Complete resolution of focal-on-diffuse myocardial activity pattern on FDG PET-CT by prolonging the dietary preparation protocol in cardiac sarcoidosis.

Patient preparation is crucial for reliable interpretation of cardiac inflammation FDG PET. We share our experience of improved reporting confidence and propose a simple approach of prolonging preparation (from 24 to 48 hours) with the high-fat, no-carbohydrate, and protein-permitted diet followed by fasting in cardiac sarcoidosis in cases with diffuse or focal-on-diffuse myocardial FDG uptake.

Prognostic value of silent myocardial infarction in patients with chronic kidney disease after kidney transplantation.

We have shown that silent myocardial infarction (SMI) on 12-lead ECG is associated with increased cardiovascular disease (CVD) risk in patients awaiting renal transplantation (RT). In this study, we evaluated the prevalence of SMI in patients undergoing RT and their prognostic value after RT. MI was determined by automated analysis of ECG. SMI was defined as ECG evidence of MI without a history of clinical MI (CMI). The primary outcome was a composite of CVD death, non-fatal MI and coronary revascularization after RT. Of the 1189 patients who underwent RT, a 12-lead ECG was available in >99%. Of the entire cohort 6% had a history of CMI while 7% had SMI by ECG. During a median follow-up of 4.6 years, 147 (12%) experienced the primary outcome (8% CVD death, 4% MI, 4% coronary revascularization) and 12% died. Both SMI and CMI were associated with an increased risk of CVD events and all-cause deaths. In a multivariable adjusted Cox-regression model, both SMI (adjusted hazard ratio 2.03 [1.25-3.30], p = .004) and CMI (2.15 [1.24-3.74], p = .007) were independently associated with the primary outcome. SMI detected by ECG prior to RT is associated with increased risk of CVD events after RT.

Prognostic value of absent left ventricular ejection fraction reserve with regadenoson SPECT MPI.

BACKGROUND: An absent left ventricular ejection fraction (LVEF) reserve with vasodilator stress with PET cardiac imaging has been shown to provide significant independent and incremental value to the perfusion images for prediction of future cardiovascular adverse events. However, the prognostic value of LVEF reserve has not been well characterized with SPECT myocardial perfusion imaging (MPI). METHODS: We studied 858 consecutive patients with normal and abnormal perfusion pattern with regadenoson SPECT MPI. Change in LVEF was calculated as post-stress LVEF-rest LVEF. Absent LVEF reserve was defined as a drop in LVEF by 5% or more on the post-stress images. The primary outcome was a composite of cardiac death, non-fatal myocardial infarction and late coronary revascularization. RESULTS: An absent LVEF reserve was more common in patients with abnormal vs normal MPI (31% vs 19%, P = .001). During a median follow-up of 32 months, the primary outcome was experienced by 31% of the study population. An absent LVEF reserve was not associated with an increased risk of the primary outcome in patients with normal (hazard ratio 1.1, 95% CI .4-2.7, P = .8) or abnormal (.75, .56-1.00, P = .05) MPI. There was no significant correlation between extent of ischemia and post-stress change in LVEF (Pearson r = - .072, P = .07). CONCLUSIONS: In patients undergoing regadenoson SPECT MPI, absent LVEF reserve is not associated with worse cardiac outcomes. Thus, routine reporting of both post-stress and rest LVEF measurements in this setting may not be necessary.

Evolution of symptoms in patients with stable angina after normal regadenoson myocardial perfusion imaging: The Radionuclide Imaging and Symptomatic Evolution study (RISE).

BACKGROUND: Assessment of quality of life in patients with stable angina and normal gated single-photon emission computed tomography myocardial perfusion imaging (MPI) remains undefined. Symptom evolution in response to imaging findings has important implications on further diagnostic testing and therapeutic interventions. METHODS: Prospective cohort study was conducted at the University of Alabama at Birmingham enrolling 87 adult participants with stable chest pain from the emergency room, hospital setting, and outpatient clinics. Patients underwent MPI with technetium-99m Sestamibi and had a normal study. Participants filled out Seattle Angina Questionnaires initially and at 3-month follow-up. RESULTS: Among the 87 participants (60 ± 12 years; 40% African American, 70% women, 29% diabetes), the mean score increased by an absolute value of 14.2 [95% CI 10.4-18.7, P < .001] in physical limitation, 23.2 [95% CI 17.1-29.4, P < .001] in angina stability, 10.9 [95% CI 7.6-14.1, P < .001] in angina frequency, and 20.6 [95% CI 16.5-24.7, P < .001] in disease perception. There was no significant change in the mean score of treatment satisfaction [- 1.4, 95% CI - 4.7 to 1.8, P = .38]. At 3-month follow-up, 28 of 87 participants (32%) were angina free. CONCLUSIONS: Patients with stable chest pain and normal MPI experience significant improvement in functional status, quality of life, and disease perception in the short term.

Effect of left ventricular mechanical dyssynchrony assessed pre-renal transplantation on cardiovascular death post transplantation.

BACKGROUND: SPECT myocardial perfusion imaging (MPI) provides an assessment of LV mechanical dyssynchrony (LVMD) which correlates with CVD outcomes in diverse populations including those awaiting renal transplant (RT). The current study examines the association of LVMD on pre-transplant MPI with long-term CVD mortality post RT. METHODS: We identified consecutive patients who underwent RT at the University of Alabama at Birmingham between 2008 and 2012 from our prospectively collected database. 675 patients in the database underwent MPI and had images amenable for phase analysis. A blinded investigator retrieved the studies and derived LVMD indices including histogram bandwidth (BW), standard deviation (SD), phase peak, phase skewness, and phase kurtosis. The primary outcome was CVD death after RT. RESULTS: The study cohort had a median age of 54 years, 56% were men, 43% had diabetes, and 7% had prior myocardial infarction. Patients were on dialysis for a median of 3.4 years prior to RT and 34% received living donor transplants. During a median follow-up time after RT of 4.7 years (IQR 3.5 to 6.3 years) 59 patients (9%) succumbed to CVD death. Patients with wider BW, wider SD, lower skewness, and lower kurtosis had an increased risk of CVD death. On multivariate adjustment, BW and skewness remained as independent predictors of CVD deaths. CONCLUSIONS: LVMD by phase analysis of gated SPECT MPI is associated with increased risk of CVD death after RT. This association is independent of demographics, comorbidities, and traditional findings on MPI and added incremental prognostic information. Assessment of LVMD should be considered for risk stratification in these patients.

The prognostic value of myocardial perfusion imaging in patients with type 2 myocardial infarction.

OBJECTIVES: The aim of this retrospective study is to evaluate the prognostic role of myocardial perfusion imaging (MPI) in patients with type 2 myocardial infarction (T2MI). BACKGROUND: T2MI is an increasingly common diagnosis in clinical practice. The management of this condition is controversial and the prognostic value of MPI has not been established in this setting. METHODS: We retrospectively studied T2MI patients who underwent vasodilator gated MPI within 90 days of T2MI at a single tertiary care institution in 2013. Abnormal myocardial perfusion was defined as the perfusion defect involving ≥ 5% of left ventricular (LV) myocardium. Abnormal LV ejection fraction (EF) was defined as < 50% by gated images. The primary outcome was a composite of death, myocardial infarction (other than index event) or coronary revascularization (CR). RESULTS: There were 234 patients (62 ± 14 years, 57% men) with T2MI (peak troponin 0.2 ng/ml, interquartile 0.1-1.4), of whom 136 (58%) had an abnormal MPI. During a median follow-up of 20 months, 155 patients (66%) had the primary outcome (39% death, 42% MI, 5% CR). An abnormal MPI was associated with an increased risk of the primary outcome with a hazard ratio of 1.56, 95%CI (1.12-2.18, P = .008) that remained statistically significant after multivariate adjustment (1.45, 95%CI (1.02-2.06, P = .04))). CONCLUSIONS: Patients with T2MI are at high risk for death or cardiac events in the intermediate term. More than one-half of patients with T2MI have an abnormal MPI and this is associated with the increased risk of cardiac events during follow-up. Risk stratification with MPI after T2MI may identify patients who would benefit from aggressive risk reduction.

Resveratrol suppresses cholestasis-induced liver injury and fibrosis in rats associated with the inhibition of TGFß1-Smad3-miR21 axis and profibrogenic and hepatic injury biomarkers.

Cholestasis caused by slowing or blockage of bile flow is a serious liver disease that can lead to liver fibrosis and cirrhosis. The link between transforming growth factor beta 1 (TGFß1), Smad family member 3 (Smad3), and microRNA 21 (miR21) in bile duct ligation (BDL)-induced liver fibrosis in the presence and absence of the anti-inflammatory and antioxidant compound, resveratrol (RSV), has not been previously studied. Therefore, we tested whether RSV can protect against BDL-induced liver fibrosis associated with the inhibition of the TGFß1-Smad3-miR21 axis and profibrogenic and hepatic injury biomarkers. The model group of rats had their bile duct ligated (BDL) for 3 weeks before being killed, whereas, the BDL-treated rats were separated into three groups that received 10, 20, and 30 mg/kg RSV daily until the end of the experiment. Using light microscopy and ultrasound examinations, we documented in the BDL group, the development of hepatic injury and fibrosis as demonstrated by hepatocytes necrosis, bile duct hyperplasia, collagen deposition, enlarged liver with increased echogenicity, irregular nodular border and dilated common bile duct, which were more effectively inhibited by the highest used RSV dosage. In addition, RSV significantly (p ≤ 0.0027) inhibited BDL-induced hepatic TGFß1, Smad3, miR21, the profibrogenic biomarker tissue inhibitor of metalloproteinases-1 (TIMP-1), malondialdehyde (MDA), interleukin-17a (IL-17a), and blood levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin. These findings show that RSV at 30 mg/kg substantially protects against BDL-induced liver injuries, which is associated with the inhibition of TGFß1-Smad3-miR21 axis, and biomarkers of profibrogenesis, oxidative stress, and inflammation.

Detection and quantitation of right ventricular reversible perfusion defects by stress SPECT myocardial perfusion imaging: A proof-of-principle study.

BACKGROUND: In patients with right dominant coronary circulation, the right ventricular (RV) myocardium and the inferior region of the left ventricular (LV) myocardium share a common source of blood flow. We hypothesized that stress/rest SPECT myocardial perfusion imaging (MPI) could detect reversible perfusion defects in the RV in some patients with LV inferior wall perfusion abnormalities. MATERIAL AND METHODS: We identified 2 groups of patients with LV inferior wall perfusion defects (with or without defects in other regions of LV myocardium) from our database. Patients in group 1 (n = 17) had reversible perfusion defects in the RV free wall by visual analysis, while patients in group 2 (n = 17) did not. The images were processed with filtered back projection and, separately, with iterative reconstruction. The images were then re-processed using an automated quantitative software that is specifically designed to include the RV in the region of interest. RESULTS: There were 76% men in group 1 and 94% in group 2 (P <0.05). The mean age was 65±20 in group 1 vs. 63±18 years in group 2 (P < 0.05). The stress type was exercise in 30% in group 1 and 35% in group 2, with the remaining patients studied with pharmacological stress testing (P = NS). The presence of RV reversible perfusion defects using filtered back projection was more evident in 13 patients (75%), while it was better seen with iterative reconstruction in 4 patients (25%). By automated analysis, the RV reversible perfusion defect size was 19 ± 14% of RV myocardium. CONCLUSION: This proof-of-principle study demonstrates that reversible RV perfusion defects suggestive of ischemia can be detected by SPECT myocardial perfusion imaging in some patients with LV inferior ischemia by visual analysis and can be quantitated by automated programs. Further studies on the diagnostic and prognostic relevance of assessing RV ischemia on SPECT MPI are needed.

The effect of renal transplantation on left ventricular function, electrocardiography, and mechanical synchrony by gated myocardial perfusion imaging.

BACKGROUND: Depressed left ventricular ejection fraction (LVEF), LV mechanical dyssynchrony (LVMD), and prolonged QTc interval predict poor outcomes in end-stage renal disease (ESRD). Renal transplantation improves mortality in ESRD patients but the effects of transplantation on these indices remain undefined. METHODS: We identified patients with myocardial perfusion imaging (MPI) before and after renal transplantation. A control group consisted of ESRD patients who underwent 2 MPIs but did not receive a transplant. Changes in LVEF, LVMD indices [phase standard deviation (SD) and bandwidth (BW)] by MPI, and electrocardiogram (ECG) indices were determined. RESULTS: The study population consisted of 32 ESRD patients (53% male, 50 ± 11 years, 59% African American, 65% diabetic). The second MPI was performed 31 months (13-59 months) after renal transplantation. LVEF (72 ± 10% vs. 67 ± 10%, P < 0.001) but not SD (22 ± 15° vs. 22 ± 11°, P = 0.9) or BW (58 ± 35° vs. 57 ± 29°, P = 0.9) improved after transplantation. There were no changes in these indices in the control group. QTc (425 ± 30 ms vs. 447 ± 32 ms, P = <0.001) but not QRS (90 ± 21 ms vs. 90 ± 21 ms, P = 0.9) improved significantly after renal transplantation. CONCLUSIONS: LVEF and QTc improved after renal transplantation but LVMD indices and QRS did not change, which suggests that LVMD and electrical dyssynchrony may be irreversible in ESRD.

Prognostic value of myocardial perfusion imaging performed pre-renal transplantation: post-transplantation follow-up and outcomes.

PURPOSE: Noninvasive stress testing is commonly performed as part of pre-renal transplantation (RT) evaluation. We evaluated the prognostic value of myocardial perfusion imaging (MPI)-myocardial perfusion, left ventricular ejection fraction (LVEF) and heart rate response (HRR)-post-RT. METHODS: Consecutive RT recipients were identified at our institution. MPI was considered abnormal when there was a perfusion defect or reduced ejection fraction. HRR to vasodilator stress was calculated as percentage change from baseline. The primary outcome was a composite of cardiovascular (CV) death, myocardial infarction (MI) and coronary revascularization (CR) post-RT; all-cause mortality was the secondary endpoint. RESULTS: Among 1189 RT recipients, 819 (69%) underwent MPI. Of those, 182 (22%) had abnormal MPI, and 31 (4%) underwent CR pre-RT. During a median follow-up of 56 months post-RT, the annual CV event and mortality rates for patients who had no MPI, normal MPI and abnormal MPI were 1.5%, 3.1% and 4.3% (p < 0.001), and 1.8%, 2.6% and 3.6% (p = 0.016), respectively. After multivariate adjustment, compared to patients without MPI, the hazard ratios (HRs) for CV events for normal and abnormal MPI were 1.47 ([0.93-2.33], p = 0.1) and 1.78 ([1.03-3.06], p = 0.04). Blunted HRR was an independent predictor of CV events (HR = 1.73 [1.04-2.86], p = 0.034) and all-cause death (HR = 2.26 [1.28-3.98], p = 0.005) after adjusting for abnormal MPI. Patients with abnormal MPI who underwent CR pre-RT had annual mortality rates similar to those with no or normal MPI (1.9% vs. 1.7-2.6%, p = 0.2), while those who did not undergo CR had higher annual mortality (4% vs. 1.7-2.6%, p = 0.003). CONCLUSIONS: One in five RT recipients who underwent screening MPI had an abnormal study, an independent predictor of CV events. A blunted HRR to vasodilator stress was associated with increased risk of CV events and death, even after adjusting for abnormal MPI. Patients with abnormal MPI who underwent CR were at low risk of mortality following RT. MPI is a useful tool to aid in risk stratification pre-RT.

The reproducibility and prognostic value of serial measurements of heart rate response to regadenoson during myocardial perfusion imaging.

PURPOSE: The heart rate response (HRR, percentage change from baseline) to regadenoson during myocardial perfusion imaging (MPI) can provide incremental prognostic value in patients with known or suspected coronary artery disease. Our purpose was to evaluate the variability and prognostic value of HRR on serial measurements. METHODS: We studied 648 consecutive patients (61 ± 11 years, 48 % with diabetes) who underwent two regadenoson MPI studies (16 ± 9 months between studies). HRR <30 % was defined as abnormal. All-cause mortality was determined by chart review and verified using the US Social Security Death Master File. RESULTS: HRR was well correlated between the two studies (intraclass correlation coefficient 0.72, 95 % CI 0.67 - 0.76) with no systematic bias (mean difference 0.88 %, p = 0.2) or proportional bias (p = 0.5) by Bland-Altman analysis in all patients and in those with normal MPI on both studies. Of the 308 patients (48 %) with normal baseline HRR (HRR-1), 33 % had developed a blunted HRR on the second MPI study (HRR-2). Older age, male gender, end-stage renal disease, and abnormal baseline left ventricular ejection fraction were independent predictors of a new-onset abnormal HRR. During a mean follow-up of 2.4 ± 1.2 years, 55 patients (8.5 %) died. Patients with a blunted HRR-1 had increased mortality risk irrespective of their HRR-2 (p = 0.9, log-rank test). Among patients with normal HRR-1, a blunted HRR-2 was an independent predictor of all-cause mortality beyond clinical and traditional MPI data (hazard ratio 2.83, 95 % CI 1.14 - 7.03). Finally, patients with a normal HRR-1 and HRR-2 had the lowest event rate, while those with any abnormal HRR had an increased risk of death (hazard ratio 2.5, 95 % CI 1.2 - 5.4). CONCLUSION: There was good correlation in the HRR to regadenoson on serial measurements without systematic or proportional biases. Patients with consistently normal HRR had the best prognosis.

The prognostic value of non-perfusion variables obtained during vasodilator stress myocardial perfusion imaging.

Myocardial perfusion imaging (MPI) is an established diagnostic test that provides useful prognostic data in patients with known or suspected coronary artery disease. In more than half of the patients referred for stress testing, vasodilator stress is used in lieu of exercise. Unlike exercise, vasodilator stress does not provide information on exercise and functional capacity, heart rate recovery, and chronotropy, and ECG changes are less frequent. These non-perfusion data provide important prognostic and patient management information. Further, event rates in patients undergoing vasodilator MPI are higher than in those undergoing exercise MPI and even in those with normal images probably due to higher pretest risk. However, there are a number of non-perfusion variables that are obtained during vasodilator stress testing, which have prognostic relevance but their use has not been well emphasized. The purpose of this review is to summarize the prognostic values of these non-perfusion data obtained during vasodilator MPI.

Effect of changes in perfusion defect size during serial regadenoson myocardial perfusion imaging on cardiovascular outcomes in high-risk patients.

BACKGROUND: The prognostic value of single-photon emission computed tomography myocardial perfusion imaging (MPI) is well established. There is a paucity of data on the prognostic value of changes in perfusion defect size (PDS) on serial MPIs. METHODS: From the MPI database at the University of Alabama at Birmingham, consecutive patients who underwent two regadenoson stress MPIs between July 2008 and March 2013 were identified. The MPIs were analyzed side-by-side using an automated software program for presence and change in PDS. Improvement in PDS was defined as a reduction ≥5% of left ventricle. A drop in left ventricular ejection fraction (LVEF) was defined as a decrease ≥5%. The primary outcome was a composite of death, myocardial infarction (MI), and coronary revascularization (CR). RESULTS: There were 698 patients (61 ± 11 years, 53% male, 48% diabetes, 25% prior MI, 49% prior CR) who underwent two regadenoson MPIs within 16 ± 9 months for clinical indications. The primary outcome occurred in 167 (24%) patients (8% death, 9% MI, 15% CR) during 24 ± 16 months of follow-up after the second MPI. The MPIs were normal in both studies in 399 (57%, Group 1), showed improvement in 94 (14%, Group 2, PDS 15% ± 16% vs 28% ± 18%, P < .001) and no change or worsening in 205 patients (29%, Group 3, 28% ± 17% vs 20% ± 17%, P < .001). The best outcomes were seen in Group 1 and the worst in Group 3 (log-rank P < .001). Similar trends were seen for the components of the primary outcome (P = .04 for death, P < .001 for MI, P < .001 for CR). In a Cox-regression model that adjusted for baseline factors including PDS and LVEF on initial MPI, the hazard ratios for primary outcome were 2.0 (P = .02) and 3.9 (P < .001) for Groups 2 and 3 compared to Group 1, respectively. In addition, an LVEF drop ≥5% was independently associated with the primary outcome (HR 1.5, P = .01). CONCLUSION: Changes in PDS and LVEF on serial MPIs provide incremental prognostic information to initial and follow-up MPI findings. Lack of improvement or an increase in PDS and a drop in LVEF identify high-risk patients.

Prognostic value of transient ischemic dilation with regadenoson myocardial perfusion imaging.

BACKGROUND: Transient ischemic dilation (TID) of the left ventricle seen on myocardial perfusion imaging (MPI) is sometimes used as a marker of severe coronary artery disease. The prognostic value of TID obtained using regadenoson, a selective adenosine A2A receptor agonist, as a stress agent for MPI has not been studied. METHODS: TID ratio was measured using an automated software program on consecutive patients with normal and abnormal perfusion pattern on regadenoson MPI at a single institution. An abnormal TID was defined as greater than 1.33. The primary outcome was a composite of cardiac death, non-fatal myocardial infarction (MI), and late coronary revascularization (CR, >90 days after MPI). RESULTS: The study population consisted of 887 patients (62 ± 12 years, 66% male, 48% diabetes, 46% prior CR, 75% with abnormal perfusion pattern, left ventricular ejection fraction-LVEF 55 ± 6%). An abnormal TID was present in 51 (6%) patients. Baseline characteristics were not different based on the presence or absence of TID. Early CR (≤90 days) was performed in 11 (22%) patients with vs 92 (11%) patients without TID (P = .04). During a mean follow-up of 29 ± 19 months, the primary outcome occurred in 271 (31%) patients (22% cardiac death, 6% MI, 9% late CR). TID was associated with increased risk of the primary outcome (log-rank P = .017), an association largely driven by late CR. In a Cox proportional model adjusted for multiple variables including perfusion defect size (PDS) and LVEF, the hazard ratio for TID was 1.92 (95% CI 1.20-3.08, P = .007). In the subset of patients with normal perfusion pattern, there was no association between TID and outcomes. CONCLUSIONS: TID on regadenoson MPI carries important prognostic information that is independent from PDS and LVEF, but this association is restricted to patients with abnormal perfusion on imaging.

New 6-nitro-4-substituted quinazoline derivatives targeting epidermal growth factor receptor: design, synthesis and in vitro anticancer studies.

Aim: Twenty compounds of 6-nitro-4-substituted quinazolines were synthesized.Materials & methods: The new derivatives were evaluated for their epidermal growth factor receptor (EGFR) inhibitory activity. The most potent derivatives were assessed for their cytotoxicity against colon cancer and lung cancer cells, in addition to normal fibroblast cells.Results & discussion: compound 6c showed a superior to nearly equal cytotoxicity in comparison to gefitinib, it also revealed a good safety profile. Compound 6c caused a cell cycle arrest at G2/M phase in addition to induction of apoptosis. A molecular docking study was conducted on the most active compounds to gain insights of their binding mode in the active site of EGFR enzyme besides ADME prediction of their physicochemical properties and drug likeness profile.

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Design and synthesis of novel multi-target tetrabromophthalimides as CBS and Topo-II inhibitors and DNA intercalators.

Microtubules are highly dynamic structures and constitute a crucial component of the cellular cytoskeleton. Besides, topoisomerases (Topo) play a fundamental role in maintaining the appropriate structure and organization of DNA. On the other hand, dual mechanism drug candidates for cancer treatment primarily aim to enhance the efficacy of cancer treatment and potentially overcome drug resistance. Hence, this work was tailored to design and synthesize new multi-target tetrabromophthalimide derivatives (2a-2k) that are capable of inhibiting the colchicine binding site (CBS) and topoisomerase II (Topo-II). The conducted in vitro studies showed that compound 2f showed the lowest IC50 value (6.7 µg mL-1) against the MDA-MB-468 cancer cell line. Additionally, compound 2f prompted upregulation of pro-apoptotic markers (caspases 3, 7, 8, and 9, Bax and p53). Moreover, some anti-apoptotic proteins (MMP2, MMP9, and BCL-2) were downregulated by compound 2f treatment. Besides, the colchicine binding assay showed that compounds 2f and 2k displayed promising inhibitory potential with IC50 values of 1.92 and 4.84 µg mL-1, respectively, in comparison with colchicine (1.55 µg mL-1). Furthermore, the Topo-II inhibition assay displayed the prominent inhibitory potential of compound 2f with an IC50 value of 15.75 µg mL-1, surpassing the IC50 of etoposide (20.82 µg mL-1). Cell cycle analysis revealed that compound 2f induced cell cycle arrest at both the G0-G1 and G2-M phases. The new candidates were docked against both the CBS (PDB ID: 5XIW) and Topo-II (PDB ID: 5CDP) targets to investigate their binding interactions and affinities as well. Accordingly, the synthesized compounds could serve as promising multi-target anticancer candidates with eligible apoptotic activity.

Identification of FDA-approved drugs that induce heart regeneration in mammals.

Targeting Meis1 and Hoxb13 transcriptional activity could be a viable therapeutic strategy for heart regeneration. In this study, we performd an in silico screening to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the resolved crystal structure of Meis1 and Hoxb13 bound to DNA. Paromomycin (Paro) and neomycin (Neo) induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay and disruption of DNA binding by electromobility shift assay. X-ray crystal structure revealed that both Paro and Neo bind to Meis1 near the Hoxb13-interacting domain. Administration of Paro-Neo combination in adult mice and in pigs after cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved left ventricular systolic function and decreased scar formation. Collectively, we identified FDA-approved drugs with therapeutic potential for induction of heart regeneration in mammals.