHF rats had reduced serum free thyroid hormone levels and cardiac tissue T3 levels, LV dysfunction, and elevated LV collagen content compared with normotensive controls. Restoration of serum and cardiac tissue thyroid hormone levels in T3-treated rats was associated with no change in heart rate, but strong trends for improvement in LV systolic function and collagen levels. For instance, end-systolic diameter, fractional shortening, systolic wall stress, and LV collagen levels were no longer significantly different from controls. In conclusion, longstanding hypertension in rats led to chronic low serum and cardiac tissue thyroid hormone levels. Long-term treatment with low-dose T3 was safe. While cardiac dysfunction could not be completely prevented in the absence of antihypertensive treatment, T3 may offer additional benefits as an adjunct therapy with possible improvement in diastolic function.

A temperature-sensitive, self-adhesive hydrogel to deliver iPSC-derived cardiomyocytes for heart repair

A temperature-sensitive, self-adhesive hydrogel to deliver iPSC-derived cardiomyocytes for heart repair

The 7-year teesside experience of primary prevention ICD indications following primary PCI (PPCI) and the potential impact of a change in NICE guidance

IntroductionThe recovery of LV function in patients with severe LV impairment in the acute phase following primary percutaneous coronary intervention (PPCI) is not well established. The indication for a primary...