Postsystolic thickening is a potential new clinical sign of injured myocardium in marfan syndrome

AbstractThe mechanisms leading to cardiac remodeling in Marfan syndrome (MFS) are a matter of debate since it could be either due to structural dysfunction of the myocardial extracellular matrix or to increased afterload caused by the dilated aorta. We aim to characterize the presence of abnormal myocardial function in MFS and to investigate its potential association with increased afterload. Aorta, left ventricle (LV) and the postsystolic thickening (PST) were analyzed in echocardiography in Fbn1C1039G/+ mice and in patients with MFS in comparison with wild type (WT) mice and healthy humans. PST was more frequent in MFS than in WT mice (p < 0.05). MFS mice with PST showed larger aorta than those without PST. Patients with MFS showed larger aorta, poorer LV function and a higher prevalence of PST (56%) than did the healthy controls (23%); p = 0.003. Blood pressure was similar. The higher prevalence of PST in an experimental murine model and in MFS patients, regardless of systemic arterial pressure, suggests an increased afterload on the LV myocardium. This finding supports the use of PST as an indicator of myocardial damage and encourage searching for novel early preventive therapy.

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Effect of cardiosphere-derived cells on segmental myocardial function after myocardial infarction: ALLSTAR randomised clinical trial

Open Heart ◽

10.1136/openhrt-2021-001614 ◽

2021 ◽

Vol 8 (2) ◽

pp. e001614

Author(s):

Mohammad R Ostovaneh ◽

Raj R Makkar ◽

Bharath Ambale-Venkatesh ◽

Deborah Ascheim ◽

Tarun Chakravarty ◽

...

Keyword(s):

Myocardial Infarction ◽

Clinical Trial ◽

Myocardial Function ◽

Randomised Clinical Trial ◽

Scar Tissue ◽

Left Ventricular ◽

Lv Function ◽

Cardiac Events ◽

Lv Dysfunction ◽

Registration Number

BackgroundMost cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility.MethodsIn this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF <45% and 15% or greater LV scar size were randomised in 2:1 ratio to receive intracoronary infusion of allogenic CDCs or placebo, respectively. Change in segmental myocardial circumferential strain (Ecc) by MRI from baseline to 6 months was compared between CDCs and placebo groups.ResultsIn total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3 (10.8) and 108 (87.1%) men). Segmental Ecc improvement was significantly greater in patients receiving CDC (−0.5% (4.0)) compared with placebo (0.2% (3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of −0.7% (3.5) in patients receiving CDC vs 0.04% (3.7) in the placebo group, p=0.04).ConclusionsIn patients with post-MI LV dysfunction, CDC administration resulted in improved segmental myocardial function. Our findings highlight the importance of segmental myocardial function indices as an endpoint in future clinical trials of patients with post-MI.Trial registration numberNCT01458405.

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Transgenic overexpression of cardiac A1adenosine receptors mimics ischemic preconditioning

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.3.h1071 ◽

2000 ◽

Vol 279 (3) ◽

pp. H1071-H1078 ◽

Cited By ~ 27

Author(s):

R. Ray Morrison ◽

Rachael Jones ◽

Anne M. Byford ◽

Alyssa R. Stell ◽

Jason Peart ◽

...

Keyword(s):

Infarct Size ◽

Functional Recovery ◽

Ischemic Preconditioning ◽

Adenosine Receptors ◽

Myocardial Function ◽

Wild Type ◽

Beneficial Effects ◽

Pressure Development ◽

Ldh Release

The role of A1adenosine receptors (A1AR) in ischemic preconditioning was investigated in isolated crystalloid-perfused wild-type and transgenic mouse hearts with increased A1AR. The effect of preconditioning on postischemic myocardial function, lactate dehydrogenase (LDH) release, and infarct size was examined. Functional recovery was greater in transgenic versus wild-type hearts (44.8 ± 3.4% baseline vs. 25.6 ± 1.7%). Preconditioning improved functional recovery in wild-type hearts from 25.6 ± 1.7% to 37.4 ± 2.2% but did not change recovery in transgenic hearts (44.8 ± 3.4% vs. 44.5 ± 3.9%). In isovolumically contracting hearts, pretreatment with selective A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine attenuated the improved functional recovery in both wild-type preconditioned (74.2 ± 7.3% baseline rate of pressure development over time untreated vs. 29.7 ± 7.3% treated) and transgenic hearts (84.1 ± 12.8% untreated vs. 42.1 ± 6.8% treated). Preconditioning wild-type hearts reduced LDH release (from 7,012 ± 1,451 to 1,691 ± 1,256 U · l−1 · g−1 · min−1) and infarct size (from 62.6 ± 5.1% to 32.3 ± 11.5%). Preconditioning did not affect LDH release or infarct size in hearts overexpressing A1AR. Compared with wild-type hearts, A1AR overexpression markedly reduced LDH release (from 7,012 ± 1,451 to 917 ± 1,123 U · l−1 · g−1 · min−1) and infarct size (from 62.6 ± 5.1% to 6.5 ± 2.1%). These data demonstrate that murine preconditioning involves endogenous activation of A1AR. The beneficial effects of preconditioning and A1AR overexpression are not additive. Taken with the observation that A1AR blockade equally eliminates the functional protection resulting from both preconditioning and transgenic A1AR overexpression, we conclude that the two interventions affect cardioprotection via common mechanisms or pathways.

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Interactions Between Antenatal Sulfadoxine-Pyrimethamine, Drug-Resistant Plasmodium falciparum Parasites, and Delivery Outcomes in Malawi

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa145 ◽

2020 ◽

Vol 222 (4) ◽

pp. 661-669 ◽

Cited By ~ 2

Author(s):

Steve M Taylor ◽

Brandt Levitt ◽

Betsy Freedman ◽

Mwayiwawo Madanitsa ◽

Kyaw-Lay Thwai ◽

...

Keyword(s):

Birth Weight ◽

Preventive Therapy ◽

Sub Saharan Africa ◽

Drug Resistant ◽

Wild Type ◽

Resistance Marker ◽

Chain Reaction ◽

Delivery Outcomes ◽

Polymerase Chain ◽

Sub Saharan

Abstract Background Sulfadoxine-pyrimethamine (SP) is used as intermittent preventive therapy in pregnancy (IPTp) for malaria in sub-Saharan Africa. The resistance marker dhps A581G has been associated with reduced IPTp-SP efficacy and enhanced morbidity in SP recipients. Methods We measured SP-resistance allele frequencies in Malawian women participating in a trial comparing IPTp with SP against intermittent screening by rapid diagnostic tests (ISTp). We genotyped polymerase chain reaction-detected parasites using deep sequencing of SP-resistance alleles. Results Among 125 placental infections, A581G-bearing parasites were associated with reduced birth weight (mean difference [MD], 252 g; 95% confidence interval [CI], 46–457; P = .017). Relative to ISTp, IPTp-SP was associated with higher birth weights in women with wild-type parasites (MD, 116 g; 95% CI, −40 to 272; P = .142) and lower birth weights in women with A581G-bearing parasites (MD, 192 g; 95% CI, −264 to 648; P = .385) (Pinteraction = .033). Similar associations were noted on gestational age (Pinteraction = .075). Amongst only IPTp-SP recipients, relative to women who last received SP > 4 weeks before delivery, recent SP receipt was associated with lower birth weight in women with wild-type parasites (MD, 118 g; 95% CI, −376 to 139; P = .361) and higher birth weight in women with A581G-bearing parasites (MD, 783 g; 95% CI, −20 to 1586; P = .054) (Pinteraction = .005). Conclusions The effectiveness in birth weight of IPTp-SP is compromised by A581G-bearing parasites, but there was no evidence that the adverse effects of these parasites are exacerbated by antenatal SP. ISRCTN Registry www.isrctn.com/ISRCTN69800930.

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Percutaneous intracoronary delivery of SERCA gene increases myocardial function: a tissue Doppler imaging echocardiographic study

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00411.2006 ◽

2006 ◽

Vol 291 (4) ◽

pp. H1773-H1779 ◽

Cited By ~ 12

Author(s):

Damien Logeart ◽

Laurent Vinet ◽

Thierry Ragot ◽

Michèle Heimburger ◽

Liliane Louedec ◽

...

Keyword(s):

Tissue Doppler Imaging ◽

Myocardial Function ◽

Realistic Model ◽

Tissue Doppler ◽

Left Ventricular ◽

Doppler Imaging ◽

Strong Increase ◽

Lv Function ◽

Maximal Rate ◽

Circumflex Artery

The aim of this study was to examine the efficiency of adenovirus-mediated overexpression of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA1a) gene in a realistic model based on percutaneous intracoronary delivery and on noninvasive functional monitoring. Catheter-based selective coronary delivery of saline or adenoviruses (Ad.CMV.SERCA1a or Ad.CMV.lacZ, 1010 plaque-forming units) was performed in the circumflex artery of rabbits. Effects were assessed and compared by using serial Doppler echocardiography, hemodynamics, and measurements of SERCA protein and Ca2+ uptake activity. On day 3, a 21% increase in SERCA proteins and a 37% increase in the maximal rate of Ca2+ uptake were observed in the transfected left ventricular (LV) walls of Ad.CMV.SERCA1a rabbits. Baseline hemodynamics and conventional echographic measurements of global LV function were poorly affected. In contrast, tissue Doppler imaging (TDI) was able to assess a strong increase in the baseline function of transfected LV walls, as assessed with maximal wall velocities (+32% and +43%, respectively) and strain rates (+18% and +30%, respectively). TDI parameters were closely related to the maximal rate of Ca2+ uptake ( r2 = 0.68 for the systolic strain rate). Serial TDI analysis during follow-up showed that the effects lasted for 7 days and were no longer detectable 15 days after adenoviruses injection. In conclusion, LV function can be increased by adenovirus-mediated overexpression of SERCA in a clinically relevant model, and TDI provides an accurate and noninvasive tool for monitoring effects on global as well as regional myocardial function.

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Adiponectin Replacement Therapy Attenuates Myocardial Damage in Leptin-deficient Mice with Viral Myocarditis

Journal of International Medical Research ◽

10.1177/147323000503300208 ◽

2005 ◽

Vol 33 (2) ◽

pp. 207-214 ◽

Cited By ~ 23

Author(s):

T Takahashi ◽

S Saegusa ◽

H Sumino ◽

T Nakahashi ◽

K Iwai ◽

...

Keyword(s):

Replacement Therapy ◽

Viral Myocarditis ◽

Myocardial Damage ◽

Encephalomyocarditis Virus ◽

Adiponectin Receptor ◽

Heart Weight ◽

Wild Type ◽

Adiponectin Receptor 1 ◽

Histological Score ◽

Deficient Mice

The effects of adiponectin replacement therapy on myocardial damage were studied in leptin-deficient (OB) mice with acute viral myocarditis. Encephalomyocarditis virus was injected intraperitoneally into OB and wild-type (WT) mice. One subgroup of OB mice received no intervention and another subgroup received daily adiponectin replacement, simultaneously with viral inoculation. Differences in heart weight, cardiac histological score, numbers of infiltrating or apoptotic cells in the myocardium and the immunoreactivity of adiponectin receptors in myocytes were determined. The reactivity of adiponectin receptor 1 in myocytes from OB mice on day 4 and day 8 after viral inoculation was significantly decreased compared with that in myocytes from WT mice; the OB mice also had elevated cardiac weights and severe inflammatory myocardial damage. Adiponectin replacement in OB mice inhibited the development of severe myocarditis by augmenting myocyte adiponectin receptor 1 reactivity. Exogenously administered adiponectin may inhibit the progression of viral myocarditis through binding to the adiponectin receptor 1 in leptin-deficient conditions.

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NADPH oxidase 4 attenuates cerebral artery changes during the progression of Marfan syndrome

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00770.2015 ◽

2016 ◽

Vol 310 (9) ◽

pp. H1081-H1090 ◽

Cited By ~ 7

Author(s):

Yara Onetti ◽

Thayna Meirelles ◽

Ana P. Dantas ◽

Katrin Schröder ◽

Elisabet Vila ◽

...

Keyword(s):

Nadph Oxidase ◽

Marfan Syndrome ◽

Cerebral Artery ◽

Structural Changes ◽

Transforming Growth Factor ◽

Aortic Aneurysms ◽

Wall Thickening ◽

Wild Type ◽

Nadph Oxidase 4 ◽

Wall Stiffness

Marfan syndrome (MFS) is a connective tissue disorder that is often associated with the fibrillin-1 ( Fbn1) gene mutation and characterized by cardiovascular alterations, predominantly ascending aortic aneurysms. Although neurovascular complications are uncommon in MFS, the improvement in Marfan patients' life expectancy is revealing other secondary alterations, potentially including neurovascular disorders. However, little is known about small-vessel pathophysiology in MFS. MFS is associated with hyperactivated transforming growth factor (TGF)-β signaling, which among numerous other downstream effectors, induces the NADPH oxidase 4 (Nox4) isoform of NADPH oxidase, a strong enzymatic source of H2O2. We hypothesized that MFS induces middle cerebral artery (MCA) alterations and that Nox4 contributes to them. MCA properties from 3-, 6-, or 9-mo-old Marfan ( Fbn1C1039G/+) mice were compared with those from age/sex-matched wild-type littermates. At 6 mo, Marfan compared with wild-type mice developed higher MCA wall/lumen (wild-type: 0.081 ± 0.004; Marfan: 0.093 ± 0.002; 60 mmHg; P < 0.05), coupled with increased reactive oxygen species production, TGF-β, and Nox4 expression. However, wall stiffness and myogenic autoregulation did not change. To investigate the influence of Nox4 on cerebrovascular properties, we generated Marfan mice with Nox4 deficiency (Nox4−/−). Strikingly, Nox4 deletion in Marfan mice aggravated MCA wall thickening (cross-sectional area; Marfan: 6,660 ± 363 μm2; Marfan Nox4−/−: 8,795 ± 824 μm2; 60 mmHg; P < 0.05), accompanied by decreased TGF-β expression and increased collagen deposition and Nox1 expression. These findings provide the first evidence that Nox4 mitigates cerebral artery structural changes in a murine model of MFS.

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Losartan Increases Survival of the Fbn1mgR/mgR Mouse Model of Marfan Syndrome in an Age-Dependent Manner

10.1101/2021.02.19.429438 ◽

2021 ◽

Author(s):

Jeffrey D. Smith ◽

Jeff Z. Chen ◽

Rebecca Phillips ◽

Alan Daugherty ◽

Mary B. Sheppard

Keyword(s):

Marfan Syndrome ◽

Angiotensin Receptor Blockers ◽

Primary Objective ◽

Dependent Manner ◽

Wild Type ◽

Age Dependent ◽

Fibrillin 1 ◽

Receptor Blockers ◽

To Receive ◽

Overall Mortality

AbstractClinical trials investigating angiotensin receptor blockers (ARB) for attenuation of thoracic aortic aneurysm in people with Marfan syndrome have demonstrated variable efficacy. The primary objective of this study was to determine whether the age of mice at the time of losartan initiation affected mortality in fibrillin-1 hypomorphic (Fbn1mgR/mgR) mice. Male (n=40) and female (n=28) Fbn1mgR/mgR mice were randomized to receive losartan in drinking water (0.6 g/L) starting at either 24 or 50 days of age. Controls included Fbn1mgR/mgR mice (20M, 14F) and wild type (15M, 15F) littermates who were not administered the drug. Mortality of Fbn1mgR/mgR males receiving losartan at postnatal day 24 (P24) was not different from wild type controls (p=0.138). Survival of Fbn1mgR/mgR males administered losartan at P50 was not different compared to Fbn1mgR/mgR males receiving no drug (p=0.194) and decreased compared to wild type mice (p=0.002). Survival analysis after P50 demonstrated increased survival of Fbn1mgR/mgR males administered losartan at P50 compared to Fbn1mgR/mgR mice receiving no drug (p=0.017). Age is a critical variable that affects the therapeutic efficacy of losartan in male Fbn1mgR/mgR mice. Since overall mortality in female Fbn1mgR/mgR mice was lower than in male Fbn1mgR/mgR mice, a survival benefit with losartan was not detected in females.

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Dapagliflozin suppresses ER stress and improves subclinical myocardial function in diabetes: from bedside to bench

10.2337/figshare.13122956 ◽

2020 ◽

Author(s):

Ada Admin ◽

Jhih-Yuan Shih ◽

Yu-Wen Lin ◽

Sudeshna Fisch ◽

Juei-Tang Cheng ◽

...

Keyword(s):

Heart Failure ◽

Er Stress ◽

Myocardial Function ◽

Sglt2 Inhibitor ◽

Left Ventricular ◽

Diabetic Rat ◽

Lv Function ◽

Diabetic Patients ◽

Symptomatic Heart Failure

Dapagliflozin (DAPA) -- a sodium glucose cotransporter 2 (SGLT2) inhibitor, is approved for treatments of diabetic patients. DAPA-HF trial disclosed its benefits in symptomatic heart failure but the underlying mechanism remains largely unknown. In this longitudinal and prospective study, we investigated changes of left ventricular (LV) functions including speckle tracking in diabetic patients free from symptomatic heart failure post DAPA treatment. Using streptozotocin-induce diabetic rat model, we measured the effects of DAPA on myocardial function. In patients with diabetes, following six months of DAPA, despite no significant changes LV ejection fraction, the diastolic function and longitudinal strain improved. Likewise, compared to control, the diabetic rat heart developed pronounced fibrosis, a decline in strain and overall hemodynamics, all of which were mitigated by DAPA treatment. In contrast, despite insulin exerting a glucose lowering effect, it failed to improve myocardial function and fibrosis. In our in vitro study, under high glucose cardiomyocytes showed significant activations of apoptosis, reactive oxygen species and ER stress associated proteins, which were attenuated by the co-incubation of DAPA. Mechanistically, DAPA suppressed ER stress, reduced myocardial fibrosis and improved overall function. The results can lead to further improvement in management of LV function in diabetic patients.

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Dapagliflozin suppresses ER stress and improves subclinical myocardial function in diabetes: from bedside to bench

10.2337/figshare.13122956.v2 ◽

2020 ◽

Author(s):

Ada Admin ◽

Jhih-Yuan Shih ◽

Yu-Wen Lin ◽

Sudeshna Fisch ◽

Juei-Tang Cheng ◽

...

Keyword(s):

Heart Failure ◽

Er Stress ◽

Myocardial Function ◽

Sglt2 Inhibitor ◽

Left Ventricular ◽

Diabetic Rat ◽

Lv Function ◽

Diabetic Patients ◽

Symptomatic Heart Failure

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Classification, prevalence, and outcomes of anticancer therapy-induced cardiotoxicity: the CARDIOTOX registry

European Heart Journal ◽

10.1093/eurheartj/ehaa006 ◽

2020 ◽

Vol 41 (18) ◽

pp. 1720-1729 ◽

Cited By ~ 21

Author(s):

José López-Sendón ◽

Carlos Álvarez-Ortega ◽

Pilar Zamora Auñon ◽

Antonio Buño Soto ◽

Alexander R Lyon ◽

...

Keyword(s):

Troponin T ◽

Myocardial Damage ◽

High Sensitivity ◽

Anticancer Therapy ◽

Left Ventricular ◽

Lv Function ◽

Cancer Therapies ◽

Research Practices ◽

High Sensitivity Troponin T

Abstract Aim Cardiotoxicity (CTox) is a major side effect of cancer therapies, but uniform diagnostic criteria to guide clinical and research practices are lacking. Methods and results We prospectively studied 865 patients, aged 54.7 ± 13.9; 16.3% men, scheduled for anticancer therapy related with moderate/high CTox risk. Four groups of progressive myocardial damage/dysfunction were considered according to current guidelines: normal, normal biomarkers (high-sensitivity troponin T and N-terminal natriuretic pro-peptide), and left ventricular (LV) function; mild, abnormal biomarkers, and/or LV dysfunction (LVD) maintaining an LV ejection fraction (LVEF) ≥50%; moderate, LVD with LVEF 40–49%; and severe, LVD with LVEF ≤40% or symptomatic heart failure. Cardiotoxicity was defined as new or worsening of myocardial damage/ventricular function from baseline during follow-up. Patients were followed for a median of 24 months. Cardiotoxicity was identified in 37.5% patients during follow-up [95% confidence interval (CI) 34.22–40.8%], 31.6% with mild, 2.8% moderate, and 3.1% with severe myocardial damage/dysfunction. The mortality rate in the severe CTox group was 22.9 deaths per 100 patients-year vs. 2.3 deaths per 100 patients-year in the rest of groups, hazard ratio of 10.2 (95% CI 5.5–19.2) (P < 0.001). Conclusions The majority of patients present objective data of myocardial injury/dysfunction during or after cancer therapy. Nevertheless, severe CTox, with a strong prognostic relationship, was comparatively rare. This should be reflected in protocols for clinical and research practices.

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