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Sunday Basic Tips
Poster: S4217 – Session: M.APS.P20
Location: Science and Technology Hall, Clinical Science Section
Embargoed for 3 p.m. CT/4 p.m. ET, Sunday, Nov. 13, 2016
Dr. Jonathan A. Kopechek
University of Louisville
Louisville, KY
[email protected]
502-852-8205
Session Assignment
IM.APS.P20 - Advances in Contrast Echocardiography, Molecular and Myocardial Imaging
(Presentation #: S4217 ; Speaking Time: 11/13/2016 3:45:00 PM - 11/13/2016 5:00:00 PM)
Abstract Title
Targeted Delivery of AntimiR-23a Using Ultrasound and Microbubbles Suppresses Cardiac Hypertrophy and
Improves Cardiac Function in vivo
Author Block
Jonathan A Kopechek, Charles F. McTiernan, Xucai Chen, Rafey Feroze, Bin Qin, Jissy Cyriac, Linda Lavery,
Daniel Whitehurst, Flordeliza S. Villanueva, Univ of Pittsburgh, Pittsburgh, PA
Disclosure Block:
J.A. Kopechek: None. C.F. McTiernan: None. X. Chen: None. R. Feroze: None. B. Qin: None. J.
Cyriac: None. L. Lavery: None. D. Whitehurst: None. F.S. Villanueva: None.
Abstract Content
Background: MicroRNAs (miRs) are dysregulated in various cardiovascular diseases. An antimiR against miR-23a suppressed
hypertension-induced cardiac hypertrophy in preclinical models, but clinical translation is limited by a lack of cardiac-targeted delivery
systems. Ultrasound-targeted microbubble (MB) destruction (UTMD) is a novel therapeutic delivery platform that utilizes MBs as nucleic
acid carriers and offers a non-invasive image-guided approach to target delivery of molecular therapeutics to the heart. We hypothesized that
cardiac delivery of an antimiR against miR-23a using UTMD suppresses cardiac hypertrophy and improves cardiac function in hypertensive
mice.
Methods: Cationic lipid MBs were loaded with negative control antimiR (NC) or antimiR-23a. C57BL/6 mice were implanted with
phenylephrine-loaded osmotic minipumps (100 mg/kg/d) and received UTMD treatments (1.3 MHz, MI setting=1.0) with 300 pmol antimiR
0, 3, and 7 days later. A third group (no phenylephrine, No-PE) of age matched mice received no treatments. At 2 weeks, miR-23a levels
were measured using RT-PCR. Left ventricular (LV)mass and function were serially assessed with echocardiography.
Results: UTMD treatment with antimiR-23a knocked down cardiac miR-23a by 41 ± 8% compared to UTMD treatment with NC (n=89/group, p<0.01). As expected, phenylephrine increased LV mass relative to No-PE mice. However, compared to treatment with UTMD +
NC, LV mass in mice with UTMD + antimiR-23a was 16 ± 2% lower after 1 week (p < 0.05), and remained lower during the study (p=0.06)
(Figure 1). By 2 weeks, fractional shortening had decreased in UTMD + NC but was preserved in UTMD + antimiR-23a (45.2% vs. 37.7%,
p < 0.05).
Conclusions: To our knowledge, this is the first study to demonstrate suppression of cardiac hypertrophy and preservation of cardiac
function with UTMD-targeted delivery of a miRNA inhibitor. Our data suggest that UTMD could be used to deliver other miRNA
therapeutics for cardiac therapy.
Sunday Basic Tips
Presentation: 251 – Session: EP.AOS.486.N
Location 346-347
Embargoed for 3 p.m. CT/4 p.m. ET, Sunday, Nov. 13, 2016
Dr. Samson Gebreab (PhD)
National Human Genome Research Institute, NIH
Genomics of Metabolic, Cardiovascular and Inflammatory Disease Branch
Bethesda, MD
[email protected]
301-451-1278
Session Assignment
EP.AOS.486.N - Functional Genomics & Epidemiology Mid-Career Research Award and Lecture
(Presentation #: 251 ; Speaking Time: 11/14/2016 2:30:00 PM - 11/14/2016 2:40:00 PM)
Abstract Title
Less Than Ideal Cardiovascular Health is Associated With Shorter Leukocyte Telomere Length: The National Health
and Nutrition Examination Surveys
Author Block
Samson Y Gebreab, Natl Human Genome Res Inst, NIH, Bethesda, MD; Zerai G Manna, Natl Insts of Health, Bethesda, MD;
Rumana J Khan, Pia Riestra, Ruihua Xu, Sharon K Davis, Natl Human Genome Res Inst, NIH, Bethesda, MD
Disclosure Block:
S.Y. Gebreab: None. Z.G. Manna: None. R.J. Khan: None. P. Riestra: None. R. Xu: None. S.K. Davis: None.
Abstract Content
Introduction: The associations between individual cardiovascular disease (CVD) risk factors and leukocyte telomere length (LTL) have
been inconclusive. This study examined the association between global cardiovascular health (CVH) as defined by American Heart
Association and LTL. Hypothesis: We hypothesize that less than ideal CVH is associated with shorter LTL. We also hypothesize the
association is modified by gender and racial/ethnicity. In addition, we hypothesize that adjusting for inflammation attenuates the association
between CVH and LTL.
Methods: Data were obtained from the 1999-2002 National Health and Nutrition Examination Survey (n= 5194). CVH was defined as a
composite score of the 7 metrics (smoking, physical activity, diet, body mass index, blood pressure, total cholesterol, fasting blood glucose)
and categorized as “poor”, “intermediate”, and “ideal”. LTL was assayed from whole blood using the quantitative PCR method relative to
standard reference DNA. Multivariable linear regression models were used to estimate the association between CVH and log-transformed
LTL.
Results: There was strong and graded association between CVH and LTL in the overall sample. Individuals with poor or intermediate CVH
was significantly associated with shorter LTL compared to ideal CVH [β =-0.034 (SE=0.013), p=0.011 and -0.024 (0.01), p=0.024,
respectively], after adjustment for age, gender, race/ethnicity, marital status, nativity, socioeconomic status, and inflammation. The
association was stronger in women [β =-0.066 (0.018), p=0.001 for poor vs. ideal CVH, and -0.051 (0.01), p<0.001 for intermediate vs. ideal
CVH] and in white [β =-0.043 (0.014), p=0.004 for poor vs. ideal CVH, and -0.029 (0.012), p<0.017 for intermediate vs. ideal CVH].
Conclusions: Our findings suggest that global CVH is associated with cellular aging, but this association varies by gender and race/ethnicity.
Additional research is needed to clarify the mechanisms that underlie these differences.
Sunday Basic Tip
Poster: M4141, Session: VA.APS.P73
Location: Science and Technology Hall, Clinical Science Section
Embargoed for 3 p.m. CT/4 p.m. ET, Sunday, Nov. 13, 2016
Yasuhide Nakayama (PhD)
National Cerebral and Cardiovascular Center Research Institute
Osaka, Japan
+81-6-6833-5004
[email protected]
Session Assignment
VA.APS.P73 - The Unique Diversity of Treatments for Peripheral Vascular Disease
(Presentation #: M4141 ; Speaking Time: 11/14/2016 10:45:00 AM - 11/14/2016 12:00:00 PM)
Abstract Title
First-in-Human Study of an Autologous In-Body Tissue-Engineered Vascular Graft (Biotube type C) for
Hemodialysis Access
Author Block
Yasuhide Nakayama, Natl Cerebral and Cardiovascular Ctr Res Inst, Osaka, Japan; Yoshiyuki Kaneko, Noriko
Okumura, Tenri Hosp, Nara, Japan
Disclosure Block:
Y. Nakayama: None. Y. Kaneko: None. N. Okumura: None.
Abstract Content
Background and Purpose: An arteriovenous (AV) fistula is the current gold standard for chronic hemodialysis access. However, a
substantial number of shunt will fail because of stenosis or obstruction at anastomotic site or venous outflow. Tissue-engineered blood
vessels have been proposed for dialysis access as an alternative to prosthetic grafts. We developed autologous connective tubular tissues
(Biotubes) formed by "in body tissue architecture" technology, based on the tissue encapsulation phenomenon. The technology represents a
novel and practical approach to regenerative medicine. Recently, Biotube with designed dimension including wall thickness was developed
as type C. This report presents the first-in-human results after a minimum of 3 months of follow-up for the first two patients implanted with
Biotube type C.
Methods and Results: Biotube vascular grafts with 5 or 6 mm in diameter and 7 cm in length were prepared as autologous connective
tubular tissues with wall thickness of ca. 1mm by embedding of molds, assembled with a silicone center rod and a stainless steel tube, into
patients abdominal subcutaneous pouches for 2 months. Two female patients had end-stage renal disease and had been receiving
heamodialysis with a high probability of failure, because of repeatable stenosis about every month at venous outflow regions. The biotubes
after stored for 1 day in a 70% alcohol solution were bypassed by end-to side anastomoses over venous stenosis region of an AV shunt.
Palpable thrill and typical turbulent flow pattern by pulsed-wave Doppler were observed. Monthly angiography showed little change in the
implanted grafts with no signs of dilation or stenosis with time points up to 3 months. Repeated puncture could be performed without grafts
damage.
Conclusion: This first human study successfully supported the concept of creating dialysis access from autologous connective tissue Biotube
grown in patients subcutaneous pouches.
Sunday Basic Tip
Poster S1000, Session: AT.APS.P88
Location: Science and Technology Hall, Basic Science Section
Embargoed for 3 p.m. CT/4 p.m. ET, Sunday, Nov. 13, 2016
Wei Huang (MD, PhD)
Universtiy of Cincinnati
Cincinnati, OH
[email protected]
513-365-6787
Session Assignment
AT.APS.P88 - Best of Basic Science Posters (Presentation #: S1000 ; Speaking Time: 11/13/2016 4:45:00 PM - 11/13/2016 6:00:00 PM)
Abstract Title
Activation of Cardiomyocyte Proliferation via Targeting Mir-128 in Infarcted Heart
Author Block
Wei Huang, Jialiang Liang, Lin Jiang, Wenfeng Cai, Paul Christian, Meifeng Xu, Yigang Wang, Universtiy of
Cincinnati, Cincinnati, OH
Disclosure Block:
W. Huang: None. J. Liang: None. L. Jiang: None. W. Cai: None. P. Christian: None. M. Xu: None. Y.
Wang: None.
Abstract Content
Background: In contrast to neonatal hearts, adult mouse cardiac regeneration ability is limited due to the ineffective reactivation
of cardiomyocyte (CM) proliferation following injury. However, it is unclear whether the underlying mechanism employed during the
neonatal period can be manipulated in the adult heart to activate endogenous CM proliferation and facilitate cardiac regeneration.
Methods and Results: Mouse hearts were harvested at postnatal days 1, 7, and 28 (P1, P7, and P28) and analyzed to screen the miRNA
involved in postnatal CM proliferation. The percentage of proliferative CM (Ki67 +) in mouse hearts was significantly decreased between P7
and P28, whereas expression of miR128 progressively increased. Gain- and loss-of-function approaches using genetic mouse models were
then developed to delineate the functional effects and mechanisms that involved in miR128-regulated CM proliferation. Cell
dedifferentiation, DNA synthesis, mitosis, and cytokinesis were analyzed by immunostaining. Cell cycle associated protein expression was
analyzed by Western blotting. In mice, overexpression of miR128 led to decreased CM proliferation. In contrast, deletion of miR128 (iKO)
induced a significant increase in CM proliferation (as quantified by increased Edu + CM population). Moreover, CDK inhibitor (p27)
transcription was epigenetically silenced by miR128 deletion through targeting SUZ12 in hearts, leading to the activation of positive cell
cycle regulators (Cyclin E and CDK2). Finally, postnatal deletion of miR128 was sufficient to induce CM reentry into the cell cycle leading
to reduced fibrosis, improved post-injury remodeling, and heart function recovery following myocardial infarction in adult mice (Fig. 1).
Conclusion: These results demonstrate miR128 is a critical regulator of postnatal CM proliferation, and could provide a promising
therapeutic option for heart repair after injury.