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Background Patients with baseline thrombocytopenia can have increased mortality and morbidity, but are typically excluded from randomized clinical trials studying acute coronary syndromes (ACS). We sought to better define the effect thrombocytopenia on clinical outcomes in ACS patients. Methods Patients identified from the NCDR Chest Pain registry at Mayo Clinic Arizona from Oct 2015 to Sep 2018 were retrospectively classified into two groups: TP (platelet Results Five hundred and thirty-six patients were identified, and 72 patients (13%) had thrombocytopenia. The median follow-up time was 1.1 years. The TP group was older (TP vs. control: mean age 73 ± 13 years vs. 70 ± 13 years; P = 0.026). In patients discharged on dual-antiplatelet therapy, the TP group had higher all-cause mortality (23% vs. 7.3%; P = 0.007) but not major bleeding events (11% vs. 5.0%; P = 0.123). Only all-cause mortality increased with the severity of thrombocytopenia (TPmod vs. TPmild vs. control: 33% vs. 24% vs. 7.3%; P = 0.007). Conclusions In patients with ACS, baseline thrombocytopenia is associated with increased all-cause mortality and all bleeding events without net MACE benefit. Further study is needed to identify the optimal antiplatelet strategy in this higher risk population.

Percutaneous transendocardial injections of therapeutic agents into the myocardium may not always be effective. We used an animal model for assessing the efficacy of the injections using linoleic acid as a testing agent. Efficacious delivery into the myocardium of a beating heart was indicated by rapidly developed local myocardial necrosis and wall motion abnormalities using echocardiography. We employed this experimental model to test our innovative technology, an acoustically active injection catheter. The Doppler ultrasound-guided acoustically active injection catheter effectively delivers the substance to the myocardium but needs further technical improvements to minimize an unwanted systemic distribution of the agent.

Context Peripheral artery disease (PAD) is highly prevalent in the general population, affecting up to 25% of patients 55 years of age or older. There is a known association with acute ischemic stroke, but limited large cohort studies exist pertaining to the relationship between PAD severity and incident ischemic stroke. Objectives To evaluate the risk of incident ischemic stroke and mortality along the spectrum of low and elevated ankle brachial index (ABI) measurement. Methods We performed a retrospective extraction of ABI data of all adult patients who underwent lower extremity physiology study for any indication from January 1, 1996 to June 30, 2018 in the Mayo Clinic health system. PAD was categorized into severe, moderate, mild, and borderline based on ABI measurements and poorly compressible arteries (PCA). These were compared with normal ABI measurements. Associations of PAD/PCA with new ischemic stroke events and all cause mortality were analyzed. Hazard ratios (HR) were calculated using multivariable Cox proportional regression with 95% confidence intervals. Results A total of 39,834 unique patients were included with a median follow up duration of 4.59 years. All abnormal ABI groups, except borderline PAD, were associated with increased risk of incident ischemic stroke after multivariate regression compared to normal ABI. A severity-dependent association was observed between PAD and ischemic stroke with moderate (HR, 1.22 [95% CI, 1.10–1.35]) and severe (HR, 1.19 [95% CI, 1.02–1.40]) categories conferring similar risk in comparison to normal ABI. Patients with PCA carried the greatest ischemic stroke risk (HR, 1.30 [95% CI, 1.15–1.46]). Similarly, abnormal ABI groups were associated with a significant risk for all cause mortality in a severity-dependent manner, with severe PAD conferring the greatest risk (HR, 3.07 [95% CI, 2.88–3.27]). Conclusions This study adds to the growing body of evidence that both PAD and PCA are independent risk factors for incident ischemic stroke and all cause mortality. The association of PAD severity and PCA with risk of ischemic stroke may help clinicians with risk stratification and determining treatment intensity.

We present a case of refractory acute hypoxemic respiratory failure due to influenza B pneumonia with concomitant large intra-atrial shunt (IAS) and severe pulmonary regurgitation in a patient with Saethre-Chotzen syndrome with prior pulmonary homograft placement. Our patient's hypoxemia improved with inhaled nitric oxide as an adjunct to mechanical ventilation without requiring extracorporeal membrane oxygenation, and eventually a percutaneous closure with a 30 mm CardioSeal patent foramen ovale closure device was accomplished. However, his peri-procedural hospital course was complicated by occluder device migration, which was retrieved with eventual surgical closure of the PFO. Nitric oxide has not demonstrated any statistically significant effect on mortality and only reported to transiently improved oxygenation in patients with hypoxemic respiratory failure. Our case demonstrates that inhaled nitric oxide may have a role in acute hypoxemic respiratory failure in a case with significant cardiac and pulmonary shunts.

Objectives Left ventricular (LV) septal hypertrophy in aortic stenosis raises diagnostic and therapeutic questions. However, the etiology and clinical consequences of this finding have not been well studied. The aim of this study was to perform a morphologic evaluation of the LV in aortic stenosis and to investigate the contributing factors and consequences of septal hypertrophy. Methods Patients with moderate or severe aortic stenosis were prospectively enrolled. Patients with previous myocardial infarction, wall motion abnormalities, at least moderate valvular regurgitation, known cardiomyopathy, an LV ejection fraction of less than 50%, and age younger than 65 years were excluded. Results Forty-one patients underwent a final analysis. Septal hypertrophy (LV septal wall thickness ≥15 mm) was confirmed in 21 of 41 patients. The septal hypertrophy group had higher peak aortic valve velocity, a higher diabetes mellitus rate, and a higher rate and longer duration of hypertension than those without septal hypertrophy. The peak aortic valve velocity (odds ratio, 7.1; 95% confidence interval, 1.4–37.1) and diabetes mellitus (odds ratio, 7.4; 95% confidence interval, 1.2–46.2) were the significant factors associated with septal hypertrophy by multivariate analysis. Intraventricular conduction disturbance on electrocardiography was more frequent in the septal hypertrophy group (P = .021). Conclusions Left ventricular septal hypertrophy was commonly observed in elderly patients with aortic stenosis, and a higher aortic valve velocity, hypertension, and diabetes mellitus were associated factors. Intraventricular conduction disturbance occurred more often in patients with septal hypertrophy than those without, which implies the pathophysiologic consequence. Further studies are needed to determine the impact of septal hypertrophy and intraventricular conduction disturbance on the prognosis of patients after aortic valve interventions.

A 61-year-old man with history of coronary artery disease and coronary artery bypass graft presented with chest pain. A left heart catheterization showed a new kink in the body of his left internal mammary artery to left anterior descending artery graft. The kink improved with inspiration, which suggests re-assessment of similar cases should be done during deep inspiration. (Level of Difficulty: Intermediate.), Graphical abstract, A 61-year-old man with history of coronary artery disease and coronary artery bypass graft presented with chest pain. A left heart catheterization…

Background: We performed a meta-analysis to evaluate the benefit of patent foramen ovale closure in stroke prevention. Methods: We searched Medline/PubMed, EMBASE, Web of Science and Cochrane central database for randomized control trials assessing the incidence of recurrent stroke after patent foramen ovale closure when compared to medical therapy. Pooled odds ratio and 95% confidence intervals were calculated using a random effects model. The heterogeneity among studies was tested using the χ2 test and inconsistency was quantified using the I2 statistic. Results: Our search strategy yielded 71 articles. We included five studies with a total of 3440 patients. Median age in the device group was 45 (43, 5.5) years and in the medical group was 45 (44.5, 46) years; 52% were male, 27.7% of patients had an atrial septal aneurysm, 25% had hypertension, and 20.5% had diabetes mellitus. The median follow-up time was 44 (34.5–50) months. The pooled odds ratio of recurrent stroke, transient ischemic attack and composite end point of stroke + transient ischemic attack + peripheral embolism in the patent foramen ovale closure versus medical therapy group were 0.4 (95% confidence interval 0.25–0.63, I2 = 57.5%), 0.93 (95% confidence interval 0.61–1.42, I2 = 0%), and 0.6 (95% confidence interval 0.44–0.82, I2 = 0%), respectively. The incidence of atrial fibrillation was found to be significantly higher in the patent foramen ovale closure group with odds ratio of 6 (95% confidence interval 3.13–11.4, I2 = 33.5%). On subgroup analysis, patent foramen ovale closure appeared to benefit males and patients with a large shunt. Number needed to treat to prevent one recurrent stroke with patent foramen ovale closure is 42. Number needed to harm to cause one atrial fibrillation with patent foramen ovale closure is 39. Conclusion: This meta-analysis of randomized trials concludes that percutaneous patent foramen ovale closure is effective in recurrent stroke prevention especially in males and in those with a large shunt.

Background Cangrelor, an intravenous, reversible P2Y12 antagonist, is approved for use in patients undergoing percutaneous coronary intervention (PCI). Objectives This study sought to evaluate the efficacy and safety of cangrelor compared with clopidogrel in subgroups that did and did not receive glycoprotein IIb/IIIa inhibitors (GPIs). Methods This pooled, patient-level analysis of the 3 CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trials analyzed all randomized patients who underwent PCI and received the study drug (n = 24,902). Only bailout/rescue GPI use was permitted, except in CHAMPION PCI, in which routine or bailout/rescue GPI use was at the site investigator’s discretion. The primary efficacy endpoint was the composite of all-cause mortality, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h after randomization. Results Overall, 3,173 patients (12.7%) received a GPI, most commonly eptifibatide (69.4%). Despite variation in indications for GPIs, baseline characteristics were well balanced between the cangrelor and clopidogrel arms in subsets receiving and not receiving GPIs. Rates of the primary composite endpoint were lower with cangrelor compared with clopidogrel in patients who did (4.9% vs. 6.5%; odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.55 to 1.01) or did not receive a GPI (3.6% vs. 4.4%; OR: 0.82; 95% CI: 0.72 to 0.94; Pint = 0.55). Cangrelor did not increase the primary safety endpoint, GUSTO-defined severe/life-threatening bleeding, in patients who did (0.4% vs. 0.5%; OR: 0.71; 95% CI: 0.25 to 1.99) or did not receive GPIs (0.2% vs. 0.1%; OR: 1.56; 95% CI: 0.80 to 3.04; Pint = 0.21). GPI use was associated with increased risk of bleeding in both treatment arms. Conclusions Cangrelor’s efficacy in reducing ischemic complications in patients undergoing PCI was maintained irrespective of GPI administration. GPI use was associated with substantially higher bleeding rates, regardless of the randomization to cangrelor or clopidogrel. (A Clinical Trial to Demonstrate the Efficacy of Cangrelor [PCI]: NCT00305162 ; Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition [PLATFORM]: NCT00385138 ; A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX] [CHAMPION]: NCT01156571 )

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 × 10 5 CD34/kg body weight), and high dose (5 × 10 5 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.

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)

33% of patients with pulmonary vein stenosis were initially diagnosed with bronchitis, pneumonia, or rarely malignancy, leading to delayed care and unnecessary invasive diagnostic testing. Misdiagnosis is common because the most frequent symptoms are nonspecific. Early recognition of pulmonary vein

The clinical benefit of patent foramen ovale (PFO) closure in patients with cryptogenic stroke (CS) for recurrent stroke prevention has been a subject of extensive debate. Prior clinical trials failed to show superiority of PFO closure versus medical therapy. Meta-analyses suggested a possible benefit of PFO closure in select patients.The objective of this study was to critically assess current evidence regarding the efficacy of PFO closure compared with medical therapy for recurrent stroke prevention in patients with CS.The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, medical librarian, and vascular neurology and interventional cardiology content experts.A randomized, controlled trial was selected for critical appraisal. This trial compared the efficacy of PFO closure and medical therapy in recurrent stroke prevention. A total of 663 patients who had a recent CS attributed to PFO, with a large interatrial shunt or with an associated atrial septal aneurysm were included. No stroke occurred among the 238 patients in the PFO closure group, whereas 14 of the 235 patients in the antiplatelet therapy group had recurrent strokes.Among patients who had a recent CS attributed to PFO with a large interatrial shunt or with an associated atrial septal aneurysm, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone.

Background Coronary atherosclerosis often involves small-caliber coronaries, yet the safety and efficacy of 2.25-mm DES have been poorly defined, with a general lack of separation of 2.25 with 2.5-mm performance. No randomized head-to-head 2.25 mm DES studies have been reported. There are several single-arm prospective studies, and we aim to systematically review all published specific 2.25-mm data to estimate composite DES-specific performance and highlight current knowledge gaps. Methods We performed a systematic literature search of PubMed, EMBASE, Web of Science and Cochrane database for clinical trials of 2.25-mm DES. Angiographic and composite clinical outcomes were compared with descriptive statistics. Results 2.25 mm-Paclitaxel (PES), sirolimus (SES), everolimus (EES) and platinum chromium EES DES-specific outcomes have been reported. Death at 12 months for SES, PES, EES and platinum chromium EES was 1.3%, 3.0%, 1.5%, and 4.4%. Rates of target vessel revascularization at 12 months for SES, PES, EES and platinum chromium EES were 5.7%, 13.3%, 8.8%, and 3.3%. Angiographic outcomes at 9 months to one year were as follows: mean late lumen loss (LLL) for SES, PES, and EES was 0.15 ± 0.11-mm, 0.28 ± 0.11-mm, and 0.16 ± 0.41-mm and mean diameter restenosis for SES, PES, and EES were 29.5 ± 6.2%, 34.7 ± 4.2%, and 20.9 ± 22.5%. Reported stent thrombosis rates for 2.25-mm DES were low ranging from 0% to 2.2% in up to 24-months of follow-up. Conclusions This systematic review summarizes and tabulates all available specific data on 2.25-mm DES. Based on our descriptive analysis, 2.25-mm DESs have a favorable safety and efficacy profile for the treatment of very small coronary lesions.

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.

Objective Optimal duration of dual antiplatelet therapy (DAPT), defined as use of both aspirin and a P2Y12 receptor inhibitor, after implantation of drug eluting stents (DES) is still subject of ongoing debate. We systematically review efficacy and safety of ≤6 months versus ≥12 months DAPT after implantation of DES. Methods PubMed, Scopus, Cochrane, and clinicaltrials.gov databases were searched for studies published until 30th November 2013. The studies were limited to randomized clinical trials. Independent observers abstracted the data on outcomes, characteristics, and qualities of studies included. Random effect model was employed for meta-analysis. Heterogeneity of studies included was analyzed using I2 statistics. Results In four randomized clinical trials published involving 8,163 patients with DES, 4,081 patients were randomized to shorter and 4,082 patients to longer duration DAPT. The P2Y12 receptor inhibitor used in all four studies was clopidogrel. Longer duration of DAPT did not reduce risk of all cause mortality (pooled OR 0.89, 95% CI 0.67–1.17, P = 0.4, I2 = 0%), myocardial infarction (pooled OR 1.16, 95% CI 0.85–1.57, P = 0.35, I2 = 0%) cardiac death (pooled OR 0.88, 95% CI 0.61–1.25, P = 0.47, I2 = 0%), stent thrombosis (pooled OR 1.29, 95% CI 0.76–2.21, P = 0.35, I2 = 0%) or cerebrovascular accidents (pooled OR 0.73, 95% CI 0.41–1.27, P = 0.26, I2 = 0%). Longer duration of DAPT was associated with increased risk of TIMI major bleeding (pooled OR 0.51, 95% CI 0.29–0.89, P = 0.02, I2 = 0%). Conclusion There was no difference in efficacy outcomes between ≤6 months of DAPT and ≥12 months of DAPT in patients with coronary artery disease and DES implantation. Moreover, longer duration of DAPT is associated with increased risk of bleeding complications. © 2014 Wiley Periodicals, Inc.

Patent foramen ovale is a common clinical finding that generally becomes a concern in the presence of transient ischemic attack or stroke. Rarely, patent foramen ovale is associated with hypoxemia in the presence of substantial right-to-left atrial shunting. We present the case of an 86-year-old woman with a pacemaker, who was initially asymptomatic notwithstanding a patent foramen ovale. Over 1.5 years, her symptoms progressed in a stepwise fashion, in the setting of progressive pacemaker-associated tricuspid regurgitation. Ultimately, the patient's symptoms and her hypoxemia resolved after percutaneous closure of her patent foramen ovale with use of a 25-mm “Cribriform” occluder device. This case highlights the fact that clinically significant right-to-left shunting requires an anatomic lesion, such as patent foramen ovale, together with elevated right atrial pressure, which in this case was contributed by severe tricuspid regurgitation.

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.

We describe a new variant of transient left ventricular (LV) ballooning in North American Caucasian patients in which only the midventricle is affected. The patients described in this case series initially presented with emotional or physical stress and had similarities to transient apical ballooning syndrome; however, this variant is unique in that the transient ballooning involves the midventricle with hypercontractility of the apical and basal segments. The presentation, clinical features, and transient nature of the reported cases in this series are similar to transient LV apical ballooning and suggest a shared pathophysiologic etiology. Sparing of the apical segment with involvement of midventricle only supports etiologies not related to an epicardial coronary artery distribution. Although the pathophysiologic mechanism of the transient ventricular ballooning syndromes and other cases of catecholamine-associated transient ventricular dysfunction are not well understood, the emergence of this new variant raises further questions in the understanding of the “brain-heart” relationship.

Background: The short-term clinical impact of intramyocardial gene transfer (GT) of the angiogenic protein vascular endothelial growth factor-2 (VEGF-2) has been previously reported to significantly reduce Canadian Cardiovascular Society (CCS) angina class and to prolong exercise treadmill test (ETT) time. We describe the safety and long-term events (>1 year) in consecutive, nonrandomized, patients who received intramyocardial VEGF-2. Methods: Thirty patients with intractable CCS class III or IV angina and no options for revascularization underwent direct intramyocardial GT of VEGF-2 naked DNA via limited thoracotomy at total doses of 0.2, 0.8, or 2.0 mg. Patients were followed for clinical events after 1 year by hospital records, follow-up visits or telephone contact. Due to one perioperative death, 29 patients were followed. Results: At a mean follow-up of 751 ± 102.5 days (range 459–959) there were four deaths (13.8%), five myocardial infarctions (MIs) (17.2%), and seven revascularization procedures (24.1%). There were 15 hospitalizations in 12 patients. At the end of the follow-up period no patient (0%) had CCS class IV angina, 3 patients (11.5%) had class III angina, and 23 (88.5%) had class I to II angina. There were two new diagnoses of cancer. Conclusion: Transthoracic intramyocardial injection of VEGF-2 is associated with an improvement of symptoms of angina in the majority of patients beyond the first year of treatment. Major clinical events such as death, MI, and repeat revascularization are uncommon during the first year but more frequent after 1 year at a rate consistent with the severity of underlying disease in this population with advanced atherosclerosis. The majority of events were the result of progression of disease in areas of the heart remote from the site of GT. A large randomized trial is planned to determine the efficacy of intramyocardial VEGF-2 injections in inoperable patients.

Pseudostenosis is a generally benign complication of percutaneous coronary intervention that is caused by the mechanical deformation of a tortuous artery by the guidewire. We describe two cases of a tortuous right coronary artery in which pseudostenosis was relieved by placing a Transit exchange catheter (Cordis) distally and subsequently removing the guidewire. This technique safely confirmed the diagnosis of pseudostenosis without losing guidewire position or requiring additional wires and balloons.

Objective To review our experience with, and profile the safety and efficacy of, the Amplatzer PFO (patent foramen ovale) occluder (APO) and Amplatzer septal occluder (ASO) used to close PFO and/or atrial septal defect (ASD) in patients with paradoxical embolism (PE). Patients and Methods Between April 1998 and November 2002, 103 patients at the Mayo Clinic in Rochester, Minn, and Scottsdale, Ariz, mean age 52.4 years, with presumed PE (transient ischemic attack [n=22], stroke [n=77], or peripheral emboli [n=4]) underwent transcatheter device closure of PFO (n=81), ASD (n=12), and ASD/PFO (n=10) with 106 devices (APO [n=22] or ASO [n=84]). Results All devices deployed successfully, and no patients died. Procedural complications included atrial fibrillation (n=2), vessel injury (n=3), profound sinus node dysfunction (n=1), and device embolization with successful retrieval (n=1). At 3 months, 7 of 95 monitored patients had trivial residual shunt; at 12 months, 2 of 28 monitored patients had trivial residual shunt. Three patients had recurrent events—2 transient ischemic attacks and 1 retinal artery occlusion—at a mean ± SD follow-up of 8.3±8.1 months (range, 1-34 months). None of these 3 patients had residual shunt or evidence of intracardiac thrombus. The average annual recurrence of all events was 3.6% at 23 months. The overall mean ± SD freedom from recurrence of all events was 98.9%±1.2% and 83.8%±10.2% at 12 and 29 months of follow-up, respectively. Conclusions Transcatheter device closure of PFO and/or ASD with use of APO/ASO in patients with presumed PE is effective and safe. Recurrent events may occur in the absence of a residual shunt.

This phase I open label, dose-escalating study shows that gene transfer of vascular endothelial growth factor-2 naked deoxyribonucleic acid by direct myocardial injection by way of thoracotomy in patients with Canadian Cardiovascular Society class 3 or 4 angina is feasible and safe. The procedure is well tolerated, with few major adverse cardiac events at 1 year, and without complications directly related to gene expression. In this prospective, nonblinded study, the procedure is associated with clinical improvement; however, there was no angiographic evidence of angiogenesis and there is a great potential for a sham or placebo effect in the study patients. A randomized phase III trial is underway that will help determine the efficacy of vascular endothelial growth factor-2 gene transfer in “no-option” patients.

Objectives We sought to test whether the ratio of peak tricuspid regurgitant velocity (TRV, ms) to the right ventricular outflow tract time-velocity integral (TVIRVOT, cm) obtained by Doppler echocardiography (TRV/TVIRVOT) provides a clinically reliable method to determine pulmonary vascular resistance (PVR). Background Pulmonary vascular resistance is an important hemodynamic variable used in the management of patients with cardiovascular and pulmonary disease. Right-heart catheterization, with its associated disadvantages, is required to determine PVR. However, a reliable noninvasive method is unavailable. Methods Simultaneous Doppler echocardiographic examination and right-heart catheterization were performed in 44 patients. The ratio of TRV/TVIRVOTwas then correlated with invasive PVR measurements using regression analysis. An equation was modeled to calculate PVR in Wood units (WU) using echocardiography, and the results were compared with invasive PVR measurements using the Bland-Altman analysis. Using receiver-operating characteristics curve analysis, a cutoff value for the Doppler equation was generated to determine PVR >2WU. Results As calculated by Doppler echocardiography, TRV/TVIRVOTcorrelated well (r = 0.929, 95% confidence interval 0.87 to 0.96) with invasive PVR measurements. The Bland-Altman analysis between PVR obtained invasively and that by echocardiography, using the equation: PVR= TRV/TVIRVOT× 10 + 0.16 , showed satisfactory limits of agreement (mean 0 ± 0.41). A TRV/TVIRVOTcutoff value of 0.175 had a sensitivity of 77% and a specificity of 81% to determine PVR >2WU. Conclusions Doppler echocardiography may provide a reliable, noninvasive method to determine PVR.

Background — This phase 1/2 study investigated the safety of percutaneous catheter-based gene transfer of naked plasmid DNA encoding for vascular endothelial growth factor 2 (phVEGF2) to left ventricular (LV) myocardium in a prospective, randomized, double-blind, placebo-controlled, dose-escalating study of inoperable patients with class III or IV angina. Methods and Results — A steerable deflectable 8F catheter with a 27-gauge needle at its distal tip was advanced percutaneously to the endocardial surface of the LV in 19 patients (age, 61±2 years) with chronic myocardial ischemia who were not candidates for conventional revascularization. Patients were randomized in a double-blind fashion to receive 6 injections (total volume, 6.0 mL) of placebo or phVEGF2 in doses of 200 μg (n=9), 800 μg (n=9), or 2000 μg (n=1) guided by LV electromechanical (NOGA) mapping with a gene-to-placebo ratio of 2:1. A total of 114 LV injections were delivered and caused no hemodynamic alterations, sustained ventricular arrhythmias, ECG evidence of infarction, or ventricular perforation. End-point analysis at 12 weeks disclosed a statistically significant improvement in Canadian Cardiovascular Society (CCS) angina class in phVEGF2-treated versus placebo-treated patients (−1.3 versus −0.1, P =0.04). Remaining efficacy end points—including change in exercise duration (91.8 versus 3.9 seconds), functional improvement by ≥2 CCS classes (9 of 12 versus 1 of 6), and Seattle Angina Questionnaire data—all showed strong trends favoring efficacy of phVEGF2 versus placebo treatment. Conclusions — This phase 1/2, double-blind, randomized trial provides preliminary data that support safety of phVEGF2 catheter-mediated myocardial gene transfer. The statistically significant reduction in anginal class and strong positive trends for remaining end points suggest that a larger phase 2/3 trial is warranted.

Background Although dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is a widely accepted strategy in patients undergoing transcatheter aortic valve replacement (TAVR), this approach is not evidence based. We therefore sought to systematically review the current evidence for this practice in terms of 30-day outcome looking at stroke, MI, bleeding, and death. Methods Relevant studies were identified through electronic literature search. Studies involving single antiplatelet therapy (SAPT) and DAPT in patients undergoing TAVR were included. Study specific risk ratios were calculated and combined using random-effects model meta-analysis. Results Analysis of data from 410 patients, stroke occurred in seven (3.16%) of SAPT and six (3.17%) of DAPT RR=1.03 (95% CI, 0.36-2.96, P=0.96). In analysis of 530 patients, MI occurred in three (1.07%) of SAPT and one (0.40%) of DAPT RR=1.97 (95% CI, 0.29-13.29, P=0.49), significant bleeding (major, life threatening and bleeding requiring transfusion) occurred in 20 (7.11%) of SAPT and 43 (17.27%) of DAPT RR=0.41 (95% CI, 0.25-0.69, P=0.0006). Number needed to harm for major or life threatening bleeding was 10. Death occurred in 15 (6.78%) of SAPT and 15 (7.94%) of DAPT (RR 0.91; 95% CI 0.46-1.79, P=0.78). Conclusion Our meta-analysis suggests that at 30 days following TAVR there is no difference between post-procedural SAPT versus DAPT for the risk of stroke or MI and DAPT may have a higher bleeding risk. Adequately powered RCTs are warranted to clarify the optimal antiplatelet treatment strategy following TAVR.

We sought to determine the safety and preliminary efficacy of transcatheter intramyocardial administration of myoblasts in patients with heart failure (HF).MARVEL is a randomized placebo-controlled trial of image-guided, catheter-based intramyocardial injection of placebo or myoblasts (400 or 800 million) in patients with class II to IV HF and ejection fraction35%. Primary end points were frequency of serious adverse events (safety) and changes in 6-minute walk test and Minnesota Living With HF score (efficacy). Of 330 patients intended for enrollment, 23 were randomized (MARVEL-1) before stopping the study for financial reasons.At 6 months, similar numbers of events occurred in each group: 8 (placebo), 7 (low dose), and 8 (high dose), without deaths. Ventricular tachycardia responsive to amiodarone was more frequent in myoblast-treated patients: 1 (placebo), 3 (low dose), and 4 (high dose). A trend toward improvement in functional capacity was noted in myoblast-treated groups (Δ6-minute walk test of -3.6 vs +95.6 vs +85.5 m [placebo vs low dose vs high dose; P = .50]) without significant changes in Minnesota Living With HF scores.In HF patients with chronic postinfarction cardiomyopathy, transcatheter administration of myoblasts in doses of 400 to 800 million cells is feasible and may lead to important clinical benefits. Ventricular tachycardia may be provoked by myoblast injection but appears to be a transient and treatable problem. A large-scale outcome trial of myoblast administration in HF patients with postinfarction cardiomyopathy is feasible and warranted.

Background After a transient ischemic episode, the subendocardial region is more severely injured than outer subepicardial layers and may regain a proportionately greater degree of mechanical function in the longitudinal direction. We sought to explore left ventricular (LV) transmural mechanics in patients with ST-segment elevation myocardial infarction (STEMI) for determining the mechanism underlying recovery of global LV function after primary percutaneous coronary intervention (PCI). Methods A total of 42 patients (62 ± 11 years old, 71% male) with a first STEMI underwent serial assessments of LV longitudinal, circumferential and radial strains (LS, CS and RS) by selective tracking of subendocardial and subepicardial regions within 48 hours and a median of 5 months after PCI. LV mechanical parameters were compared with sixteen age and gender matched normal controls. Results In comparison with controls, endocardial and epicardial LS were markedly attenuated at 48 hours following PCI (P < 0.001). An improvement in LV ejection fraction (EF > 5%) following PCI was seen in 24 (57%) patients and was associated with improvement in endocardial and epicardial LS (P < 0.001 and P = 0.003, respectively) and endocardial CS (P = 0.01). Radial strain and wall motion score index, however, remained persistently abnormal. The change in endocardial LS (OR 1.2, 95% CI 1.03 to 1.42, P = 0.01) and the change in epicardial LS (OR 1.2, 95% 1.03 to 1.46, P = 0.02) were significantly associated with the improvement in LVEF, independent of the location of STEMI and the presence of underlying multivessel disease. Conclusions In patients with STEMI treated by PCI, the recovery of LV subendocardial shortening strain seen in the longitudinal direction underlies the improvement in LV global function despite persistent abnormalities in radial mechanics and wall motion score index.

We describe a 79-year-old male with recurrent high-grade liposarcoma who developed postoperative chest pain, dyspnea, and hypoxia suspicious for acute pulmonary embolism (PE). However, electrocardiogram (ECG) was suggestive of an acute ST-elevation myocardial infarction (MI). Heparin was initiated and emergent coronary angiography was performed, which demonstrated a "cutoff sign" in the distal left anterior descending artery (LAD) consistent with coronary embolism. A patent foramen ovale (PFO) and bilateral pulmonary emboli were subsequently identified. It was concluded that the patient had suffered an acute PE, with a portion of clot traversing the PFO and entering the LAD, resulting in a simultaneous acute ST-elevation MI. While the case described is rare, the underlying anatomical variant is common and may have practical significance. We discuss the literature regarding PFO with acute PE and paradoxical emboli.

Systemic vascular resistance (SVR) is an integral therapeutic component of patients with heart failure and shock. We hypothesized that the ratio of the peak mitral regurgitant velocity (MRV) (m/s) to left ventricular outflow time-velocity integral (TVI(LVOT)) (cm) by Doppler would provide a noninvasive correlate of SVR.SVR was correlated to MRV/TVI(LVOT) in 33 patients undergoing right heart catheterization. Receiver operating characteristic curves were generated to determine the best-balanced sensitivity and specificity to identify SVR14 Wood units (WU) and10 WU.MRV/TVI(LVOT) correlated well with SVR (r = 0.842, 95% confidence interval 0.7-0.92, P.001, Y = 0.459 + 49.397*X). By receiver operating characteristics, MRV/TVI(LVOT)0.27 had a 70% sensitivity and a 77% specificity to identify SVR14 WU. MRV/TVI(LVOT)0.2 had a 92% sensitivity and a 88% specificity to identify SVR10 WU.Doppler echocardiography provides a reliable noninvasive assessment of SVR.

We performed a simultaneous Doppler and invasive study to validate the role of Doppler-derived peak pulmonary regurgitant velocity as a reliable noninvasive measure of pulmonary artery mean pressure. Assessment of right atrial pressure, as shown in this study, enhances the use of this Doppler parameter as a correlate of pulmonary artery mean pressure.

HypothesisTo help establish institution baseline measurements and compare resuscitation performance in different simulation and clinical (live) environments.MethodsWe retrospectively compared GWTG-R metrics for ventricular fibrillation or pulseless ventricular tachycardia (VF/pVT) resuscitation perf

Aim The benefit of preventive percutaneous coronary intervention (PCI) in ST elevation myocardial infarction (STEMI) has been shown in randomised trials. However, all the randomised trials are underpowered to detect benefit in cardiac death. We aim to systematically review evidence on the cardiac mortality benefit of preventive PCI in patients presenting with acute STEMI in randomised patient populations. Methods PubMed, Scopus, Cochrane and clinicaltrials.gov databases were searched for studies published until 30 September 2013. The studies were limited to randomised clinical trials. Independent observers abstracted the data on outcomes, characteristics and qualities of studies included. Fixed effect model was employed for meta-analysis. Heterogeneity of studies included was analysed using I 2 statistics. Results In three randomised clinical trials published, involving 748 patients with acute STEMI and multivessel disease, 416 patients were randomised to preventive PCI and 332 to culprit-only PCI. Patients undergoing preventive PCI had significant lower risk of cardiovascular deaths (pooled OR 0.39, 95% CI 0.18 to 0.83, p=0.01, I 2 =0%), repeat revascularisation (pooled OR 0.28, 95% CI 0.18 to 0.44, p=0.00001, I 2 =0%) and non-fatal myocardial infarction (pooled OR 0.38, 95% CI 0.20 to 0.75, p=0.005, I 2 =0%) compared with culprit-only revascularisation. Conclusions In patients presenting with acute STEMI and significant multivessel coronary artery disease, based on our data, preventive PCI is associated with lower risk of cardiovascular mortality compared with primary PCI of only the culprit artery. This finding needs to be confirmed in larger adequately powered randomised clinical trials.

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.