Rare survival of left ventricular free wall rupture following myocardial infarction.

Myocardial free wall rupture is a rare but usually fatal complication of acute myocardial infarction (MI) especially if it occurs out of hospital and occurs in 2-4% of patients who suffer from acute MI. Rapid diagnosis is essential but not always easy as diagnostic tests may be inconclusive. In this case report authors examine a rare and unique patient survival after left ventricular free wall rupture following MI. The patient developed chest pain and hypotension in the hospital and was taken directly to the catheterization laboratory where a diagnostic angiogram showed a high-grade occlusion of a very small marginal branch, fluoroscopy demonstrated a large pericardial effusion, which was drained then auto transfused back to the patient using a femoral vein sheath. Rapid diagnostic testing including transesophageal echocardiography with Definity, transthoracic echocardiography, aortography and left ventriculography were all negative for dissection and rupture. Despite the negative diagnostic test, a high index of suspicion for rupture led to urgent surgical exploration where a large 4-cm hole was found in the lateral wall. Repair was successful and the patient left the hospital about several weeks later.

"Protocol for a phase 2, randomized, double-blind, placebo-controlled, safety and efficacy study of dutogliptin in combination with filgrastim in early recovery post-myocardial infarction": study protocol for a randomized controlled trial.

BACKGROUND: Regenerative therapies offer new approaches to improve cardiac function after acute ST-elevation myocardial infarction (STEMI). Previous trials using bone marrow cells, selected stem cell populations, or cardiac stem cell progenitors require invasive procedures and had so far inconclusive results. A less invasive approach utilizes granulocyte-colony stimulating factor (G-CSF) to mobilize stem cells to circulating blood and induce neovascularization and differentiation into endothelial cells and cardiomyocytes. Stromal cell-derived factor 1 alpha (SDF-1α) is an important chemokine for initiating stem cell migration and homing to ischemic myocardium. SDF-1α concentrations can be increased by inhibition of CD26/DPP4. Dutogliptin, a novel DPP4 inhibitor, combined with stem cell mobilization using G-CSF significantly improved survival and reduced infarct size in a murine model. METHODS: We test the safety and tolerability and efficacy of dutogliptin in combination with filgrastim (G-CSF) in patients with STEMI (EF < 45%) following percutaneous coronary intervention (PCI). Preliminary efficacy will be analyzed using cardiac magnetic resonance imaging (cMRI) to detect > 3.8% improvement in left ventricular ejection fraction (LV-EF) compared to placebo. One hundred forty subjects will be randomized to filgrastim plus dutogliptin or matching placebos. DISCUSSION: The REC-DUT-002 trial is the first to evaluate dutogliptin in combination with G-CSF in patients with STEMI. Results will lay the foundation for an appropriately powered cardiovascular outcome trial to test the efficacy of this combined pharmacological strategy. TRIAL REGISTRATION: EudraCT no.: 2018-000916-75 . Registered on 7 June 2018. IND number: 123717.

Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials.

Aims: Autologous CD34+ (auto-CD34+) cells represent an attractive option for the treatment of refractory angina. Three double-blinded randomized trials (n = 304) compared intramyocardial (IM) auto-CD34+ cells with IM placebo injections to affect total exercise time (TET), angina frequency (AF), and major adverse cardiac events (MACE). Patient-level data were pooled from the Phase I, Phase II ACT-34, ACT-34 extension, and Phase III RENEW trials to determine the efficacy and safety of auto-CD34+ cells. Methods and results: Treatment effects for TET were analysed using an analysis of covariance mixed-effects model and for AF using Poisson regression in a log linear model with repeated measures. The Kaplan-Meier rate estimates for MACE were compared using the log-rank test. Autologous CD34+ cell therapy improved TET by 46.6 s [3 months, 95% confidence interval (CI) 13.0 s-80.3 s; P = 0.007], 49.5 s (6 months, 95% CI 9.3-89.7; P = 0.016), and 44.7 s (12 months, 95% CI - 2.7 s-92.1 s; P = 0.065). The relative frequency of angina was 0.78 (95% CI 0.63-0.98; P = 0.032), 0.66 (0.48-0.91; P = 0.012), and 0.58 (0.38-0.88; P = 0.011) at 3-, 6- and 12-months in auto-CD34+ compared with placebo patients. Results remained concordant when analysed by treatment received and when confined to the Phase III dose of 1 × 105 cells/kg. Autologous CD34 + cell therapy significantly decreased mortality (12.1% vs. 2.5%; P = 0.0025) and numerically reduced MACE (38.9% vs. 30.0; P = 0.14) at 24 months. Conclusion: Treatment with auto-CD34+ cells resulted in clinically meaningful durable improvements in TET and AF at 3-, 6- and 12-months, as well as a reduction in 24-month mortality in this patient-level meta-analysis.

Public unawareness of physician reimbursement.

OBJECTIVES: To assess subjects' perception of healthcare costs and physician reimbursement. BACKGROUND: The lack of transparency in healthcare reimbursement leaves patients and physicians unaware of the distribution of health care dollars. METHODS: Anonymous survey-based study by means of convenience sampling. Participants were asked to estimate the total hospital cost and physician fee for one of the six medical procedures (n = 250). RESULTS: On the average for all 6 procedures, patients estimated the total cost was $36,177, ∼1,540% more than the actual Medicare rate of $7,333. Similarly, patients estimated the physician fee was $7,694, 1,474% more the actual Medicare rate of $589. CONCLUSION: Patients' perception of the total cost and physician fee are significantly higher than Medicare rates for all 6 procedures. This lack of insight may have widespread negative implications on the patient-physician relationship, on political trends to reduce physician reimbursement, and on a physician's desire to continue practicing medicine.

Gastrointestinal and Hepatic Disease in Fibromyalgia.

Fibromyalgia (FM) has historically been associated with several diseases in gastroenterology and hepatology. The most substantiated evidence pertains to irritable bowel syndrome (IBS). The pathogeneses of FM and IBS remain unclear, but it is likely related to dysregulation within the brain-gut axis, resulting in a hyperalgesic state. IBS and FM share other similarities, including a female predominance, fatigue, insomnia, and susceptibility to psychiatric state. These common manifestations and pathogeneses serve as a foundation for overlapping, multidisciplinary treatment modalities.

PreSERVE-AMI: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Intracoronary Administration of Autologous CD34+ Cells in Patients With Left Ventricular Dysfunction Post STEMI.

RATIONALE: Despite direct immediate intervention and therapy, ST-segment-elevation myocardial infarction (STEMI) victims remain at risk for infarct expansion, heart failure, reinfarction, repeat revascularization, and death. OBJECTIVE: To evaluate the safety and bioactivity of autologous CD34+ cell (CLBS10) intracoronary infusion in patients with left ventricular dysfunction post STEMI. METHODS AND RESULTS: Patients who underwent successful stenting for STEMI and had left ventricular dysfunction (ejection fraction≤48%) ≥4 days poststent were eligible for enrollment. Subjects (N=161) underwent mini bone marrow harvest and were randomized 1:1 to receive (1) autologous CD34+ cells (minimum 10 mol/L±20% cells; N=78) or (2) diluent alone (N=83), via intracoronary infusion. The primary safety end point was adverse events, serious adverse events, and major adverse cardiac event. The primary efficacy end point was change in resting myocardial perfusion over 6 months. No differences in myocardial perfusion or adverse events were observed between the control and treatment groups, although increased perfusion was observed within each group from baseline to 6 months (P<0.001). In secondary analyses, when adjusted for time of ischemia, a consistently favorable cell dose-dependent effect was observed in the change in left ventricular ejection fraction and infarct size, and the duration of time subjects was alive and out of hospital (P=0.05). At 1 year, 3.6% (N=3) and 0% deaths were observed in the control and treatment group, respectively. CONCLUSIONS: This PreSERVE-AMI (Phase 2, randomized, double-blind, placebo-controlled trial) represents the largest study of cell-based therapy for STEMI completed in the United States and provides evidence supporting safety and potential efficacy in patients with left ventricular dysfunction post STEMI who are at risk for death and major morbidity. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01495364.

Gastrointestinal Bleeding Due to Gastrointestinal Tract Malignancy: Natural History, Management, and Outcomes.

BACKGROUND: Gastrointestinal (GI) tumor bleeding can vary from occult bleeding to massive hemorrhage and can be the presenting sign of malignancy. AIMS: Our primary aims were to: (1) characterize the natural history, treatment, and outcomes in patients with GI tumor bleeding and (2) compare and contrast bleeding in upper GI (UGI)/small bowel (SB) and lower GI malignancies. METHODS: Patients with endoscopically confirmed tumor bleeding were identified through search of consecutive electronic medical records: Bleeding was determined by the presence of melena, hematochezia, hematemesis, or fecal occult blood. Comprehensive clinical and management data were abstracted. RESULTS: A total of 354 patients with GI tumors were identified: 71 had tumor bleeding (42 UGI/SB and 29 colonic). GI bleeding was the initial presenting symptom of malignancy in 55/71 (77%) of patients; 26/71 patients had widely metastatic disease at presentation. Further, 15 of 26 patients with metastatic disease presented with GI bleeding. Visible bleeding was present in 14/42 (33%) and 4/29 (14%) of UGI/SB and colonic tumors, respectively. Endoscopic hemostasis was attempted in 10 patients, and although initial control was successful in all, bleeding recurred in all of these patients. The most common endoscopic lesion was clean-based tumor ulceration. Overall mortality at 1 year was 57% for esophageal/gastric, 14% for SB, and 33% for colonic tumors. CONCLUSIONS: When patients with GI malignancy present with GI bleeding, it is often the index symptom. Initial endoscopic hemostasis is often successful, but rebleeding is typical. Esophageal and gastric tumors carry the poorest prognosis, with a high 1-year mortality rate.

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).

Autologous CD34+ Cell Therapy for Refractory Angina: 2-Year Outcomes From the ACT34-CMI Study.

An increasing number of patients have refractory angina despite optimal medical therapy and are without further revascularization options. Preclinical studies indicate that human CD34+ stem cells can stimulate new blood vessel formation in ischemic myocardium, improving perfusion and function. In ACT34-CMI (N = 167), patients treated with autologous CD34+ stem cells had improvements in angina and exercise time at 6 and 12 months compared to placebo; however, the longer-term effects of this treatment are unknown. ACT34 was a phase II randomized, double-blind, placebo-controlled clinical trial comparing placebo, low dose (1 × 105 CD34/kg body weight), and high dose (5 × 105 CD34/kg) using intramyocardial delivery into the ischemic zone following NOGA® mapping. To obtain longer-term safety and efficacy in these patients, we compiled data of major adverse cardiac events (MACE; death, myocardial infarction, acute coronary syndrome, or heart failure hospitalization) up to 24 months as well as angina and quality of life assessments in patients who consented for 24-month follow-up. A total of 167 patients with class III-IV refractory angina were randomized and completed the injection procedure. The low-dose-treated patients had a significant reduction in angina frequency (p = 0.02, 0.035) and improvements in exercise tolerance testing (ETT) time (p = 0.014, 0.017) compared to the placebo group at 6 and 12 months. At 24 months, patients treated with both low-and high-dose CD34+ cells had significant reduction in angina frequency (p = 0.03). At 24 months, there were a total of seven deaths (12.5%) in the control group versus one (1.8%) in the low-dose and two (3.6%) in the high-dose (p = 0.08) groups. At 2 years, MACE occurred at a rate of 33.9%, 21.8%, and 16.2% in control, low-, and high-dose patients, respectively (p = 0.08). Autologous CD34+ cell therapy was associated with persistent improvement in angina at 2 years and a trend for reduction in mortality in no-option patients with refractory angina.

The History of Coronary Stenting.

The history of coronary angioplasty began with the groundbreaking work of Andreas Grüntzig, who was the first to use balloon-expandable catheters for the treatment of flow-limiting atherosclerotic coronary artery lesions. Thereafter, early investigators tested self-expanding springs as a solution to abrupt closure and restenosis seen with balloon angioplasty but these devices suffered from difficult delivery and a high complication rate. Julio Palmaz and Richard Schatz introduced the first balloon-expandable stent as a mechanical support to improve vessel patency. Their pioneering work launched a new era in the treatment of coronary artery disease.

Idiopathic Splenic Artery Pseudoaneurysm Rupture as an Uncommon Cause of Hemorrhagic Shock.

Splenic artery pseudoaneurysms are infrequently encountered but critical to recognize. Limited literature to date describes associations with pancreatitis, trauma, and rarely peptic ulcer disease. Hemorrhage and abdominal pain are the most common manifestations. There is typically overt gastrointestinal blood loss but bleeding can also extend into the peritoneum, retroperitoneum, adjacent organs, or even a pseudocyst. Most patients with ruptured splenic artery pseudoaneurysms present with hemodynamic instability. Here, we describe a patient recovering from acute illness in the intensive care unit but with otherwise no obvious risk factors or precipitants for visceral pseudoaneurysm. He presented with acute onset altered mental status, nausea, and worsening back and abdominal pain and was found to be in hypovolemic shock. The patient was urgently stabilized until more detailed imaging could be performed, which ultimately revealed the source of blood loss and explained his rapid decompensation. He was successfully treated with arterial coiling and embolization. Thus, we herein emphasize the importance of prompt recognition of hemorrhagic shock and of aggressive hemodynamic stabilization, as well as a focused diagnostic approach to this problem with specific treatment for splenic artery pseudoaneurysm. Finally, we recommend that multidisciplinary management should be the standard approach in all patients with splenic artery pseudoaneurysm.

Predisposing factors for positive D-Xylose breath test for evaluation of small intestinal bacterial overgrowth: a retrospective study of 932 patients.

AIM: To investigate, in the largest cohort to date, patient characteristics and associated risk factors for developing small intestinal bacterial overgrowth (SIBO) using the D-Xylose breath test (XBT). METHODS: We performed a retrospective cross-sectional study to analyze patient characteristics who underwent the XBT for evaluation of SIBO. Diagnostic testing with the XBT was performed based on a clinical suspicion for SIBO in patients with symptoms of bloating, abdominal pain, abdominal distension, weight loss, diarrhea, and/or constipation. Consecutive electronic medical records of 932 patients who completed the XBT at the University of Florida between 2005 and 2009 were reviewed. A two-way Analysis of Variance (ANOVA) was used to test for several associations including age, gender, and body mass index (BMI) with a +XBT. A two-way ANOVA was also performed to control for the differences and interaction with age and between genders. A similar analysis was repeated for BMI. Associations between medical conditions and prior surgical histories were conducted using the Mantel-Haenszel method for 2 by 2 contingency tables, stratified for gender. Reported odds ratio estimates reflect the odds of the prevalence of a condition within the +XBT group to that of the -XBT group. P values of less than 0.05 (two-sided) were considered statistically significant. RESULTS: In the 932 consecutive eligible subjects studied, 513 had a positive XBT. A positive association was found between female gender and a positive XBT (P = 0.0025), and females with a positive test were, on average, greater than 5 years older than those with a negative test (P = 0.024). The mean BMI of positive XBT subjects was normal (24.5) and significantly lower than the subjects with a negative XBT (29.5) (P = 0.0050). A positive XBT was associated with gastroesophageal reflux disease (GERD) (OR = 1.35; 95%CI: 1.02-1.80, P = 0.04), peptic ulcer disease (PUD) (OR = 2.61; 95%CI: 1.48-4.59, P < 0.01), gastroparesis (GP) (OR = 2.04; 95%CI: 1.21-3.41, P < 0.01) and steroid use (OR = 1.35; 95%CI: 1.02-1.80, P = 0.01). Irritable bowel syndrome, independent proton-pump inhibitor (PPI) usage, or previous abdominal surgery was not significantly associated with a positive XBT. No single subdivision by gender or PPI use was associated with a significant difference in the odds ratios between any of the subsets. CONCLUSION: Female gender, lower BMI, steroid use, PUD, GERD (independent of PPI use), and GP were more prevalent in patients with SIBO, determined by a positive XBT. Increasing age was associated with SIBO in females, but not in males.

A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: design of the RENEW study.

Preclinical trials indicate that CD34+ cells represent an effective angiogenic stem cell component. Early-phase clinical trials suggest that intramyocardial administration of autologous CD34+ cells may improve functional capacity and symptoms of angina. RENEW is a pivotal phase 3 trial designed to determine the efficacy of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ stem cells for the treatment for patients with refractory angina and chronic myocardial ischemia. Patients (n = 444) receiving maximally tolerated antianginal therapies and lacking conventional revascularization options with Canadian Cardiovascular Society class III or IV angina and ischemia on stress testing will be randomized 2:1:1 to cell therapy (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial injection of 1 × 10(5) autologous CD34(+) cells/kg), active control (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial placebo injection), or open-label standard of care. The primary efficacy end point is change in exercise treadmill time in the treated vs active control patients, with 90% power to detect a 60-second difference in exercise time between cell-treated (n = 200) and active control (n = 100) patients. Key secondary end points include total number of anginal episodes per week and the incidence of independently adjudicated major adverse cardiac events and serious adverse events. RENEW will be the first adequately powered study aimed at definitively determining the efficacy of a cell therapy (intramyocardially delivered autologous CD34+ cells) for improvement of functional capacity in patients with refractory angina.

Incidence and clinical significance of cardiac biomarker elevation during stem cell mobilization, apheresis, and intramyocardial delivery: an analysis from ACT34-CMI.

BACKGROUND: Cell therapy is a promising therapeutic for a variety of cardiovascular conditions including refractory angina. Elevation of cardiac biomarkers during cell delivery has been frequently described, but the clinical implications have never been studied. METHODS: ACT34-CMI was a randomized double-blind study assessing the use of intramyocardial delivery of autologous CD34(+) cells for the treatment of refractory angina. Patients (n = 167) underwent G-CSF-mediated (5 µg/[kg day] × 5 days) stem cell mobilization, apheresis, and intramyocardial injection of 1 × 10(5)/kg or 5 × 10(5)/kg CD34(+) cells or placebo. Troponin and creatinine kinase MB were assessed at baseline (n = 161), after cell mobilization and apheresis (n = 153 and 143, respectively), and post-intramyocardial injection (n = 155 and 141, respectively). Major adverse cardiac events (MACE) included death, myocardial infarction, acute congestive heart failure, urgent revascularization, or sustained ventricular arrhythmia. RESULTS: Seven (4.3%) subjects had troponin above the upper limits of normal (ULN) at baseline. Thirty-four (22.2%) and 11 (7.2%) subjects had troponin levels > ULN or >3× ULN after cell mobilization and apheresis, whereas 72 (46.1%) and 39 (25.2%) subjects had troponin elevations > ULN or >3× ULN, respectively, after intramyocardial injections. Age, but no other preprocedural factors, was predictive of troponin elevation. Periprocedural troponin elevation was not associated with an increased risk of MACE during 1 year, especially in cell therapy-treated patients. CONCLUSIONS: Troponin elevation is common during stem cell harvesting and intramyocardial administration, is usually asymptomatic, and does not appear to be associated with long-term MACE in subjects undergoing stem cell mobilization and intramyocardial injection.

Intramyocardial, autologous CD34+ cell therapy for refractory angina.

RATIONALE: A growing number of patients with coronary disease have refractory angina. Preclinical and early-phase clinical data suggest that intramyocardial injection of autologous CD34+ cells can improve myocardial perfusion and function. OBJECTIVE: Evaluate the safety and bioactivity of intramyocardial injections of autologous CD34+ cells in patients with refractory angina who have exhausted all other treatment options. METHODS AND RESULTS: In this prospective, double-blind, randomized, phase II study (ClinicalTrials.gov identifier: NCT00300053), 167 patients with refractory angina received 1 of 2 doses (1×10(5) or 5×10(5) cells/kg) of mobilized autologous CD34+ cells or an equal volume of diluent (placebo). Treatment was distributed into 10 sites of ischemic, viable myocardium with a NOGA mapping injection catheter. The primary outcome measure was weekly angina frequency 6 months after treatment. Weekly angina frequency was significantly lower in the low-dose group than in placebo-treated patients at both 6 months (6.8±1.1 versus 10.9±1.2, P=0.020) and 12 months (6.3±1.2 versus 11.0±1.2, P=0.035); measurements in the high-dose group were also lower, but not significantly. Similarly, improvement in exercise tolerance was significantly greater in low-dose patients than in placebo-treated patients (6 months: 139±151 versus 69±122 seconds, P=0.014; 12 months: 140±171 versus 58±146 seconds, P=0.017) and greater, but not significantly, in the high-dose group. During cell mobilization and collection, 4.6% of patients had cardiac enzyme elevations consistent with non-ST segment elevation myocardial infarction. Mortality at 12 months was 5.4% in the placebo-treatment group with no deaths among cell-treated patients. CONCLUSIONS: Patients with refractory angina who received intramyocardial injections of autologous CD34+ cells (10(5) cells/kg) experienced significant improvements in angina frequency and exercise tolerance. The cell-mobilization and -collection procedures were associated with cardiac enzyme elevations, which will be addressed in future studies.

Recommendations for successful training on methods of delivery of biologics for cardiac regeneration: a report of the International Society for Cardiovascular Translational Research.

The field of myocardial regeneration (angiogenesis and myogenesis) might prove to play an important role in the future management of cardiovascular disease. Stem cells are currently undergoing testing in Phase I and Phase II clinical trials. Methods of delivery will affect the outcome of such therapies, perhaps significantly. This document provides suggested guidance in 4 methods of delivery: endocardial, intracoronary, coronary sinus, and epicardial.