Short communication: the cardiac myosin binding protein C Arg502Trp mutation: a common cause of hypertrophic cardiomyopathy.

RATIONALE: The myosin-binding protein C isoform 3 (MYBPC3) variant Arg502Trp has been identified in multiple hypertrophic cardiomyopathy (HCM) cases, but compelling evidence to support or refute the pathogenicity of this variant is lacking. OBJECTIVE: To determine the prevalence, origin and clinical significance of the MYBPC3 Arg502Trp variant. METHODS AND RESULTS: The prevalence of MYBPC3 Arg502Trp was ascertained in 1414 sequential HCM patients of primarily European descent. MYBPC3 Arg502Trp was identified in 34 of these 1414 unrelated HCM patients. Segregation of MYBPC3 Arg502Trp with clinical status was assessed in family members. Disease haplotypes were examined in 17 families using two loci flanking MYBPC3. Family studies identified an additional 43 variant carriers, many with manifest disease, yielding a calculated odds ratio of 11 000:1 for segregation of MYBPC3 Arg502Trp with HCM. Analyses in 17 families showed at least 4 independent haplotypes flanked MYBPC3 Arg502Trp. Eight individuals (4 probands and 4 family members) also had another sarcomere protein gene mutation. Major adverse clinical events occurred in approximately 30% of MYBPC3 Arg502Trp carriers by age 50; these were significantly more likely (P<0.0001) when another sarcomere mutation was present. CONCLUSIONS: MYBPC3 Arg502Trp is the most common and recurrent pathogenic mutation in a diverse primarily European descent HCM cohort, occurring in 2.4% of patients. MYBPC3 Arg502Trp conveys a 340-fold increased risk for HCM by 45 years of age, when more than 50% of carriers have overt disease. HCM prognosis worsens when MYBPC3 Arg502Trp occurs in the setting of another sarcomere protein gene mutation.

Safety issues related to treating bifurcation lesions.

Treating bifurcation lesions is a challenge in interventional cardiology. There is evidence that the anatomic morphology of the lesions plays a role not only in procedural success and complication rates, but also in the selection of stenting technique. Bifurcation angle, assessment of lesion severity, and acute stent thrombosis all pose a challenge to the interventionist. Safety issues related to treatment of bifurcation coronary disease is discussed. Assessment of lesions both before and after stenting using intravascular ultrasound in addition to quantitative coronary angiography may result in fewer complications.

Comparison of surgical pericardial drainage with percutaneous catheter drainage for pericardial effusion.

OBJECTIVE: We sought to investigate the outcomes for different treatments of pericardial effusions. BACKGROUND: The optimal initial management for symptomatic pericardial effusions remains controversial. METHODS: We performed a 3-year retrospective, single-institution study comparing open surgical drainage to percutaneous pericardiocentesis for symptomatic pericardial effusions. RESULTS: Between 2007 and 2009, a total of 193 patients underwent an initial drainage procedure for a pericardial effusion (n = 121 [62.7%] pericardiocentesis; n = 72 [37.3%] open surgical drainage). Compared to those treated with pericardiocentesis, treatment with open surgical drainage was associated with a higher complication rate (4.9% vs 26.4%; P<.0001; odds ratio [OR], 6.9; 95% confidence interval [CI], 2.6-18.2). Treatment with pericardiocentesis was associated with a higher rate of repeat procedures to drain a recurrent effusion compared to open surgical drainage (28.9% vs 2.8%; P<.0001; OR, 14.2; 95% CI, 3.3-61.3). Thirty-day mortality (19.8% surgical group vs 18.1% pericardiocentesis group; P=.8) and long-term survival (P=.4) did not differ between the groups. CONCLUSION: There is no significant difference in overall mortality between open surgical drainage and percutaneous pericardiocentesis for symptomatic pericardial effusions. There may be more procedural complications following surgical drainage of a pericardial effusion, and a greater need for repeat procedures if the effusion is drained using pericardiocentesis.

Pre-procedural risk quantification for carotid stenting using the CAS score: a report from the NCDR CARE Registry.

OBJECTIVES: We developed and internally validated a risk score to predict in-hospital stroke or death after carotid artery stenting (CAS). BACKGROUND: A tool that accurately assesses CAS risk could aid clinical decision making and improve patient selection. METHODS: Patients undergoing CAS without acute evolving stroke from April 2005 through June 2011 as part of the NCDR Carotid Artery Revascularization and Endarterectomy (CARE) Registry were included. In-hospital stroke or death was modeled using logistic regression with 35 candidate variables. Internal validation was achieved with bootstrapping, and model discrimination and calibration were assessed. RESULTS: A total of 271 (2.4%) primary endpoint events occurred during 11,122 procedures. Independent predictors of stroke or death included impending major surgery, previous stroke, age, symptomatic lesion, atrial fibrillation, and absence of previous ipsilateral carotid endarterectomy. The model was well calibrated with moderate discriminatory ability (C-statistic: 0.71) overall, and within symptomatic (C-statistic: 0.68) and asymptomatic (C-statistic: 0.72) subgroups. The inclusion of available angiographic variables did not improve model performance (C-statistic: 0.72, integrated discrimination improvement 0.001; p = 0.21). The NCDR CAS score was developed to support prospective risk quantification. CONCLUSIONS: The NCDR CAS score, comprising 6 clinical variables, predicts in-hospital S/D after CAS. This tool may be useful to assist clinicians in evaluating optimal management, share more accurate pre-procedural risks with patients, and improve patient selection for CAS.

Long-term impact of chronic kidney disease in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention: the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial.

OBJECTIVES: This study sought to investigate the impact of chronic kidney disease (CKD) in patients undergoing percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) with different antithrombotic strategies. BACKGROUND: CKD is associated with increased risk of adverse ischemic and hemorrhagic events after primary PCI for STEMI. METHODS: HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial was a multicenter, international, randomized trial comparing bivalirudin monotherapy or heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) during primary PCI in STEMI. CKD, defined as creatinine clearance <60 ml/min, was present at baseline in 554 of 3,397 patients (16.3%). Patients were followed for 3 years. Net adverse cardiac event (NACE) was defined as the composite of death, reinfarction, ischemia-driven target vessel revascularization (TVR), stroke or non-coronary artery bypass grafting (CABG)-related major bleeding. RESULTS: Patients with CKD compared with patients without had higher rates of NACE (41.4% vs. 23.8%, p < 0.0001), death (18.7% vs. 4.4%, p < 0.0001), and major bleeding (19.3% vs. 6.7%, p < 0.0001). Multivariable analysis identified baseline creatinine as an independent predictor of death at 3 years (hazard ratio: 1.51, 95% confidence interval: 1.21 to 1.87, p < 0.001). Patients with CKD randomized to bivalirudin monotherapy versus heparin plus GPI had no significant difference in major bleeding (19.0% vs. 19.6%, p = 0.72) or death (19.0% vs. 18.4%, p = 0.88) at 3 years. In patients with CKD, there was no difference in the rates of TVR in bare-metal stents (BMS) versus drug-eluting stents (DES) at 3 years (14.1% vs. 15.1%, p = 0.8). CONCLUSIONS: STEMI patients with CKD have significantly higher rates of death and major bleeding compared with those without CKD. In patients with CKD, there appears to be no benefit of bivalirudin compared with heparin + GPI, or DES versus BMS during primary PCI in improving clinical outcomes.

The relative effects of abciximab and tirofiban on platelet inhibition and C-reactive protein during coronary intervention.

BACKGROUND: We sought to compare the efficacy of tirofiban and abciximab on platelet inhibition as well as their effects of platelet inhibition on C-reactive protein levels during percutaneous coronary intervention (PCI). METHODS: Using a randomized, double-blind study design, 95 consecutively eligible patients were randomized to receive either tirofiban or abciximab before undergoing native coronary artery revascularization with a stent. Clinical endpoints were death, nonfatal MI, target vessel revascularization (TVR) with coronary artery bypass grafting or PCI within 30 days of the study procedure. The medications were compared for differences in platelet aggregation as measured by a rapid function platelet assay, as well as measurements of the inflammatory marker C-reactive protein (CRP) at frequent intervals following drug administration during PCI. RESULTS: A total of 95 patients were randomized to abciximab (n = 44) or tirofiban (n= 51). There was no significant difference in platelet aggregation documented throughout the procedure (10-, 20-, 30-, 45-minute time points). In diabetic patients abciximab had significantly lower platelet inhibition as compared to tirofiban at 10 minutes (84.17 +/- 8.28% vs. 90.40 +/- 5.79%; p = 0.0097). Using a Spearman correlation coefficient model, hs-CRP demonstrated an inverse relationship with platelet inhibition over time (-0.7307, p = 0.0002) in patients treated with abciximab. CONCLUSION: There is no major difference in platelet inhibition between tirofiban and abciximab during PCI. In this study, tirofiban showed a greater inhibition in diabetic subsets at the first time point within PCI. Platelet inhibition may be inversely related to the levels of CRP during PCI.

Endothelial progenitor cells delivered into the pericardial space incorporate into areas of ischemic myocardium.

OBJECTIVE: Our objective was to determine whether autologous endothelial progenitor cells (EPCs) delivered into the pericardial space will migrate to and incorporate into ischemic myocardium in a porcine model. BACKGROUND: Use of EPCs to enhance neovascularization and preserve myocardial function in ischemic tissue is undergoing intense scrutiny as a potential therapy. Delivery into the pericardial sac may overcome some of the limitations of currently employed cell delivery techniques. METHODS: EPCs were immunopurified from peripheral blood of Yorkshire pigs by selecting for the CD31 surface antigen, and adherent cells were cultured for 3-5 days. After myocardial ischemia was induced in the left anterior descending (LAD) artery, either autologous DiI (1,1'-dioctadecyl-1-3,3,3',3'-tetramethylindocarbocyanine perchlorate)-labeled EPCs (n=10) or serum-free medium (SFM; n=8) was delivered into the pericardial space using a percutaneous transatrial approach. Animals were sacrificed on Day 7 or 21. Echocardiography was performed at baseline, during ischemia, and on Day 7 in six SFM group animals and six EPC group animals. RESULTS: On Day 7, EPCs were identified in the left ventricular (LV) anterior wall or anterior septum in all six EPC-treated animals (cell density of 626 ± 122/mm(2)). On Day 21, EPCs were identified in the LV anterior wall or anterior septum in three of four EPC-treated animals (cell density of 267 ± 167/mm(2)). These cells showed dual staining for DiI and Bandeiraea simplicifolia lectin I (a marker of both native and exogenous endothelial cells). At the Day 7 follow-up, echocardiography demonstrated that fractional shortening in the EPC-treated group was 30.6 ± 3.4, compared with 22.6 ± 2.8 in SFM controls (P=.05). CONCLUSIONS: EPCs can migrate from the pericardial space to incorporate exclusively into areas of ischemic myocardium and may have favorable effects on LV function.

Effect of a standardized radiation dose reduction protocol on diagnostic accuracy of coronary computed tomographic angiography.

Although numerous strategies for radiation dose decrease in coronary computed tomographic angiography are effective, their combined impact on diagnostic performance is not known. We therefore assessed the effect of a standardized coronary computed tomographic angiographic protocol on diagnostic accuracy. We evaluated 80 consecutive patients from 3 sites with coronary computed tomographic angiography and quantitative coronary angiography. All sites initially used nonstandardized protocols; 2 sites then initiated a standardized protocol, and 1 site continued its nonstandardized protocol as a time-overlapping control. Two blinded readers interpreted coronary computed tomographic angiographic studies; a third obtained consensus. A blinded core laboratory performed quantitative coronary angiography. Each segment was graded as <50% or > or =50% diameter stenosis. Compared to those using nonstandardized protocols (n = 35), studies using standardized protocols (n = 45) had a trend to increased use of prospective gating (p = 0.09), lower voltage (p <0.01), decreased current (p <0.01), and shorter scan length (p <0.01). Median (interquartile range) radiation dose decreased from 5.7 mSv (4.0 to 10.8) to 2.0 mSv (1.3 to 3.4, p <0.001). There were no significant differences in sensitivity (100%, 20 of 20, vs 100%, 18 of 18, p = 1.0), specificity (93%, 14 of 15, vs 85%, 23 of 27, p = 0.61), or accuracy (97%, 34 of 35, vs 91%, 41 of 45, p = 0.27) by patient; sensitivity (83%, 33 of 40, vs 83%, 25 of 30, p = 0.93), specificity (92%, 86 of 93, vs 92%, 134 of 146, p = 0.85), or accuracy (89%, 119 of 133, vs 90%, 159 of 176, p = 0.80) by artery; or sensitivity (80%, 44 of 55, vs 72%, 26 of 36, p = 0.74), specificity (94%, 332 of 353, vs 94%, 499 of 531, p = 0.96), or accuracy (92%, 376 of 408, vs 93%, 525 of 567, p = 0.80) by segment. In conclusion, a standardized dose-decrease protocol for coronary computed tomographic angiography decreases radiation dose without affecting diagnostic performance.

Low power ultrasound delivered through a PTCA-like guidewire: preclinical feasibility and safety of a novel technology for intracoronary thrombolysis.

BACKGROUND: Low power ultrasound delivered through an angioplasty-like guidewire may be effective for intracoronary thrombolysis. We evaluated the preclinical feasibility and safety of such wire. METHODS AND RESULTS: In 15 anesthetized Yucatan minipigs, the ultrasonic wire was advanced percutaneously into all three coronaries. Each coronary was randomized to long activation (6 minutes), short activation (3 minutes), or control (3 minutes indwelling, no activation). The energy delivered was 0.14 +/- 0.01 W/cm of active length (20 kHz). No changes in heart rate, rhythm, or arterial pressure occurred during wire positioning or activation. Mean lumen diameter (MLD) by quantitative angiography was not significantly different pre- and postintervention (2.36 +/- 0.12 mm vs 2.36 +/- 0.11 mm for long activation, P = 0.96; 2.33 +/- 0.15 mm vs 2.34 +/- 0.14 mm for short activation, P = 0.54; 2.30 +/- 0.12 mm vs 2.33 +/- 0.12 mm for control, P = 0.21). There were no angiographic stenoses at 60 or 90 days follow-up. Compared with baseline, MLD at follow-up increased in all the three groups (2.40 +/- 0.13 mm vs 2.53 +/- 0.11 mm, P = 0.004 for long activation; 2.37 +/- 0.17 mm vs 2.52 +/- 0.14 mm, P = 0.023 for short activation; 2.20 +/- 0.12 mm vs 2.33 +/- 0.11 mm, P = 0.001 for the control group). By histology, there were no clinically significant pathologic changes in coronary morphology. CONCLUSION: Use of a transverse cavitation therapeutic wire is feasible and well tolerated acutely in the normal porcine coronary. At 60 and 90 days, no angiographically apparent damage, no clinically significant pathologic changes, and no adverse events were seen. This technology may be safely used during percutaneous coronary intervention. Further studies are justified to evaluate its efficacy for intracoronary thrombus ablation.

Angioscopy and ischemic heart disease.

Angioscopy allows direct visualization of the coronary artery lumen and provides detailed information regarding the surface characteristics of the vessel wall and specific lesions causing acute coronary syndromes. Disruption of a plaque, ulceration, tears, fissures, lipid-rich or fibrous lesions, and luminal or mural thrombus can be readily detected in vivo. Characterization of culprit lesions in various coronary syndromes reveals the different mechanisms of ischemia. The predominant lesion in acute myocardial infarction is an ulcerated, yellow plaque with thrombus. In unstable angina, different substrates can be seen, from the lipid-rich lesion with thrombus to the fibrous smooth plaque, reflecting a varied physiopathology. Because of its ability to detect superficial lipid pools, angioscopy may be valuable for the detection of vulnerable plaques.