Derivation and validation of Pd/Pa in the assessment of residual ischemia post-intervention: A prospective all-comer registry.

BACKGROUND: Measurement of post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) demonstrates residual ischemia in a large percentage of cases deemed angiographically successful which, in turn, has been associated with worse long-term outcomes. It has recently been shown that a resting pressure index, Pd/Pa, has prognostic value post stenting, however, its diagnostic value relative to FFR post-PCI has not been evaluated. METHODS: The diagnostic accuracy of Pd/Pa in identifying ischemia (FFR≤0.80) pre- and post-PCI was evaluated. Three patient subsets were analyzed. A reference pre-PCI cohort of 1,255 patients (1,560 vessels) was used to measure the accuracy of pre-PCI Pd/Pa vs. FFR. A derivation post-PCI group of 574 patient (664 vessels) was then used to calculate the diagnostic accuracy of post-PCI Pd/Pa vs. FFR. A final prospective validation cohort of 230 patients (255 vessels) was used to test and validate the diagnostic performance of post-PCI Pd/Pa. RESULTS: Median Pd/Pa and FFR were 0.90 (IQR 0.90-0.98) and 0.80 (IQR 0.71-0.88) in the reference pre-PCI model, 0.96 (IQR 0.93-1.00) and 0.87 (IQR 0.77-0.90) in the post-PCI derivation model, and 0.94 (IQR 0.89-0.97) and 0.84 (IQR 0.77-0.90) in the post-PCI validation model respectively. There was a strong linear correlation between Pd/Pa and FFR in all three models (p < 0.0001). Using ROC analysis, the optimal Pd/Pa cutoff value to predict a FFR ≤ 0.80 was ≤0.92 (AUC 0.87) in the pre-PCI model, ≤0.93 (AUC 0.85) in the post-PCI derivation model, and ≤ 0.90 (AUC 0.91) in the post-PCI validation model. Using a hybrid strategy of post-PCI Pd/Pa and post-PCI FFR when necessary (25% patients), overall diagnostic accuracy was improved to 95%. CONCLUSIONS: Pd/Pa has excellent diagnostic accuracy for identifying ischemia post-intervention. Using a hybrid strategy of post-PCI Pd/Pa first, and FFR afterwards, if required, adenosine administration can be avoided in over 75% of physiologic assessments post intervention.

Use of "super-glue" to seal a perforation during chronic total occlusion coronary intervention and the potential to "unglue" it.

Coronary perforation remains a dreaded complication of chronic total occlusion (CTO) percutaneous coronary intervention (PCI). We present a case of successful CTO recanalization complicated by a perforation treated by n-butyl-cyanoacrylate (medical "super-glue"). We also present an in vitro experiment showing that a glue plug in a plastic tube can acutely be passed by a low tip load guide wire and undergo balloon angioplasty recreating a lumen. These results suggest that n-butyl-cyanoacrylate glue may be an alternative for treating perforation during CTO PCI with the possibility of recanalizing the vessel through the glue plug at a later time.

Retrograde recanalization of a nonchronic total occlusion lesion.

The use of the retrograde approach to treat chronic total occlusion (CTO) has improved overall success rate in this lesion subgroup. Its use to treat complex non-CTO lesions unable to be revascularized by an antegrade approach has not been described. We report a case of the use of the retrograde approach to recanalize a non-CTO lesion under Impella support in a patient with critical stenosis and poor left ventricular function. The retrograde approach may be an alternate pathway in selected non-CTO lesions where the antegrade has been unsuccessful.

Comparative effectiveness of coronary CT angiography vs stress cardiac imaging in patients following hospital admission for chest pain work-up: The Prospective First Evaluation in Chest Pain (PERFECT) Trial.

BACKGROUND: Because the frequency of cardiac event rates is low among chest pain patients following either performance of coronary CT angiography (CCTA) or stress testing, there is a need to better assess how these tests influence the central management decisions that follow from cardiac testing. The present study was performed to assess the relative impact of CCTA vs stress testing on medical therapies and downstream resource utilization among patients admitted for the work-up of chest pain. METHODS: The admitted patients were randomized in a 1:1 ratio to either cardiac imaging stress test or CCTA. Primary outcomes were time to discharge, change in medication usage, and frequency of downstream testing, cardiac interventions, and cardiovascular re-hospitalizations. We randomized 411 patients, 205 to stress testing, and 206 to CCTA. RESULTS: There were no differences in time to discharge or initiation of new cardiac medications at discharge. At 1 year follow-up, there was no difference in the number of patients who underwent cardiovascular downstream tests in the CCTA vs stress test patients (21% vs 15%, P = .1) or cardiovascular hospitalizations (14% vs 16%, P = .5). However, there was a higher frequency of invasive angiography in the CCTA group (11% vs 2%, P = .001) and percutaneous coronary interventions (6% vs 0%, P < .001). CONCLUSIONS: Randomization of hospitalized patients admitted for chest pain work-up to either CCTA or to stress testing resulted in similar discharge times, change in medical therapies at discharge, frequency of downstream noninvasive testing, and repeat hospitalizations. However, a higher frequency of invasive coronary angiography and revascularization procedures were performed in the CCTA arm. (ClinicalTrials.gov number, NCT01604655.).

Prospective Evaluation of the Strategy of Functionally Optimized Coronary Intervention.

Background Long-term outcomes after percutaneous coronary intervention (PCI) relate in part to residual ischemia in the treated vessel, as reflected by post-PCI fractional flow reserve (FFR). The strategy of FFR after PCI and treatment of residual ischemia-known as functionally optimized coronary intervention (FCI)-may be feasible and capable of improving outcomes. Methods and Results Feasibility and results of FCI using an optical-sensor pressure wire were prospectively evaluated in an all-comer population with 50% to 99% lesions and ischemic FFR (≤0.80; ClinicalTrials.gov identifier NCT03227588). FCI was attempted in 250 vessels in 226 consecutive patients. The PCI success rate was 99.6% (249/250 vessels). FCI technical success-that is, FFR before and after PCI and PCI itself using the FFR wire-was 92% (230/250 vessels). Incidence of residual ischemia in the treated vessel was 36.5%. Approximately a third of these vessels (34.5%, n=29) were considered appropriate for further intervention, with FFR increasing from 0.71±0.07 to 0.81±0.06 (P<0.001). Pressure wire pullback showed FFR ≤0.8 at distal stent edge was 7.9% and 0.7% proximal to the stent. FFR increase across the stent was larger in the ischemic than in the nonischemic group (0.06 [interquartile range: 0.04-0.08] versus 0.03 [interquartile range: 0.01-0.05]; P<0.0001) compatible with stent underexpansion as a contributor to residual ischemia. Conclusions FCI is a feasible and safe clinical strategy that identifies residual ischemia in a large proportion of patients undergoing angiographically successful PCI. Further intervention can improve ischemia. The impact of this strategy on long-term outcomes needs further study.

Prolonged Balloon Inflation to Effect Full Stent Expansion in Critical CAD During Left Ventricular Support.

The extent to which a stent is expanded is a primary factor in determining both short- and long-term outcomes during percutaneous coronary intervention (PCI). This paper presents the first case of prolonged balloon inflation using the pressure optimization protocol allowing full stent expansion during PCI of critical coronary artery disease with severely reduced ejection fraction using the Impella. (Level of Difficulty: Intermediate.).

Protective effects of Terminalia arjuna against Doxorubicin-induced cardiotoxicity.

Terminalia arjuna has been marked as a potential cardioprotective agent since vedic period. The present study was aimed to investigate the effects of butanolic fraction of Terminalia arjuna bark (TA-05) on Doxorubicin (Dox)-induced cardiotoxicity. Male wistar rats were used as in vivo model for the study. TA-05 was administered orally to Wistar rats at different doses (0.42 mg/kg, 0.85 mg/kg, 1.7 mg/kg, 3.4 mg/kg and 6.8 mg/kg) for 6 days/week for 4 weeks. Thereafter, all the animals except saline and TA-05-treated controls were administered 20 mg/kg Dox intraperitonially. There was a significant decrease in myocardial superoxide dismutase (38.94%) and reduced glutathione (23.84%) in animals treated with Dox. Concurrently marked increase in serum creatine kinase-MB (CKMB) activity (48.11%) as well as increase in extent of lipid peroxidation (2.55-fold) was reported. Co-treatment of TA-05 and Dox resulted in an increase in the cardiac antioxidant enzymes, decrease in serum CKMB levels and reduction in lipid peroxidation as compared to Dox-treated animals. Electron microscopic studies in Dox-treated animals revealed mitochondrial swelling, Z-band disarray, focal dilatation of smooth endoplasmic reticulum (SER) and lipid inclusions, whereas the concurrent administration of TA-05 led to a lesser degree of Dox-induced histological alterations. These findings suggest that butanolic fraction of Terminalia arjuna bark has protective effects against Dox-induced cardiotoxicity and may have potential as a cardioprotective agent.

Synthesis and evaluation of 4/5-hydroxy-2,3-diaryl(substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anticancer agents.

A new series of 2,3-diaryl-4/5-hydroxy-cyclopent-2-en-1-one analogues replacing the cis double bond of combretastatin A-4 (CA-4) by 4/5-hydroxy cyclopentenone moieties was designed and synthesized. The analogues displayed potent cytotoxic activity (IC50<1 microg/mL) against a panel of human cancer cell lines and endothelial cells. The most potent analogues 11 and 42 belonging to the 5-hydroxy cyclopentenone class were further evaluated for their mechanism of action. Both of the analogues led to cell cycle arrest at G2/M phase and induced apoptosis in endothelial cells. Antitubulin property of 42 was superior to 11 and comparable to CA-4. The compound 42 had better aqueous solubility, metabolic stability, and pharmacokinetic profile than CA-4 and also demonstrated significant tumor regression in the human colon xenograft model. Our data suggests that cis-restricted analogues of CA-4 are a new class of molecules that have the potential to be developed as novel agents for the treatment of cancer.

Anticancer and anti-inflammatory activities of 1,8-naphthyridine-3-carboxamide derivatives.

Several 1,8-naphthyridine-3-carboxamide derivatives (8-23) were synthesized and tested for in vitro cytotoxicity against eight cancer cell lines and a normal cell line. Compound 12 exhibited high cytotoxicity (IC(50)=1.37microM) in HBL-100 (breast) cell line while compounds 17 (IC(50)=3.7microM) and 22 (IC(50)=3.0microM) have shown high cytotoxicity in KB (oral) and SW-620 (colon) cell lines, respectively. The synthesized 1,8-naphthyridine-3-carboxamides were also evaluated for anti-inflammatory and myeloprotective activities, indicated by modulation in cytokine and chemokine levels secreted by dendritic cells.

Utilizing Post-Intervention Fractional Flow Reserve to Optimize Acute Results and the Relationship to Long-Term Outcomes.

OBJECTIVES: This study sought to evaluate the impact of fractional flow reserve (FFR) after percutaneous coronary intervention (PCI) on subsequent in-lab interventional management vessels that had undergone pre-PCI FFR and its prognostic value in predicting long-term (>1 year) outcomes. BACKGROUND: Post-PCI FFR has been shown to be a predictor of intermediate-term (6 months) adverse events. However, its impact on immediate post procedure clinical decision making and long-term outcomes is not known. METHODS: Consecutive patients undergoing PCI who had pre- and post-PCI FFR evaluations were followed for major adverse cardiovascular events (MACE). RESULTS: In the study 574 patients (664 lesions) were followed for 31 ± 16 months. PCI led to significant improvement in FFR from 0.65 ± 0.14 to 0.87 ± 0.08 (p < 0.0001). Despite satisfactory angiographic appearance, 143 lesions (21%) demonstrated post-PCI FFR in the ischemic range (FFR ≤0.81). After subsequent interventions, FFR in this subgroup increased from 0.78 ± 0.08 to 0.87 ± 0.06 (p < 0.0001). Final FFR cutoff of ≤0.86 had the best predictive accuracy for MACE and ≤0.85 for TVR. Patients who achieved final FFR >0.86 had significantly lower MACE compared to the final FFR ≤0.86 group (17% vs. 23%; log-rank p = 0.02). Final FFR ≤0.86 had incremental prognostic value over clinical and angiographic variables for MACE prediction. CONCLUSIONS: Post-PCI FFR reclassified 20% of angiographically satisfactory lesions, which required further intervention thereby providing an opportunity for complete functional optimization at the time of the index procedure. This is particularly important as FFR post-PCI FFR was a powerful independent predictor of long-term outcomes.

The interplay of physician awareness and reporting of incidentally found coronary artery calcium on the clinical management of patients who underwent noncontrast chest computed tomography.

Studies have shown that coronary artery calcium (CAC) incidentally identified on a noncontrast chest computed tomography (NCCT) performed for noncardiac indications has diagnostic and prognostic value. The frequency by which radiologists report incidental CAC and its impact on patient management are unknown. This study included 204 consecutive patients (63 ± 17 years, 59% men) without a history of coronary artery disease referred for an NCCT for noncardiac indications. The presence of CAC was determined by an expert cardiologist and compared with the radiology report. For each patient, the medical record was reviewed for changes in medications. Physicians caring for these patients were surveyed regarding their awareness and the clinical importance of incidental CAC after their patients had been discharged from the hospital. There were 108 of 201 patients (53%) with a CAC score >0 as determined by an expert reader. The interpreting radiologist reported the presence of CAC in 74 of 108 patients (69%). Of the 74 patients, there was an increase in stain and aspirin prescription of 4% and 5%, respectively. Of the 132 physicians surveyed, 54% of physicians surveyed believed that CAC on an NCCT scan was analogous to the presence of coronary artery disease, 23% were aware that incidental CAC was reported, and only 4% said they would make medical management decisions based on the finding of incidental CAC. In conclusion, incidental CAC is under-reported by the interpreting radiologists and suggests an integral role for a cardiovascular imaging specialist. When incidental CAC is reported, physicians are not cognizant of the meaning and importance of this finding. This lack of knowledge is reflected in the negligible impact reported incidental CAC has on clinical management decisions.

Predictors of ischemia in patients referred for evaluation of exertional dyspnea: a stress echocardiography study.

BACKGROUND: There are conflicting data on the incidence of ischemia by stress echocardiography in patients referred for dyspnea without accompanying chest pain. METHODS: A total of 311 consecutive patients with exertional dyspnea (without chest pain) referred to the echocardiography lab for ischemia evaluation from August 2008 to March 2012 were evaluated. Exercise by Bruce protocol or dobutamine stress echocardiography was performed. Resting left ventricular ejection fraction and segmental wall motion abnormalities were assessed. Multivariate logistic regression analysis was used to identify independent predictors of ischemia on stress echocardiography. RESULTS: The mean age was 61 years (range, 20-96 years), with 196 women (63%). Exercise stress was performed in 114 patients (37%); the rest of the patients underwent dobutamine stress. The patient population had a high burden of obesity, diastolic dysfunction, and pulmonary hypertension. Thirty patients (10%) had evidence of stress-induced ischemia (nine [8%] with exercise and 21 [11%] with dobutamine). In multivariate analysis, male gender (odds ratio, 2.8; P = .03), history of coronary artery disease (odds ratio, 3.5; P = .02), and resting wall motion abnormalities (odds ratio, 16.6; P < .01) were independent predictors of inducible ischemia. CONCLUSIONS: The incidence of stress-induced ischemia is low in patients referred for stress echocardiography with exertional dyspnea (without chest pain). Ischemia is more likely to be present in men with histories of coronary artery disease and resting wall motion abnormalities.

Synthesis of quinazolines as tyrosine kinase inhibitors.

In the present review, the discovery and development of quinazoline as tyrosine kinase inhibitors has been described. The synthesis of most potent quinazoline inhibitors of EGFR, VEGFR and PDGRF has been discussed. Structure activity relationship for quinazoline as tyrosine kinase inhibitors has been established. It was found that C-4, C-6 and C-7 positions in quinazoline are appropriate sites for designing new tyrosine kinase inhibitors. This review should help the medicinal chemist in designing more effective tyrosine kinase inhibitors.

Synthesis and structure-activity relationships of potent antitumor active quinoline and naphthyridine derivatives.

The disease of cancer has been ranked second after cardiovascular diseases and plant-derived molecules have played an important role for the treatment of cancer. Nine cytotoxic plant-derived molecules such as vinblastine, vincristine, navelbine, etoposide, teniposide, taxol, taxotere, topotecan and irinotecan have been approved as anticancer drugs. Recently, epothilones are being emerging as future potential anti-tumor agents. However, targeted cancer therapy has now been rapidly expanding and small organic molecules are being exploited for this purpose. Amongst target specific small organic molecules, quinazoline was found as one of the most successful chemical class in cancer chemotherapy as three drugs namely Gefitinib, Erlotinib and Canertinib belong to this series. Now, quinazoline related chemical classes such as quinolines and naphthyridines are being exploited in cancer chemotherapy and a number of molecules such as compounds EKB-569 (52), HKI-272 (78) and SNS-595 (127a) are in different phases of clinical trials. This review presents the synthesis of quinolines and naphthyridines derivatives, screened for anticancer activity since year 2000. The synthesis of most potent derivatives in each prototype has been delineated. A brief structure activity relationship for each prototype has also been discussed. It has been observed that aniline group at C-4, aminoacrylamide substituents at C-6, cyano group at C-3 and alkoxy groups at C-7 in the quinoline ring play an important role for optimal activity. While aminopyrrolidine functionality at C-7, 2'-thiazolyl at N-1 and carboxy group at C-3 in 1,8-naphthyridine ring are essential for eliciting the cytotoxicity. This review would help the medicinal chemist to design and synthesize molecules for targeted cancer chemotherapy.

Betulinic acid derivatives as anticancer agents: structure activity relationship.

Betulinic acid, a pentacyclic triterpene, is widely distributed throughout the tropics. It possesses several biological properties such as anticancer, anti-inflammatory, antiviral, antiseptic, antimalarial, spermicidal, antimicrobial, antileshmanial, antihelmentic and antifeedent activities. However, betulinic acid was highly regarded for its anticancer and anti-HIV activities. Anticancer role of betulinic acid appeared by inducing apoptosis in cells irrespective of their p53 status. Due to high order safety in betulinic acid, a number of structural modifications carried out to improve its potency and efficacy. The C-1, C-2, C-3, C-4, C-20 and C-28 positions are the diversity centers in betulinic acid, and the derivatives resulted on various structural modifications at these positions screened for their anticancer activity. This review presents the structure activity relationship carried out on C-1, C-2, C-3, C-4, C-20, C-28, A-ring, D-ring and E-ring modified betulinic acid derivatives. We have compiled the most active betulinic acid derivatives along with their activity profile in each series. Structure activity relationship studies revealed that C-28 carboxylic acid was essential for the cytotoxicity. The halo substituent at C-2 position in betulinic acid enhanced the cytotoxicity. Though the relation of the cytotoxicity with the nature of substituents at C-3 position could not be generalized but the ester functionality appeared to be a better substituent for enhancing the cytotoxicity. An interesting observation is that the three rings skeleton (A, B and C rings) had played an important role in eliciting anticancer activity, which could be a new molecular skeleton to design new anticancer drugs.

Synthesis of 13-amino costunolide derivatives as anticancer agents.

A number of costunolide derivatives (4a-p) have been synthesized and evaluated for their in vitro cytotoxicity against eight tumor and a non-tumor cell lines. Compound 4d showed around 2-fold better cytotoxicity against SW-620 (colon) cell line with improved safety index than costunolide (1). While compounds 4e, 4g, and 4p have shown around 2- to 3-fold better cytotoxicity against MIAPaCa2 (pancreas), K-562 (leukemia) and PA-1 (ovary) cell lines as well as better safety index in comparison to costunolide (1). Compound 4p also exhibited cytotoxicity against HBL100 (breast) cell line with 2-fold better safety index. Structure-activity relationship has been described.