Circulating humanin is lower in coronary artery disease and is a prognostic biomarker for major cardiac events in humans.

BACKGROUND: Humanin is an endogenous mitochondria-derived peptide that plays critical roles in oxidative stress, inflammation and CAD. In this study, we measured the levels of circulating humanin, markers of oxidative stress and inflammation in patients with unstable angina and MI and studied the relationship between these parameters and major adverse cardiac events (MACE). METHODS: A total of 327 subjects were recruited from the inpatient department at First Hospital of Jilin University and divided into 3 groups [control, angina and myocardial infarction (MI)] based on the clinical data and the results of the angiography. Serum humanin and thiobarbituric acid reactive substances (TBARS) were measured at the time of initial admission. The hospitalization data and MACE of all patients were collected. RESULTS: Circulating humanin levels were lower in the angina group compared to controls [124.22 ±â€¯63.02 vs. 157.77 ±â€¯99.93 pg/ml, p < 0.05] and even lower in MI patients [67.17 ±â€¯24.35 pg/ml, p < 0.05 vs controls] and oxidative stress marker were higher in MI patients compared to the control and angina groups [12.94 ±â€¯4.55 vs. 8.26 ±â€¯1.66 vs. 9.06 ±â€¯2.47 umol/ml, p < 0.05]. Lower circulating humanin levels was an independent risk factor of MI patients. Circulating humanin levels could be used to predict MACE in angina group. CONCLUSIONS: Lower circulating humanin levels was an independent risk factor for CAD, and a potential prognostic marker for mild CAD. GENERAL SIGNIFICANCE: Humanin may become a new index for the diagnosis and treatment of CAD.

Spinal cord stimulation reduces cardiac pain through microglial deactivation in rats with chronic myocardial ischemia.

Angina pectoris is cardiac pain that is a common clinical symptom often resulting from myocardial ischemia. Spinal cord stimulation (SCS) is effective in treating refractory angina pectoris, but its underlying mechanisms have not been fully elucidated. The spinal dorsal horn is the first region of the central nervous system that receives nociceptive information; it is also the target of SCS. In the spinal cord, glial (astrocytes and microglia) activation is involved in the initiation and persistence of chronic pain. Thus, the present study investigated the possible cardiac pain­relieving effects of SCS on spinal dorsal horn glia in chronic myocardial ischemia (CMI). CMI was established by left anterior descending artery ligation surgery, which induced significant spontaneous/ongoing cardiac pain behaviors, as measured using the open field test in rats. SCS effectively improved such behaviors as shown by open field and conditioned place preference tests in CMI model rats. SCS suppressed CMI­induced spinal dorsal horn microglial activation, with downregulation of ionized calcium­binding adaptor protein­1 expression. Moreover, SCS inhibited CMI­induced spinal expression of phosphorylated­p38 MAPK, which was specifically colocalized with the spinal dorsal horn microglia rather than astrocytes and neurons. Furthermore, SCS could depress spinal neuroinflammation by suppressing CMI­induced IL­1ß and TNF­α release. Intrathecal administration of minocycline, a microglial inhibitor, alleviated the cardiac pain behaviors in CMI model rats. In addition, the injection of fractalkine (microglia­activating factor) partially reversed the SCS­produced analgesic effects on CMI­induced cardiac pain. These results indicated that the therapeutic mechanism of SCS on CMI may occur partially through the inhibition of spinal microglial p38 MAPK pathway activation. The present study identified a novel mechanism underlying the SCS­produced analgesic effects on chronic cardiac pain.

Effectiveness and Safety of Extracorporeal Shockwave Myocardial Revascularization in Patients With Refractory Angina Pectoris and Heart Failure.

Extracorporeal shockwave myocardial revascularization (ESMR) is a therapy for refractory angina pectoris. Our aim was to assess the efficacy and safety of ESMR in the management of patients with stable coronary artery disease (CAD) and heart failure as well as its effects on inflammation and angiogenesis. In this single-arm prospective trial, we included 48 patients with CAD, myocardial ischemia assessed by radionuclide imaging, echocardiographic evidence of left ventricular systolic dysfunction and without revascularization options. Changes in angina grading score, myocardial perfusion, left ventricular ejection fraction, and six-minute walk test after ESMR therapy were used for efficacy assessment. Changes of inflammation and angiogenesis biomarkers were also evaluated. ESMR therapy was performed using a commercially available cardiac shockwave generator system (Cardiospec; Medispec). After 9 weeks of ESMR therapy, a significant improvement was found regarding the initial angina class, severity of ischemia, left ventricular ejection fraction, and six-minute walk test in most patients. No deleterious side effects after treatment were detected. Regarding biomarkers, endothelial progenitor cells and angiopoietin-3 were significantly increased whereas IL-18 and TGF-ß were significantly decreased after ESMR in the total group. Notably, VEGF, IL-1ß, and lipoxin A4 levels were significantly increased only in patients with myocardial ischemia improvement. In conclusion, ESMR therapy is safe and effective in most but not all patients with CAD and heart failure. ESMR is associated with increased markers of angiogenesis and decreased markers of inflammation. Myocardial ischemia improvement after ESMR is associated with increased markers of angiogenesis and pro-resolving mediators.

Recent updates on novel therapeutic targets of cardiovascular diseases.

In recent times cardiovascular diseases (CVDs) are the leading cause of mortality universally, caused more or less 17.7 million casualties with 45% of all illnesses (except communicable ones) in 2015 as per World Health Organization (WHO). According to American National Center for Health Statistics, cardiac disorders are costliest. Moreover, health care expenditures related to cardiac disorders are anticipated to exceed than diabetes and Alzheimer's. Straining of reactive oxygen species with diminished neutralization & inflammation critically adds to atherosclerosis and also proceed to other cardiovascular diseases such as cardiac remodeling and myocardial infarction (MI). In the past few years, researchers revealed multiple drug targets from animal studies and evaluated them in the therapeutics of cardiac disorders, which offered exciting clues for novel therapeutic strategies. Although, only few newer agents approved clinically and actual approaches for treatment are lagging behind. Several novel drugs found effective for the treatment of hypertension, congestive heart failure, cardiac arrhythmia and angina pectoris. Detailed mechanism of action, basic and clinical pharmacology of all novel drugs has been discussed in this review.

Inflammation, non-endothelial dependent coronary microvascular function and diastolic function-Are they linked?

PURPOSE: Systemic inflammation and coronary microvascular dysfunction (CMD) may be causal drivers of heart failure with preserved ejection fraction (HFpEF). We tested the hypothesis that subclinical inflammation is associated with non-endothelial dependent CMD and diastolic dysfunction. METHODS: In a cross-sectional study of 336 women with angina but no flow limiting coronary artery stenosis (180 with diabetes) and 95 asymptomatic controls, blood samples were analysed for 90 biomarkers of which 34 were part of inflammatory pathways. CMD was assessed as coronary flow velocity reserve (CFVR) by transthoracic Doppler echocardiography and defined as CFVR<2.5. We used E/e' as an indicator of diastolic function in age-adjusted linear regressions to assess correlations between biomarkers, CFVR and diastolic function. RESULTS: CMD was found in 59% of participants whereas only 4% fulfilled strict criteria for diastolic dysfunction. Thirty-five biomarkers, 17 of them inflammatory, were negatively correlated with CFVR and 25, 15 inflammatory, were positively correlated with E/e'. A total of 13 biomarkers, 9 inflammatory, were associated with both CFVR and E/e'. CFVR and E/e' were only correlated in the subgroup of patients with CMD and signs of increased filling pressure (E/e'>10) (p = 0.012). CONCLUSION: This is the first study to link a large number of mainly inflammatory biomarkers to both CMD and E/e', thus confirming a role of inflammation in both conditions. However, despite a high prevalence of CMD, few patients had diastolic dysfunction and the data do not support a major pathophysiologic role of non-endothelial dependent CMD in diastolic dysfunction.

Network pharmacology-based therapeutic mechanism of Kuanxiong aerosol for angina pectoris.

ETHNOPHARMACOLOGICAL RELEVANCE: Kuanxiong aerosol has been reported to be an effective and safe clinical treatment for angina pectoris (AP). AIM OF THE STUDY: To explore the potential pharmacological mechanism of Kuanxiong aerosol by combined methods of network pharmacology prediction and experimental verification. MATERIALS AND METHODS: Networks of Kuanxiong aerosol-associated targets and AP-related genes were constructed through STRING database. Potential targets and pathway enrichment analysis related to the therapeutic efficacy of Kuanxiong aerosol were identified using Cytoscape and Database for Annotation, Visualization and Integrated Discovery (DAVID). To explore the mechanism of action of Kuanxiong aerosol, its in vitro effects on myocardial hypoxia, inflammatory cytokines, and oxidative injury, and its in vivo pharmacological effects on myocardial ischemia and cardiac fibrosis were studied in rat models. RESULTS: Network pharmacology analysis revealed that the potential targets mainly include the Fas ligand (FASLG), interleukin 4 (IL4), and catalase (CAT), which mediated the processes of apoptosis, and cellular responses to hypoxia, lipopolysaccharide (LPS), reactive oxygen species (ROS), and mechanical stimulus. Multiple pathways, such as the hypoxia-inducible factor 1 (HIF1) and tumor necrosis factor (TNF) pathways were found to be closely related to the pharmacological protective mechanism of Kuanxiong aerosol against AP. In addition, Kuanxiong aerosol suppressed the hypoxia, LPS, and hydrogen peroxide (H2O2)-induced injuries of H9c2 cardiomyocytes through the regulation of HIF1A, suppressed expression of IL6 and TNF, and antioxidant property. In the rat model of myocardial ischemia, Kuanxiong aerosol was found to lower the creatine kinase (CK), creatine kinase-myocardial band (CK-MB), and lactate dehydrogenase (LDH) levels, without altering the hemodynamic function. Kuanxiong aerosol was capable of attenuating cardiac fibrosis and improving cardiac function in a cardiac fibrosis rat model. CONCLUSIONS: This study revealed that the pharmacological mechanisms of Kuanxiong aerosol for AP therapy were related to anti-myocardial ischemia, anti-inflammation, and anti-oxidation via a non-hemodynamic manner, indicating that Kuanxiong aerosol is a preferable drug clinically for AP treatment due to its both preventive and protective effects.

N-terminal Pro B-type Natriuretic Peptide and High-sensitivity Cardiac Troponin as Markers for Heart Failure and Cardiovascular Disease Risks According to Glucose Status (from the Multi-Ethnic Study of Atherosclerosis [MESA]).

The role of NT-proBNP and hs-cTnT levels in predicting heart failure (HF) and cardiovascular disease (CVD) events in persons with prediabetes (pre-DM) and diabetes mellitus (DM) is not well-established. We examined the individual and combined relations of N-terminal natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) levels among asymptomatic adults with pre-DM and DM with the development of incident HF and CVD events. 5,584 participants with biomarker measures aged 45 to 84 years were included from the Multi-Ethnic Study of Atherosclerosis, of which 4,090 were normoglycemic, 799 had pre-DM, and 695 had DM at baseline and were followed for 12.4 ± 3.8 years. In those with DM, HF incidence rates per 1,000 person-years ranged from 3.2 to 39.4 across quartiles of NT-proBNP and 0.6 to 18.2 for hs-cTnT, respectively. Corresponding values for CVD incidence per 1,000 person-years ranged from 13.7 to 39.4 for NT-proBNP and 13.2 to 35.4 for hs-cTnT. Multivariate adjusted HRs were highest when both NT-proBNP and hs-cTnT were above versus below the median in those with pre-DM/DM (16.7 for incident HF and 2.1 for CVD events, both p <0.01). In conclusion, the combination of both biomarkers to traditional risk factors in participants who were normoglycemic or with pre-DM or DM improved risk prediction for both incident HF and total CVD events in an ethnically diverse population.

Refractory Angina: From Pathophysiology to New Therapeutic Nonpharmacological Technologies.

Despite optimal combination of guideline-directed anti-ischemic therapies and myocardial revascularization, a substantial proportion of patients with stable coronary artery disease continues to experience disabling symptoms and is often referred as "no-option." The appraisal of the pathways linking ischemia to symptom perception indicates a complex model of heart-brain interactions in the generation of the subjective anginal experience and inspired novel approaches that may be clinically effective in alleviating the angina burden of this population. Conversely, the prevailing ischemia-centered view of angina, with the focus on traditional myocardial revascularization as the sole option to address ischemia on top of medical therapy, hinders the experimental characterization and broad-scale clinical implementation of strongly needed therapeutic options. The interventionist, often the first physician to establish the diagnosis of refractory angina pectoris (RAP) following coronary angiography, should be aware of the numerous emerging technologies with the potential to improve quality of life in the growing population of RAP patients. This review describes the current landscape and the future perspectives on nonpharmacological treatment technologies for patients with RAP, with a view on the underlying physiopathological rationale and current clinical evidence.

Activation of cardiac AMPK-FGF21 feed-forward loop in acute myocardial infarction: Role of adrenergic overdrive and lipolysis byproducts.

Fibroblast growth factor 21 (FGF21) is a metabolic hormone having anti-oxidative and anti-hypertrophic effects. However, the regulation of FGF21 expression during acute myocardial infarction (AMI) remains unclear. We tested blood samples from 50 patients with AMI and 43 patients with stable angina pectoris (sAP) for FGF21, fatty acid binding protein 4 (FABP4), a protein secreted from adipocytes in response to adrenergic lipolytic signal, and total and individual fatty acids. Compared with sAP patients, AMI patients had higher serum FGF21 levels on admission, which were significantly correlated with peak FABP4 and saturated fatty acids (SFAs) but not with peak levels of cardiac troponin T. In mice, myocardial ischemia rapidly induced FGF21 production by the heart, which accompanied activation of AMP-activated protein kinase (AMPK)-dependent pathway. Like AICAR, an activator of AMPK, catecholamines (norepinephrine and isoproterenol) and SFAs (palmitate and stearate) significantly increased FGF21 production and release by cardiac myocytes via AMPK activation. Recombinant FGF21 induced its own expression as well as members of down-stream targets of AMPK involved in metabolic homeostasis and mitochondrial biogenesis in cardiac myocytes. These findings suggest that adrenergic overdrive and resultant adipose tissue lipolysis induce cardiac AMPK-FGF21 feed-forward loop that potentially provides cardioprotection against ischemic damage.

The many faces of myocardial ischaemia and angina.

Obstructive disease of the epicardial coronary arteries is the main cause of angina. However, a number of patients with anginal symptoms have normal coronaries or non-obstructive coronary artery disease (CAD) despite electrocardiographic evidence of ischaemia during stress testing. In addition to limited microvascular vasodilator capacity, the coronary microcirculation of these patients is particularly sensitive to vasoconstrictor stimuli, in a condition known as microvascular angina. This review briefly summarizes the determinants and control of coronary blood flow (CBF) and myocardial perfusion. It subsequently analyses the mechanisms responsible for transient myocardial ischaemia: obstructive CAD, coronary spasm and coronary microvascular dysfunction in the absence of epicardial coronary lesions, and variable combinations of structural anomalies, impaired endothelium-dependent and/or -independent vasodilation, and enhanced perception of pain. Lastly, we exemplify mechanism of angina during tachycardia. Distal to a coronary stenosis, coronary dilator reserve is already recruited and can be nearly exhausted at rest distal to a severe stenosis. Increased heart rate reduces the duration of diastole and thus CBF when metabolic vasodilation is no longer able to increase CBF. The increase in myocardial oxygen consumption and resulting metabolic vasodilation in adjacent myocardium without stenotic coronary arteries further acts to divert blood flow away from the post-stenotic coronary vascular bed through collaterals.

Serotonin-Mediated Cardiac Analgesia via Ah-Type Baroreceptor Activation Contributes to Silent Angina and Asymptomatic Infarction.

Silent angina is a critical phenomenon in the clinic and is more commonly associated with women patients suffering from myocardial ischemia. Its underlying cause remains mysterious in medicine. With our recent discovery of female-specific Ah-type baroreceptor neurons (BRNs), we hypothesize that cardiac analgesia is due to the direct activation of Ah-type BRNs by elevated levels of circulating serotonin (5-HT) myocardial infarction (MI) patients. Electromyography and the tail-flick reflex were assessed in control and MI-model rats to evaluate 5-HT-mediated BP regulation as well as peripheral and cardiac nociception. 5-HT or a 5-HT receptor agonist was microinjected into the nodose ganglion to confirm the involvement of the afferent pathway of the baroreflex arc. An inward current was observed in identified BRNs by applying a whole-cell patch-clamp technique in conjunction with qRT-PCR to verify the afferent-specific action of 5-HT and the expression of 5-HT receptors. Although the tail-flick reflex and mean arterial pressure were dramatically reduced in female MI rats with elevated serum 5-HT, intrapericardial capsaicin-evoked muscular discharges were significantly inhibited in comparing with those of males, which were mimicked by microinjection of 5-HT or SR57227A into the nodose. Ah-type BRNs displayed robust inward currents at lower concentrations of 5-HT than the C-type or the A-type, with significantly increased expression and cellular distribution of 5-HT3AR but not 5-HT3BR compared to the A- and C-types. Activation of 5-HT3AR in Ah-type BRNs by 5-HT contributes significantly to cardiac analgesia, which may suggest the pathogenic condition that silent angina occurs mainly in female patients.

Tanshinol borneol ester, a novel synthetic small molecule angiogenesis stimulator inspired by botanical formulations for angina pectoris.

BACKGROUND AND PURPOSE: Tanshinol borneol ester (DBZ) is a novel synthetic compound derived from Dantonic® , a botanical drug approved in 26 countries outside the United States for angina pectoris and currently undergoing FDA Phase III clinical trial. Here, we investigated the angiogenic effects of (S)-DBZ and (R)-DBZ isomers in vitro and in vivo. EXPERIMENTAL APPROACH: A network pharmacology approach was used to predict molecular targets of DBZ. The effects of DBZ isomers on proliferation, migration, and tube formation of human endothelial cells were assessed. For in vivo approaches, the transgenic Tg (vegfr2:GFP) zebrafish and C57BL/6 mouse Matrigel plug models were used. ELISA and western blots were used to quantitate the release and expression of relevant target molecules and signalling pathways. KEY RESULTS: DBZ produced a biphasic modulation on proliferation and migration of three types of human endothelial cells. Both DBZ isomers induced tube formation in Matrigel assay and a 12-day co-culture model in vitro. Moreover, DBZ promoted Matrigel neovascularization in mice and partially reversed the vascular disruption in zebrafish induced by PTK787. Mechanistically, DBZ enhanced the cellular levels of VEGF, VEGFR2, and MMP-9, as well as activating Akt and MAPK signalling in endothelial cells. Selective inhibition of PI3K and MEK significantly attenuated its angiogenic effects. CONCLUSIONS AND IMPLICATIONS: These data reveal, for the first time, that DBZ promotes multiple key steps of angiogenesis, at least in part through Akt and MAPK signalling pathways, and suggest it may be potentially developed further for treating myocardial infarction and other cardiovascular diseases.

Intramyocardial autologous CD34+ cell therapy for refractory angina: A meta-analysis of randomized controlled trials.

BACKGROUND: Previous studies have demonstrated that intramyocardial human CD34+ cells may relieve symptoms and improve clinical outcomes in chronic refractory angina unresponsive to optimal medical therapy or not amenable to revascularization. METHODS: We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the impact of human CD34+ cells compared with placebo in chronic refractory angina. Primary efficacy outcomes in our analysis were angina frequency and exercise time. Primary safety outcomes included major adverse cardiovascular events such as myocardial infarction (MI), stroke and death. RESULTS: Three eligible randomized trials including 269 patients (placebo = 90, CD34+ = 179) were included. Dose of auto-CD34+ cells ranged from 5 × 104 to 5 × 105 cells/kg. Follow-up ranged from 6 to 24 months. In a pooled analysis, administration of CD34+ cells decreased the risk of all-cause mortality [OR 0.24, 95% CI (0.08-0.73), p = 0.01], reduced angina frequency [mean difference -2.91, 95% CI (-4.57 to -1.25), p = 0.0006] and improved exercise time [mean difference 58.62 s, 95% CI (21.19 to 96.06), p = 0.02] compared with control group. However, there was no significant difference in the risk of myocardial infarction (MI) and stroke between groups. CONCLUSION: In a meta-analysis, intra-myocardial CD34+ cell therapy was superior to placebo in improving risk of all - cause mortality, angina frequency with an increase in exercise time, without a significant increase in adverse events. This analysis supports further trials of CD34+ cell therapy for ischemic heart disease.

Increased serum levels of fetuin B in patients with coronary artery disease.

BACKGROUND: Recent evidence indicates a pivotal role for fetuin B, one of the cystatin superfamily of cysteine protease inhibitors, in the pathogenesis of metabolic diseases. This study investigated whether serum fetuin B levels are associated with the presence of coronary artery disease. METHODS: Serum fetuin B levels were assessed in 87 patients with coronary artery disease (41 with acute coronary syndromes and 46 with stable angina pectoris) and 87 healthy controls using an enzyme-linked immunosorbent assay. The association of serum fetuin B levels with cardiac risk factors was analyzed. RESULTS: Serum fetuin B levels were significantly higher in patients with coronary artery disease than those in healthy controls (90.7 ± 32.1 vs. 110.0 ± 32.7 µg/ml, P < 0.001), extremely elevated in group with acute coronary syndromes (115.0 ± 35.2 µg/ml). Pearson correlation analysis showed that serum fetuin B levels were positively associated with the levels of total cholesterol (r = 0.276, P < 0.001), low-density lipoprotein cholesterol (r = 0.363, P < 0.001), and fasting blood glucose (r = 0.159, P < 0.05). In addition, multiple logistic regression analyses revealed that fetuin B was independently associated with the presence of coronary artery disease (OR, 1.019; 95% CI, 1.009 to 1.029; P < 0.001) and acute coronary syndromes (OR, 1.017; 95% CI, 1.006 to 1.028; P < 0.01). CONCLUSIONS: Our data revealed that high fetuin B levels are associated with the presence of coronary artery disease and acute coronary syndromes, and that fetuin B may serve as a potential biomarker for coronary artery disease.

Impact of glycemic variability on the occurrence of periprocedural myocardial infarction and major adverse cardiovascular events (MACE) after coronary intervention in patients with stable angina pectoris at 6months follow-up.

BACKGROUND: We explored the impact of glycemic variability on the occurrence of periprocedural myocardial infarction and major adverse cardiovascular events (MACE) after coronary intervention in patients with stable angina pectoris (SAP) at 6months follow-up. METHODS: From May 2015 to April 2016, a total of 746 patients with SAP were divided to high glycemic variability group (H group) (n=261) and low glycemic variability group (L group) (n=485). The primary end point was incidence of periprocedural myocardial infarction and MACE at 6months follow-up. RESULTS: The occurrence of periprocedural myocardial infarction occurred in 18.8% of patients in H group and in 12.4% in L group (P=0.03). The incidence of MACE at 6months follow-up was 9.6% in H group and 4.5% in L group (P=0.01). Multivariable analysis suggested that high glycemic variability conferred a 53% risk increment of 6months follow-up MACE (odds ratio 2.13, 95% confidence interval 1.85-5.38; P=0.01). CONCLUSIONS: The trial shows that higher blood glucose variability was correlated with higher incidence of periprocedural myocardial infarction and MACE at 6months follow-up.

Relationship between the Level of Circulating CD45+ Platelets and Development of Restenosis after Implantation of Drug-Eluting Stents to Patients with Coronary Heart Disease.

The study was carried out in 126 patients with stable angina pectoris, who underwent elective coronary artery stenting with drug-eluting stents and follow-up angiography within 6-12 months thereafter. Five significant risk factors of restenosis were identified by binary comparisons of different variables. The logistic regression equation that included the level of CD45-positive platelets, diabetes, small vessel stenting, number of simultaneously implanted stents in one patient, and lesion length demonstrates the highest level of prediction of in-stent restenosis (OR=22.8; p<0.001). ROC-analysis demonstrated high prognostic value of the logit model (area under ROC curve 0.87, p<0.001). The data suggest that a close relationship exists between the development of restenosis and the level of circulating CD45+ platelets.

Development of protocatechualdehyde proliposomes-based sustained-release pellets with improved bioavailability and desired pharmacokinetic behavior for angina chronotherapy.

The present study was aimed to develope a proliposomal formulation to decrease the hepatic first-pass metabolism of protocatechualdehyde (PD), followed by pellet coating to modify the drug release for angina chronotherapy. PD proliposomes were prepared by depositing PD-phospholipid complex on mannitol powders to improve the drug encapsulation. Afterwards, the PD proliposomes were prepared into pellet cores via extrusion-spheronization using 10% κ-carrageenan as pelletization aid prior to the development of PD sustained-release pellets (PD-SRPs). Eudragit® NE 30D was chosen as coating material and the desired drug release profile of PD-SRPs was calculated for formulation optimization by deconvolution based on the circadian rhythm of variant angina. A high similarity factor (f2=85.72) was achieved when the coating weight was 30% and the sustained release behavior also prevented the destruction of liposomes by gastric fluids. Pharmacokinetic studies revealed a basically consistent trend between the actual and the predicted plasma concentration-time curve with absolute percent errors (%PE) of concentrations <10% in 2-12h. Meanwhile, a relative bioavailability of 200% was achieved compared with pure PD. Therefore, the development of proliposomes-based PD-SRPs was an effective strategy to provide both improved oral bioavailability and desired drug plasma concentration-time course for angina chronotherapy.

The RENEW Trial: Efficacy and Safety of Intramyocardial Autologous CD34(+) Cell Administration in Patients With Refractory Angina.

OBJECTIVES: This study tested whether intramyocardial (IM) administration of mobilized, purified autologous CD34(+) cells would improve total exercise time (TET) and angina frequency in patients with refractory angina. BACKGROUND: IM administration of autologous CD34(+) cells has been associated consistently with improvements in functional capacity and angina symptoms in early phase clinical trials. METHODS: RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) was a randomized, double-blind, multicenter trial comparing IM CD34(+) administration with no intervention (open-label standard of care) or IM placebo injections (active control). The primary efficacy endpoint was change in TET at 12 months. Key secondary endpoints include changes in angina frequency at 3, 6, and 12 months, and TET at 3 and 6 months. The key safety analysis was the incidence of major adverse cardiovascular events through 24 months. RESULTS: The sponsor terminated the study for strategic considerations after enrollment of 112 of planned 444 patients. The difference in TET between patients treated with cell therapy versus placebo was 61.0 s at 3 months (95% confidence interval (CI): -2.9 to 124.8; p = 0.06), 46.2 s at 6 months (95% CI: -28.0 to 120.4; p = 0.22), and 36.6 s at 12 months (95% CI: -56.1 to 129.2; p = 0.43); angina frequency was improved at 6 months (relative risk: 0.63; p = 0.05). Autologous CD34(+) cell therapy seemed to be safe compared with both open-label standard of care and active control (major adverse cardiovascular events 67.9% [standard of care], 42.9% (active control), 46.0% [CD34(+)]). CONCLUSIONS: Due to early termination, RENEW was an incomplete experiment; however, the results were consistent with observations from earlier phase studies. These findings underscore the need for a definitive trial. (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34(+) Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina [RENEW]: NCT01508910).