Igal A. Sebag

Transcatheter heart valve failure: a systematic review

AIMSnA comprehensive description of transcatheter heart valve (THV) failure has not been performed. We undertook a systematic review to investigate the aetiology, diagnosis, management, and outcomes of THV failure.nnnMETHODS AND RESULTSnThe systematic review was performed in accordance with the PRISMA guidelines using EMBASE, MEDLINE, and Scopus. Between December 2002 and March 2014, 70 publications reported 87 individual cases of transcatheter aortic valve implantation (TAVI) failure. Similar to surgical bioprosthetic heart valve failure, we observed cases of prosthetic valve endocarditis (PVE) (n = 34), structural valve failure (n = 13), and THV thrombosis (n = 15). The microbiological profile of THV PVE was similar to surgical PVE, though one-quarter had satellite mitral valve endocarditis, and surgical intervention was required in 40% (75% survival). Structural valve failure occurred most frequently due to leaflet calcification and was predominantly treated by redo-THV (60%). Transcatheter heart valve thrombosis occurred at a mean 9 ± 7 months post-implantation and was successfully treated by prolonged anticoagulation in three-quarters of cases. Two novel causes of THV failure were identified: late THV embolization (n = 18); and THV compression (n = 7) following cardiopulmonary resuscitation (CPR). These failure modes have not been reported in the surgical literature. Potential risk factors for late THV embolization include low prosthesis implantation, THV undersizing/underexpansion, bicuspid, and non-calcified anatomy. Transcatheter heart valve embolization mandated surgery in 80% of patients. Transcatheter heart valve compression was noted at post-mortem in most cases.nnnCONCLUSIONnTranscatheter heart valves are susceptible to failure modes typical to those of surgical bioprostheses and unique to their specific design. Transcatheter heart valve compression and late embolization represent complications previously unreported in the surgical literature.

Lifelong Exposure to Bisphenol A Alters Cardiac Structure/Function, Protein Expression, and DNA Methylation in Adult Mice

Bisphenol A (BPA) is an estrogenizing endocrine disruptor compound of concern. Our objective was to test whether lifelong BPA would impact cardiac structure/function, calcium homeostasis protein expression, and the DNA methylation of cardiac genes. We delivered 0.5 and 5.0 µg/kg/day BPA lifelong from gestation day 11 or 200 µg/kg/day from gestation day 11 to postnatal day 21 via the drinking water to C57bl/6n mice. BPA 5.0 males and females had increased body weight, body mass index, body surface area, and adiposity. Echocardiography identified concentric remodeling in all BPA-treated males. Systolic and diastolic cardiac functions were essentially similar, but lifelong BPA enhanced male and reduced female sex-specific differences in velocity of circumferential shortening and ascending aorta velocity time integral. Diastolic blood pressure was increased in all BPA females. The calcium homeostasis proteins sarcoendoplasmic reticulum ATPase 2a (SERCA2a), sodium calcium exchanger-1, phospholamban (PLB), phospho-PLB, and calsequestrin 2 are important for contraction and relaxation. Changes in their expression suggest increased calcium mobility in males and reduced calcium mobility in females supporting the cardiac function changes. DNA methyltransferase 3a expression was increased in all BPA males and BPA 0.5 females and reduced in BPA 200 females. Global DNA methylation was increased in BPA 0.5 males and reduced in BPA 0.5 females. BPA induced sex-specific altered DNA methylation in specific CpG pairs in the calsequestrin 2 CpG island. These results suggest that continual exposure to BPA impacts cardiac structure/function, protein expression, and epigenetic DNA methylation marks in males and females.

Sex hormone control of left ventricular structure/function: mechanistic insights using echocardiography, expression, and DNA methylation analyses in adult mice

Calcium flux into and out of the sarco(endo)plasmic reticulum is vitally important to cardiac function because the cycle of calcium entry and exit controls contraction and relaxation. Putative estrogen and androgen consensus binding sites near to a CpG island are present in the cardiac calsequestrin 2 (CSQ2) promoter. Cardiomyocytes express sex hormone receptors and respond to sex hormones. We hypothesized that sex hormones control CSQ2 expression in cardiomyocytes and so affect cardiac structure/function. Echocardiographic analysis of male and female C57bl6n mice identified thinner walled and lighter hearts in females and significant concentric remodeling after long-term gonadectomy. CSQ2 and sodium-calcium exchanger-1 (NCX1) expression was significantly increased in female compared with male hearts and decreased postovariectomy. NCX1, but not CSQ2, expression was increased postcastration. CSQ2 expression was reduced when H9c2 cells were cultured in hormone-deficient media; increased when estrogen receptor-α (ERα), estrogen receptor-β (ERβ), or androgen agonists were added; and increased in hearts from ERβ-deficient mice. CSQ2 expression was reduced in mice fed a diet low in the methyl donor folic acid and in cells treated with 5-azadeoxycytidine suggesting an involvement of DNA methylation. DNA methylation in CpG in the CSQ2 CpG island was significantly different in males and females and was additionally changed postgonadectomy. Expression of DNA methyltransferases 1, 3a, and 3b was unchanged. These studies strongly link sex hormone-directed changes in CSQ2 expression to DNA methylation with changed expression correlated with altered left ventricular structure and function.

Cardiotoxicity of Cancer Therapeutics: Current Issues in Screening, Prevention, and Therapy

In the context of modern cancer chemotherapeutics, cancer survivors are living longer and being exposed to potential comorbidities related to non-cancer side effects of such treatments. With close monitoring of cancer patients receiving potentially cardiotoxic medical therapies, oncologists, and cardiologists alike are identifying patients in both clinical and subclinical phases of cardiovascular disease related to such chemotherapies. Specifically, cardiotoxicity at the level of the myocardium and potential for the development of heart failure are becoming a growing concern with increasing survival of cancer patients. Traditional chemotherapeutic agents used commonly in the treatment of breast cancer and hematologic malignancies, such as anthracyclines and HER-2 antagonists, are well known to be associated with cardiovascular sequelae. Patients often present without symptoms and an abnormal cardiac imaging study performed as part of routine evaluation of patients receiving cardiotoxic therapies. Additionally, patients can present with signs and symptoms of cardiovascular disease months to years after receiving the chemotherapies. As the understanding of the physiology underlying the various cancers has grown, therapies have been developed that target specific molecules that represent key aspects of physiologic pathways responsible for cancer growth. Inhibition of these pathways, such as those involving tyrosine kinases, has lead to the potential for cardiotoxicity as well. In view of the potential cardiotoxicity of specific chemotherapies, there is a growing interest in identifying patients who are at risk of cardiotoxicity prior to becoming symptomatic or developing cardiotoxicity that may limit the use of potentially life-saving chemotherapy agents. Serological markers and novel cardiac imaging techniques have become the source of many investigations with the goal of screening patients for pre-clinical cardiotoxicity. Additionally, studies have been performed.

Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny

Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs. Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart. Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0μg/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5-14.5. At 3months, male progeny were left sedentary or were swim trained for 4weeks. Echocardiography of isoflurane anesthetized mice revealed similar cardiac structure/function in all sedentary mice, but evidence of systolic dysfunction and increased diastolic relaxation after swim training at higher DES doses. The calcium homeostasis proteins, SERCA2a, phospholamban, phospho-serine 16 phospholamban and calsequestrin 2, are important for cardiac contraction and relaxation. Immunoblot analyses of ventricle homogenates showed increased expression of SERCA2a and calsequestrin 2 in DES mice and greater molecular remodeling of these proteins and phospho-serine 16 phospholamban in swim trained DES mice. DES increased cardiac DNA methyltransferase 3a expression and DNA methylation in the CpG island within the calsequestrin 2 promoter in heart. Thus, gestational DES epigenetically altered ventricular DNA, altered cardiac function and expression, and reduced the ability of adult progeny to cardiac remodel when physically challenged. We conclude that gestational exposure to estrogenizing EDCs may impact cardiac structure/function in adult males.

Unsupervised dealiasing and denoising of color-Doppler data

Color Doppler imaging (CDI) is the premiere modality to analyze blood flow in clinical practice. In the prospect of producing new CDI-based tools, we developed a fast unsupervised denoiser and dealiaser (DeAN) algorithm for color Doppler raw data. The proposed technique uses robust and automated image post-processing techniques that make the DeAN clinically compliant. The DeAN includes three consecutive advanced and hands-off numerical tools: (1) statistical region merging segmentation, (2) recursive dealiasing process, and (3) regularized robust smoothing. The performance of the DeAN was evaluated using Monte-Carlo simulations on mock Doppler data corrupted by aliasing and inhomogeneous noise. Fifty aliased Doppler images of the left ventricle acquired with a clinical ultrasound scanner were also analyzed. The analytical study demonstrated that color Doppler data can be reconstructed with high accuracy despite the presence of strong corruption. The normalized RMS error on the numerical data was less than 8% even with signal-to-noise ratio as low as 10dB. The algorithm also allowed us to recover highly reliable Doppler flows in clinical data. The DeAN is fast, accurate and not observer-dependent. Preliminary results showed that it is also directly applicable to 3-D data. This will offer the possibility of developing new tools to better decipher the blood flow dynamics in cardiovascular diseases.

Cardiac structure/function, protein expression, and DNA methylation are changed in adult female mice exposed to diethylstilbestrol in utero

The detrimental effects of in utero exposure to the non-steroidal estrogen diethylstilbestrol (DES) are particularly marked in women. Fetal hearts express estrogen receptors, making them potentially responsive to DES. To examine whether gestational exposure to DES would impact the heart, we exposed pregnant C57bl/6n dams to DES (0.1, 1.0, and 10.0 μg·(kg body mass)(-1)·day(-1)) on gestation days 11.5-14.5, and examined the measured cardiac structure/function and calcium homeostasis protein expression in adult females. At baseline, echocardiography revealed eccentric hypertrophy in mice treated with 10.0 μg·(kg body mass)(-1)·day(-1) DES, and immunoblots showed increased SERCA2a in all DES-treated mice. Mice were swim-trained to assess cardiac remodeling. Swim-trained vehicle-treated mice developed eccentric hypertrophy without changing SERCA2 or calsequestrin 2 expression. In contrast, no DES-treated mice hypertrophied, and all increased in SERCA2a and calsequestrin 2 expression after training. To determine whether DES-induced changes in DNA methylation is part of the mechanism for its long-term effects, we measured DNA methyltransferase expression and DNA methylation. Global DNA methylation and DNA methyltransferase 3a expression were unchanged. However, DES-treated mice had increased DNA methylation in the calsequestrin 2 promoter. Thus, gestational exposure to DES altered female ventricular DNA, cardiac structure/function, and calcium homeostasis protein expression. We conclude that gestational exposure to estrogenizing compounds may impact cardiac structure/function in adult females.

Cardiac response to doxorubicin and dexrazoxane in intact and ovariectomized young female rats at rest and after swim training

The impact of cancer therapies on adult cardiac function is becoming a concern as more children survive their initial cancer. Cardiovascular disease is now a significant problem to adult survivors of childhood cancer. Specifically, doxorubicin (DOX) may be particularly harmful in young girls. The objective of this study was to characterize DOX damage and determine the ability of dexrazoxane (DEX) to reduce DOX-mediated cardiac damage in sedentary and swim-trained female rats. Female Sprague-Dawley rats were left intact or ovariectomized (OVX) at weaning then injected with DEX (60 mg/kg) before DOX (3 mg/kg), DOX alone, or PBS. Rats were separated into sedentary and swim cohorts. Body weight was reduced in DOX:DEX- but not PBS- or DOX-treated rats. Echocardiographic parameters were similar in sedentary rats. Swim training revealed greater concentric remodeling in DOX-treated rats and reduced fractional shortening in DOX:DEX-treated rats. Calsequestrin 2 was reduced with DOX and increased with DOX:DEX postswim. Sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a was reduced and calsequestrin 2 reduced further by swim training only in intact rats. OVX rats were heavier and developed eccentric remodeling post-swim with DOX and eccentric hypertrophy with DOX:DEX. Changes in SERCA2a and calsequestrin 2 expression were not observed. Ovariectomized DOX- and DOX:DEX-treated rats stopped growing during swim training. DEX coinjection did not relieve DOX-mediated cardiotoxicity in intact or hormone-deficient rats. DOX-mediated reductions in growth, cardiac function, and expression of calcium homeostasis proteins were exacerbated by swim. DEX coadministration did not substantially relieve DOX-mediated cardiotoxicity in young female rats. Ovarian hormones reduce DOX-induced cardiotoxicity.

The impact of doxorubicin and dexrazoxane injection of prepubertal female rats on pregnancy outcome and cardiac function postpartum

Childhood cancer survivors can develop significant cardiac dysfunction in adulthood as a consequence of their cancer treatment. Studies have linked heart failure during pregnancy to childhood doxorubicin (DOX) exposure. We hypothesized that DOX injection would reduce cardiac function peripartum and that DOX-treated dams would show greater cardiac remodeling postweaning. Weanling female Sprague-Dawley rats were injected with phospate-buffered saline, DOX (3 mg/kg), or DOX plus the cardioprotectant dexrazoxane (DEX; 60 mg/kg) and followed for 2 pregnancies. DOX and DOX:DEX dams were fertile, but had fewer pups and more pup losses. Echocardiography, 1-day postpartum after each pregnancy, revealed greater increases in cardiac mass and eccentric hypertrophy in DOX-treated dams and early dilation in DOX:DEX dams. The expression of calcium homeostasis proteins can change after DOX treatment and cardiac remodeling. SERCA2a expression did not change. Reductions in phospholamban and phospho-serine 16-specific phospholamban expression in DOX dams were not relieved by DEX coinjection. DOX binds and inactivates calsequestrin 2 expression so increased calsequestrin 2 expression in DOX:DEX-treated dams suggests some DEX compensation. The eccentric hypertrophy and dilation development, despite compensatory changes in proteins controlling calcium cycling, suggest DOX damage with repeat pregnancy that was not alleviated fully by DEX.

Sex-specific cardiovascular responses to control or high fat diet feeding in C57bl/6 mice chronically exposed to bisphenol A.

The increased pericardial fat which often accompanies overall obesity is thought to alter cardiac structure/function and increase the risk for atrial fibrillation. We hypothesized that chronic exposure to bisphenol A (BPA) would induce pericardial fat, cardiac hypertrophy or arrhythmia. C57bl/6n dams were exposed to BPA (25 ng/ml drinking water) beginning on gestation day 11 and progeny continued on 2.5 ng BPA/ml drinking water. The progeny of control dams (VEH) and dams treated with diethylstilbestrol (DES, 1 μg/kg/day, gestation days 11u2fff14) had tap water. After weaning progeny were fed either a control (CD) or high fat diet (HFD) for 3 months. Pericardial fat was present in CD-BPA and CD-DES and not CD-VEH mice, and was increased in all HFD mice. Catecholamine challenge revealed no differences in males, but BPA-exposed females had longer P-wave and QRS complex duration. Only CD-BPA and CD-DES females developed cardiac hypertrophy which was independent of increased blood pressure. Calcium homeostasis protein expression changes in HFD-BPA and HFD-DES mice predict reduced SERCA2 activity in males and increased SERCA2 activity in females. Thus, chronic BPA exposure induced pericardial fat in the absence of HFD, and female-specific changes in cardiac hypertrophy development and cardiac electrical conduction after a catecholamine challenge.