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HIGHLIGHTS FROM JACC IN 2005

Highlights of the Year in JACC 2005

Anthony N. DeMaria, MD^_*,_*, Ori Ben-Yehuda, MD^_*, Daniel Berman, MD, Gregory K. Feld, MD^_*, Geoffrey S. Ginsburg, MD, PhD, Barry H. Greenberg, MD^_*, Wilbur Y.W. Lew, MD^_*, David Sahn, MD and Sotirios Tsimikas, MD^_*

^_* Cardiology Division, University of California-San Diego, San Diego, California
Cedars-Sinai Medical Center, Los Angeles, California
Duke University, Durham, North Carolina
Pediatric Cardiology, Oregon Health and Science University, Portland, Oregon

Manuscript received November 11, 2005; accepted November 11, 2005.

^_* Reprint requests and correspondence: Dr. Anthony N. DeMaria, Cardiology Division, UCSD Medical Center, 200 West Arbor Drive, San Diego, California 92103-8411. (Email: ademaria{at}usd.edu).

	Noninvasive cardiology

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Tissue Doppler and strain
Considerable efforts continue to be devoted to the field of tissue Doppler recordings and the measurements of LV strain that can be derived from them. Yu et al. (6) described a novel tool to assess LV systolic asynchrony that could be applied to the identification of responders of cardiac resynchronization therapy. The new method, termed tissue synchronization imaging, transforms the timing of regional peak velocities into color codes that enables immediate visual identification of systolic contractile delays in orthogonal walls. The authors applied this methodology and found that tissue synchronization imaging allowed quick recognition of asynchronous areas that could then be assessed for time to peak systolic velocity so as to predict the likelihood of reverse remodeling in response to cardiac resynchronization therapy. The same investigators evaluated whether strain rate imaging derived from tissue Doppler recordings could reliably distinguish transmural from nontransmural myocardial infarction (MI) (7). In a group of 47 consecutive patients, they compared data obtained by strain rate imaging with that provided by contrast-enhanced magnetic resonance imaging (MRI) using the delayed enhancement technique. Peak systolic strain rate was significantly lower in transmural infarction segments than in non-transmural segments, and a cutoff value for strain rate >–0.59 s^–1 detected transmural infarction with a sensitivity of 90% and a specificity of 96%. Thus, the readily available tool of strain rate imaging can be of value in distinguishing transmural from non-transmural infarction.

The assessment of myocardial tissue velocities has traditionally been based upon conventional Doppler techniques; however, a new methodology consisting of ultrasound speckle tracking by two-dimensional imaging has recently been developed. Notomi et al. (8) validated this speckle tracking imaging to accurately assess ventricular torsion in comparison with tagged MRI and Doppler tissue imaging. A good correlation was observed between speckle tracking and MRI (r = 0.93) that was slightly superior to the correlation with Doppler tissue imaging (0.76). Thus, two-dimensional ultrasound speckle tracking provides an important new technique for the assessment of myocardial velocities and ventricular torsion.

Three-dimensional echocardiography
Three-dimensional echocardiography continues to find important applications in addressing physiological issues. Watanabe et al. (9) used three-dimensional echo techniques to quantify mitral valve tenting in patients with ischemic mitral regurgitation. They observed three-dimensional geometric deformity of the mitral leaflets and annulus in patients with ischemic mitral regurgitation, helping to clarify the mechanism and point to the diagnostic utility of the technique. With a broad beam spectral Doppler transducer similar to that employed for three-dimensional echocardiography, Buck et al. (10) examined the vena contracta as an approach to quantify mitral regurgitation and correlated regurgitant stroke volume by this method to MRI in 24 patients with r = 0.93. Thus, broad-beam spectral Doppler methods of quantifying the vena contracta show promise as a technique to measure regurgitant stroke volume in mitral regurgitation.

Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy continues to be the object of intense interest among cardiologists. Controversy continues regarding the optimal therapeutic approach in patients with refractory symptoms. Ommen et al. (11) reported the long-term effects of surgical septal myectomy upon survival in 1,337 patients with hypertrophic cardiomyopathy, 289 of whom underwent surgical myectomy. In this retrospective study, they demonstrated that surgical septal myectomy performed to relieve outflow obstruction and symptoms in hypertrophic cardiomyopathy was associated with a long-term survival equivalent to that of the general population and superior to that of obstructive cardiomyopathy without operation. In an accompanying editorial, Watkins and McKenna (12) comment that, although no randomized data yet exist, the report by Ommen et al. (11) could be interpreted as evidence that surgical relief of obstruction improves long-term survival in adults. An additional issue that has attracted attention concerns the transition of hypertrophic cardiomyopathy to a dilated-hypokinetic form. Biagini et al. (13) reported on a total of 222 consecutive hypertrophic cardiomyopathy adult patients who were prospectively followed for a mean of 11 ± 9 years. Twelve patients evolved dilated-hypokinetic ventricle for an incidence of 5.3 per 1,000 patient years. These patients were younger at first evaluation, more often had a family history of hypertrophic cardiomyopathy or sudden death, and showed a greater interventricular septal and posterior wall thickness. Cardiovascular survival was lower among these dilated-hypokinetic patients. In an accompanying editorial, Ommen (14) commented that the propensity to presentation at a young age and greater hypertrophy support the concept that energetic crisis and ultimate energetic failure may lead to the late-stage transformation from hypertrophy to dilatation.

Valvular heart disease
The value of vasodilator therapy in the prophylactic treatment of patients with aortic regurgitation was the subject of intense investigation in the past year. Scognamiglio et al. (15) reported on the ten-year follow-up of their initial cohort of 266 patients with aortic regurgitation undergoing aortic valve replacement, 134 of whom had previously been treated with nifedipine and 132 with placebo. Although the interval to surgery was longer in the nifedipine-treated patients, operative mortality was similar, and ejection fraction normalized in these patients whereas it remained abnormal in 28% of the placebo control group. At 10 years of follow-up, the nifedipine-treated group continued to manifest a higher ejection fraction (62% vs. 48%, p < 0.001) and a higher survival (85% vs. 78%) than control subjects. In an accompanying editorial, Bashore (16) commented that these data imply that nifedipine afterload reduction induces a benefit that persists long after the aortic regurgitation is resolved, even in those with an abnormal ventricle.

Intravascular ultrasound (IVUS)
The last year witnessed resurgence of interest in IVUS. The technique was applied by Hong et al. (17) to define the site of plaque rupture in all three native coronary vessels in patients with acute coronary syndrome (ACS). Their data demonstrated that plaque ruptures occurred primarily in the proximal segments of the left anterior descending artery (LAD) and the proximal and distal segments of the right coronary artery while occurring throughout the circumflex. These data could potentially have significance for the application of percutaneous intervention. Two studies evaluated new techniques by which to assess the tissue characteristics of coronary plaques. Kawasaki et al. (18) derived integrated backscatter values using radiofrequency signals from a 40-MHz IVUS catheter. Three-dimensional reconstruction and color coded mapping were then performed. Plaques were displayed in terms of fibrous volume, lipid volume, and mixed lesions. They demonstrated that statin therapy reduced the lipid component in patients with stable angina without reducing the degree of stenosis. Murashige et al. (19) applied wavelet analysis of radiofrequency IVUS signals to detect lipid laden plaque. As compared with histology, wavelet analysis enabled in vitro as well as in vivo detection of lipid laden plaque, a characteristic associated with vulnerability. Finally, IVUS was applied in two multicenter studies assessing coronary vasculopathy among heart transplant recipients (20,21). The studies, in which patient populations may have overlapped, yielded similar results and demonstrated that progression of intimal thickness 0.5 mm in the first year after transplantation seems to be a reliable surrogate marker for subsequent mortality, non-fatal major adverse cardiac events (MACE), and the development of angiographic coronary artery vasculopathy through five years after transplantation.

Contrast echocardiography
Progress continues in the development of contrast echocardiographic methodology as well as the application of contrast echo in the clinical setting. In a report dealing with spontaneous echo contrast, Bernhardt et al. (22) prospectively performed 12-month follow-up transesophageal echocardiography and cerebral MRI in patients with AF. The findings in 128 patients with dense spontaneous contrast were compared with those of 143 patients with faint spontaneous contrast. During follow-up, six patients died owing to embolic events and 19 (15%) patients with dense contrast exhibited MRI evidence of silent embolism. Patients with events were also observed to have lower left atrial appendage peak emptying velocities. Thus, this study demonstrated that silent embolization was surprisingly frequent in patients with dense spontaneous echo contrast. In an accompanying editorial, Goldman et al. (23) commented that this study reinforces the dangers of AF, even with apparent anticoagulation, and points to dense spontaneous contrast as an important risk factor for events.

Although myocardial contrast echocardiography (MCE) to study perfusion has been the object of much clinical investigation, clinical applications have not yet clearly emerged. In a very large study, Tong et al. (24) compared MCE in nearly 1,000 patients presenting to the emergency room with chest pain and a nondiagnostic electrocardiogram (ECG) with the Thrombolysis In Myocardial Infarction (TIMI) risk score to predict adverse events. Myocardial contrast echocardiography was performed by standard methods in the emergency room, and patients were followed for 24-h and 30-day events including death, MI, unstable angina, or revascularization. Only 2 of 523 patients with normal regional contractile function by echo had a primary event, and myocardial perfusion further classified these patients into intermediate and high risk groups. These results were superior to the TIMI score for risk stratification. In an accompanying editorial, Vannan et al. (25) pointed to the challenges of implementing MCE in the emergency room as well as the important economic considerations; however, they indicated that these data demonstrate that MCE may play a unique role in the identification of myocardial ischemia in patients presenting to the emergency room. The use of MCE in conjunction with stress testing presents issues in addition to those for contrast echo performed at rest, particularly with regard to feasibility and safety. Tsutsui et al. (26) performed dobutamine stress MCE in 1,486 patients over four years with a variety of agents and instruments. They found that MCE was feasible for analysis of 95% of wall segments at peak stress and yielded a higher accuracy for detecting patients with angiographically significant coronary disease than analysis of wall motion (84% vs. 66%; p < 0.001). No increased incidence of arrhythmias was observed with the contrast agent. Thus, these data attest to the suitability of dobutamine stress MCE for clinical application. Finally, MCE was assessed as a possible method to provide measurements of the elusive parameter of absolute myocardial blood flow. Vogel et al. (27) first validated an algorithm to derive myocardial blood flow from contrast echocardiography in vitro. Subsequently, they performed studies in healthy volunteers and patients with coronary artery disease (CAD). They found a linear relationship between measures of myocardial blood flow by MCE and positron emission tomography (R² = 0.88) and a good correlation between the methods in regard to coronary flow reserve in patients with CAD (r² = 0.73). Thus, these very promising data suggest that MCE may be capable of providing clinical information regarding absolute myocardial blood flow.

	Interventional cardiology

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Sotirios Tsimikas, MD.   Drug-eluting stents (DES)
Sirolimus versus paclitaxel
The TAXi trial (28) was a single-center study that randomized 202 patients to sirolimus-eluting stents (SES) versus paclitaxel-eluting stents (PES) in an unselected and relatively high-risk population. Follow-up was limited to clinical events at seven months; the study showed a MACE and target lesion revascularization (TLR) rate of 6% and 3%, respectively, in the SES group and 4% and 2%, respectively, in the PES group, with no statistical differences between groups. This was the first randomized trial to report comparisons between DES. The clinical outcomes of patients treated with SES (n = 508) and PES (n = 576) were evaluated in unselected patients treated in two sequential prospective registries at the Rotterdam Cardiology Hospital (29). At one year, outcomes were not significantly different, with MACE rates of 13.9% in the PES group and 10.5% in the SES group and target vessel revascularization: 5.4% versus 3.7%, respectively. The trends toward higher crude rates with PES were explained by higher baseline risk in the PES group.

Stent thrombosis
The issue of stent thrombosis (ST) after implantation of DES has received significant attention in the past year, owing to the significant mortality associated with it and reports documenting late stent thrombosis (>30 days after stent implantation), particularly after withdrawal of anti-platelet therapy. In a meta-analysis of 10 randomized trials comparing bare-metal stents (BMS; n = 2,602) with SES and PES (n = 2,428), Moreno et al. (30) showed that the incidence of ST was not increased in patients receiving DES (0.58% vs. 0.54% for BMS; p = 1.0) and was similar between patients receiving SES or PES (0.57% vs. 0.58%). The clinical follow-up was 9 to 12 months, and patients with PES received a mean of 4.2 months of clopidogrel versus 2 months for SES and 1 month for BMS. Six of 15 of the DES thromboses occurred beyond 30 days and were strongly associated with absence of thienopyridine therapy and stent length. These results were generally echoed by those of Bavry et al. (31), who performed an independent meta-analysis evaluating eight randomized trials of PES versus BMS.

Additional data from the Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry comprising three sequential cohorts of 506 consecutive patients with BMS, 1,017 consecutive patients with SES, and 989 consecutive patients treated with PES, reflecting an unselected population, showed that the 30-day incidence of ST was 1.4% (n = 6) in BMS, 1.5% (n = 15) in SES, and 1.6% (n = 16) in PES (32). Bifurcation stenting in the setting of acute myocardial infarction (AMI) was a strong independent risk factor for ST (odds ratio 12.9, p < 0.001). Follow-up (mean 1.5 years) of this group of patients showed eight (0.35%) cases of late angiographic stent thrombosis, three with SES (at 2, 25, and 26 months), and five with PES (at 6, 7, 8, 11, and 14.5 months) (33). Three cases were related to complete cessation of antiplatelet therapy; two cases occurred after cessation of clopidogrel but receiving aspirin therapy, and three cases occurred while receiving aspirin monotherapy. Interestingly, there were no cases of late angiographic stent thrombosis in patients receiving dual antiplatelet therapy.

Several studies evaluated the mechanisms behind these observations. Ajzenberg et al. (34) showed that shear-induced platelet aggregation was significantly increased in patients suffering ST compared with patients without stent thrombosis and normal volunteers. Wenaweser et al. (35) also showed that resistance to aspirin therapy, measured by adenosine-diphosphate platelet aggregation, was present in patients with previous stent thrombosis. Both of these studies were small and retrospective and were carried out in patients with BMS. Nonetheless, they support the notion that certain patients are at inherently higher risk of ST. Using IVUS, Fujii et al. (36) showed that patients with ST tend to have stent under-expansion and residual reference segment stenosis, further implicating procedural factors in ST.

Efficacy of DES in various clinical scenarios
In unprotected left main CAD, Park et al. (37) performed SES placement in 102 consecutive patients with preserved LV function and compared the results with 121 patients treated with BMS. There were no incidents of death, stent thrombosis, Q-wave MI, or emergent bypass surgery during hospital stay in either group. At six-month angiographic follow-up, the SES group showed a lower late lumen loss (0.05 mm vs. 1.27 mm, p < 0.001) and a lower restenosis rate (7.0% vs. 30.3%, p < 0.001) compared with the BMS group. At 12 months, the rate of freedom from death, MI, and TLR was 98.0% in the SES group and 81.4% in the BMS group (p = 0.0003). These results are better than one would have predicted.

In saphenous vein grafts, Ge et al. (38) evaluated the in-hospital and six-month clinical and angiographic outcomes of DES implantation in 61 consecutive patients with saphenous vein graft lesions and compared them with 89 consecutive patients treated with BMS in the 24 months immediately before the introduction of DES. The rate of in-hospital MACE was similar between the two groups, but six month MACE was 11.5% in the DES group and 28.1% in the BMS group (p = 0.02). The DES group had a significantly lower incidence of in-segment restenosis (10.0% vs. 26.7%, p = 0.03), TLR (3.3% vs. 19.8%, p = 0.003), and target vessel revascularization (4.9% vs. 23.1%, p = 0.003). Diabetes and age of saphenous vein graft were independent predictors of MACE at six-month follow-up.

In diabetes mellitus, women, ACS, and left anterior descending lesion subgroups, the TAXUS IV trial evaluated PES versus BMS in 1,314 patients undergoing elective percutaneous coronary intervention (PCI) of de novo coronary lesions. Diabetes and women were pre-specified subgroup analyses. Medically treated diabetes was present in 318 patients (24%), 105 of whom required insulin. Paclitaxel-eluting stent reduced the rate of 9-month binary angiographic restenosis by 81%, TLR by 65%, target vessel revascularization by 53%, and MACE by 44%. The one-year rates of cardiac death, MI, and subacute thrombosis were comparable between the groups. In the insulin-requiring subgroup, the TAXUS stent reduced angiographic restenosis by 82% and TLR by 68% (39). Women assigned to PES had restenosis rates and late loss similar to men, but higher absolute rates of TLR (7.6% vs. 3.2%, p = 0.03), primarily owing to higher co-morbidities than men (40). Similar benefits were noted in patients presenting with ACS (41) and treatment of the LAD (42). Furthermore, the need for bypass surgery at one year was reduced among patients randomized to PES (2.6% vs. 6.3%, p = 0.02). The findings for the LAD were further substantiated by Seung et al. (43), who showed similar benefits compared with BMS. Although these studies show improved clinical benefits with PES, they were not necessarily powered to evaluate differences between groups and were also not randomized.

Relationship of late lumen loss to TLR
Ellis et al. (44) evaluated the relationship between angiographic late loss and TLR in the TAXUS IV trial by defining the relationship between in-stent and in-segment late loss, the shape of the late loss histogram (variance and skewedness) and nine-month TLR. Late loss was closely related to TLR for both PES and BMS both in-stent and in-segment. For individual patients (mean reference vessel of 2.8 ± 0.5 mm), the probability of a 5% to 10% risk of TLR was not apparent until in-segment late loss was >0.50 to 0.65 mm. At greater late losses, the late loss TLR relationship was steep and nearly linear. Higher rates of TLR were also related to higher variance and skewedness. In an accompanying editorial, Kereiakes et al. (45) suggest that the biological relationship of angiographic late loss is different between DES and BMS and more appropriate statistical methodology is required to analyze these relationships, particularly as it relates to the mean late loss. They suggest that the minimum difference in late loss between two different stents and its relationship to TLR is not known but may be clinically relevant when patients with higher rates of restenosis are studied, such as those with multivessel disease or complex lesions.

Treatment of bifurcation lesions
Bifurcation lesions remain a challenging lesion subset in interventional cardiology, and various techniques have been recently promoted with the use of DES. Ge et al. (46) reported the long-term outcomes after implantation of DES in bifurcation lesions with the "crush" technique in 181 consecutive patients. Restenosis of the main branch was 11.5%, of the side branch 21.6%, and TLR was 14.9%. Three cases (1.7%) of intraprocedural stent thrombosis and five (2.8%) cases of postprocedural stent thrombosis occurred. Final kissing balloon inflation was associated with more favorable long-term outcomes. In this study, the improved rates of TLR over historical controls seemed to be diminished by the increased risk of ST. Costa et al. (47) evaluated IVUS findings after crush-stenting of bifurcation lesions and showed that the majority of side branch lesions were underexpanded, which could not be detected angiographically, and that incomplete stent apposition was present in >60% of lesions. These findings suggest potential mechanisms for both restenosis and stent thrombosis. Future studies will evaluate dedicated bifurcation stents, as was suggested by the Safety and Feasibility of a Novel Dedicated Stent for the Treatment of Bifurcation Coronary Lesions (FRONTIER) stent registry (48), presumably with drug coatings.

Public reporting of PCI results
Moscucci et al. (49) compared demographics, indications, and outcomes of 11,374 patients included in an eight-hospital PCI database in Michigan where no public reporting is present, with 69,048 patients in a statewide PCI database in New York, where public reporting is present. Patients in Michigan more frequently underwent PCI for AMI and cardiogenic shock and were generally higher risk than those in New York. The unadjusted in-hospital mortality rate was significantly lower in New York than in Michigan; however, after adjustment for co-morbidities, there was no significant difference in mortality between the two groups (adjusted odds ratio 1.05, 95% confidence interval 0.84 to 1.31, p = 0.70). The authors concluded that a case selection bias driven by fear of public reporting of high mortality rates in New York may be a potential explanation for the differences in case mix and mortality rates.

IVUS studies
Fassa et al. (50) determined that the lower range of minimal luminal area in normal left main coronary arteries (n = 121) was 7.5 mm². Intravascular ultrasound was then performed on 214 patients with angiographically indeterminate left main coronary arteries lesions with deferral of revascularization if the minimal luminal area was larger than 7.5 mm². During a mean follow-up period of 3.3 ± 2.0 years, there was no significant difference in MACE between patients with a minimal luminal area <7.5 mm² who underwent revascularization and those with a minimal luminal area 7.5 mm² deferred for revascularization. The authors concluded that IVUS is an accurate method to assess angiographically indeterminate left main coronary arteries lesions and that deferring revascularization for patients with a minimum lumen area 7.5 mm² seemed to be safe.

A second study demonstrated that IVUS examination of native coronary arteries does not result in an acceleration of the atherosclerotic process (51).

Peripheral arterial disease: Femoropopliteal disease
Scheinert et al. (52) performed a systematic X-ray screening in 93 patients and showed that stent fractures were detected in 45 of 121 treated legs and 64 of 261 stents. Fracture rates were 13.2% for stented length 8 cm, 42.4% for stented length >8 to 16 cm, and 52.0% for stented length >16 cm. Restenosis was present at the site of stent fracture in 21 cases and occlusion in 22 cases. The primary patency rate at 12 months was significantly lower for patients with stent fractures. There is a considerable risk of stent fractures after long segment femoral artery stenting, which is associated with a higher in-stent restenosis and reocclusion rate.

Renal artery stenting
Rocha-Singh et al. (53) enrolled 208 hypertensive patients with de novo or restenotic 70% aorto-ostial renal artery stenoses who underwent implantation of a balloon-expandable stent after unsuccessful percutaneous transluminal renal angioplasty. The nine-month restenosis rate was 17.4% and systolic/diastolic blood pressure was decreased. The 24-month cumulative rate of major adverse events was 19.7%. This uncontrolled study suggests that renal artery stenting reduces the number of anti-hypertensive medications and stabilizes the creatinine level.

Patent foramen ovale and migraine headache
Two studies were reported that suggest that closure of a patent foramen ovale or atrial septal defect (ASD) reduces the incidence of migraine headache. Azarbal et al. (54) followed 89 adult patients who underwent transcatheter closure of a patent foramen ovale/ASD. At three months after the procedure, migraine headache disappeared completely in 75% of patients with aura and in 31% of patients without aura. Of the remaining patients, 40% had significant improvement. Reisman et al. (55) followed 162 consecutive patients with paradoxical cerebral embolism who underwent transcatheter patent foramen ovale closure for prevention of recurrent cryptogenic stroke or transient ischemic attack. Before the procedure, migraine was present in 35% of patients, and 68% experienced migraine with aura. Complete resolution of migraine symptoms occurred in 56% of patients, and 14% of patients reported a significant reduction in migraine frequency. Although these are observational studies with a strong potential for placebo effect, they set the stage for future randomized trials.

Fractional flow reserve
Angiographic analysis of jailed side branches after stent placement is suboptimal. Koo et al. (56) evaluated 97 jailed side branch lesions (vessel size >2.0 mm, >50% diameter stenosis). No lesion with <75% stenosis had fractional flow reserve <0.75. Among 73 lesions with 75% stenosis, only 20 lesions were functionally significant. The authors concluded that fractional flow reserve measurement in jailed side branch lesions is both safe and feasible and suggests that most of these angiographically significant lesions do not have functional significance.

	Nuclear cardiology, cardiac computed tomography, and Cardiovascular Magnetic Resonance (CMR)

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Daniel S. Berman, MD.   Single-photon emission computed tomography (SPECT)
Myocardial perfusion SPECT (MPS) has become one of the most widely used cardiac imaging methods and plays a central role in guiding decisions regarding the need for considering revascularization in patients with known or suspected CAD. Perhaps the most important publication regarding SPECT in 2005 was the American College of Cardiology Foundation/American Society of Nuclear Cardiology Appropriateness Criteria for SPECT, representing the first in a series of technical documents from the American College of Cardiology that will systematically categorize cardiovascular tests and procedures used by cardiologists in daily practice. A 12-member technical panel of diverse background considered a broad spectrum of potential indications, categorizing them as inappropriate, uncertain, and appropriate. The results are expected to have a significant impact on physician decision making and reimbursement policy (57).

To identify which asymptomatic diabetic patients are candidates for screening with MPS, Rajagopalan et al. (58) examined 1,427 asymptomatic diabetic patients without known CAD who underwent MPS. High-risk findings on stress MPS were present in 18% and were associated with a 5.9% annual mortality rate. Of patients with high-risk MPS who had coronary angiography, 61% were found to have high risk angiographic findings. Electrocardiographic Q waves and/or evidence of peripheral arterial disease identified the patients most suitable for screening.

Leslie et al. (59) reported prognostic value of lung uptake of radioactivity in 718 patients undergoing stress 99mTc-sestamibi MPS who were followed up mean 5.6 years. The stress lung-to-heart ratio (LHR) provided a small but significant improvement in risk stratification when added to clinical, stress test, perfusion, and LV volume information (global chi-square 168.6 vs. 150.7, p < 0.00001). Stress LHR is an adjunctive prognostic measure in patients with known or suspected CAD.

Positron emission tomography
Invasive angiographic assessments of coronary vasomotor function have demonstrated that impairment of endothelium-related coronary flow increases—endothelial dysfunction—independently predicts future cardiovascular events. With 13N-ammonia positron emission tomography in 72 patients with normal coronary angiograms, Schindler et al. (60) were the first to demonstrate that impaired myocardial blood flow increases in response to cold pressor testing—a noninvasive method for assessing coronary endothelial dysfunction—are at increased risk for cardiovascular events.

Patient outcome after myocardial viability assessment remains a topic of clinical interest. Desideri et al. (61) studied 261 patients with ischemic cardiomyopathy, of whom 167 were treated medically and 94 were revascularized after undergoing F-18 fluorodeoxyglucose positron emission tomography for assessment of viability. The cardiac death rate was significantly less in the revascularized patients compared with medically treated patients (13% vs. 24%, p < 0.05). Medically treated patients with ischemic cardiomyopathy and large areas of viable myocardium by positron emission tomography (>20% of the LV) are at high risk for cardiac death.

Coronary calcium
The year 2005 saw the publication of several studies documenting that the coronary artery calcium is associated with cardiovascular disease events. In a prospective, population-based study of 4,613 asymptomatic participants, Arad et al. (62) in the St. Francis Heart Study evaluated the relationships among coronary calcification, coronary disease risk factors, c-reactive protein (CRP), and atherosclerotic cardiovascular disease events. During 4.3 years, 119 had sustained at least one cardiovascular disease event (cardiac death, non-fatal MI, PCI, or stroke). Nearly 10% of the patients had coronary artery calcium scores >400, indicating advanced coronary atherosclerosis; in these patients, rates for CAD event was 3.26% per year. The coronary artery calcium score predicted CAD events independently of standard risk factors and CRP (p = 0.004), was superior to the Framingham risk index in the prediction of events (area under the ROC curve of 0.79 ± 0.03 vs. 0.69 ± 0.03, p = 0.0006), and enhanced stratification of those falling into the Framingham categories of low, intermediate, and high risk (p < 0.0001). In an accompanying editorial, Grundy (63) noted that the coronary artery calcium measurements seem to have clinical utility in the patients with intermediate risk (10% to 20% 10-year risk of coronary heart disease death or MI) but not in other groups. It is anticipated that the increasing data will increase the degree of acceptance of coronary artery calcium as a measurement that is useful in guiding management decision in patients with intermediate risk.

Taylor et al. (64) reported similar findings in 2,000 healthy men and women ages 40 to 50 years in active military duty. Coronary calcium was found in 22.4% of men and 7.9% of women. No events occurred in women, attributed to the young age of the study population. Coronary calcium was associated with an 11.8-fold increased risk for incident coronary heart disease (p = 0.002) in a Cox model controlling for the Framingham risk score. The marginal cost effectiveness, assuming a 30% improvement in survival associated with primary prevention among at-risk men, was modeled to be $37,633 per quality-adjusted life year saved.

Multislice computed tomography (MSCT)
Continued advances in MSCT imaging technology have resulted in increasing interest from the cardiology community in coronary computed tomography angiography, which promises to become the first clinically accurate noninvasive coronary artery imaging method. In 2005, with the help of the American College of Cardiology, the Society of Cardiovascular Computed Tomography was formed and by the fourth quarter had over 1,000 members. Four manufacturers were delivering 64-slice MSCT scanners in 2005, with spatial resolution as low as 0.4 mm and rotation time as fast as 330 ms. In one of the first correlative studies with a 64-slice scanner, Raff et al. (65) studied 70 consecutive patients undergoing invasive coronary angiography by using 64-slice spiral CT. In 935 (88%) of 1,065 segments, high correlation was observed between quantitative CT assessment and quantitative coronary angiography with a Spearman correlation coefficient of 0.76 (p < 0.0001). Bland-Altman analysis revealed minimal bias with mean difference in percent stenosis of 1.3 ± 14.2%. Specificity, sensitivity, and positive and negative predictive values for the presence of significant stenoses were: by segment (n = 935), 86%, 95%, 66%, and 98%, respectively; by artery (n = 279), 91%, 92%, 80%, and 97%, respectively; by patient (n = 70), 95%, 90%, 93%, and 93%, respectively. The authors noted that patients with coronary artery calcium scores >400, heart rates over 70 beats/min, and obesity remain a challenge even with the 64-slice scanner.

Multislice computed tomography may become clinically useful in the noninvasive diagnosis of in-stent restenosis. In what was reported as the first study of its type, Gaspar et al. (66) examined 65 patients with 111 coronary stents who had MSCT with a 40-slice scanner and were referred for repeat invasive coronary angiography. in-stent restenosis (60% luminal narrowing by quantitative coronary angiography) was found in 18 (16.2%) of the stented segments and in 16 (24.6%) patients. Narrowing of the stented segment was graded 1 to 4 according to the proportion of the vessel lumen that was poorly enhanced. The MSCT findings correlated with coronary restenosis, with restenosis in only 1 of 59 (1.6%) multidetector CT grade 1 segments, but in more than three-quarters (12 of 15, 80%) of multidetector CT grade 4 segments (sensitivity 72.2%, specificity 92.5%, positive predictive value 65.0%, negative predictive value 94.5%). Using MSCT grades 3 or 4 combined for restenosis, sensitivity of MSCT was 88.9%, specificity 80.6%. Although promising, the method currently is dependent not only on the scanner used and issues such as heart rate but also on stent type, size, and location. Potentially already useful to rule out in-stent restenosis in patients with some but relatively low clinical suspicion, this application will nevertheless require further refinement before it becomes a routine clinical tool.

The ability of CT to assess myocardial viability in a manner analogous to the delayed enhancement by CMR was studied by Mahnken et al. (67). They compared contrast-enhanced 16-slice MSCT with contrast-enhanced CMR in 28 patients within two weeks after MI. There was excellent agreement between late-enhancement CMR and late-enhancement MSCT (kappa = 0.878). Whereas the images did not appear to provide as high contrast as observed with CMR, the authors concluded that late-enhancement MSCT seems to be as reliable as delayed contrast-enhanced CMR in assessing infarct size and myocardial viability in AMI. This approach could prove useful as an added procedure (at lower radiation dose) to CT coronary angiography and in patients needing viability assessment but unable to undergo CMR.

CMR
The potential of delayed enhancement CMR to assess myocardial infarct size can be of both clinical and research importance. Ibrahim et al. (68) demonstrated that in patients after AMI and successful reperfusion, infarct size by CMR is stable over time and matches well with SPECT perfusion defect. Thirty-three patients were examined by delayed enhancement CMR and SPECT 7 ± 2 days after AMI and successful coronary intervention. All patients showed myocardial delayed enhancement in the infarct region. Delayed enhancement CMR MI extent was stable over time and agreed well with SPECT within an average difference of 3% of the LV myocardium. Contrast-enhanced–MRI under standardized conditions can accurately assess myocardial infarct size in vivo and may be attractive for serving as a surrogate end point early after AMI.

Already widely appreciated as clinically useful in assessment of patients with MI, CMR is emerging as a useful tool for assessing a variety of other cardiac conditions. As an example, a study by Abdel-Aty et al. (69) has shown that a combined approach with three CMR sequences (T2-weighted imaging [edema], early and late gadolinium enhancement) provides a high diagnostic accuracy and is a useful tool in the diagnosis and assessment of patients with suspected acute myocarditis. In 25 patients with suspected acute myocarditis and 23 healthy control subjects, the best diagnostic performance was obtained when "any-two" of the three sequences were positive in the same patient yielding a 76% sensitivity, 95.5% specificity, and 85% diagnostic accuracy.

Cardiovascular magnetic resonance is an excellent tool for classifying heart failure patients with the presence or absence of underlying CAD. In patients with heart failure but without clinical suspicion of CAD, CMR might offer a valid alternative to coronary angiography for the detection of CAD. Soriano et al. (70) reported 71 patients with heart failure without history of MI, with neither Q waves nor clinical data suggesting CAD, undergoing both delayed enhancement-CMR and coronary angiography. Twenty-one patients in the angiographically proven CAD group (21 of 26, 81%) showed subendocardial and/or transmural enhancement, whereas only 4 of 45 (9%) in the unobstructed coronary arteries group had this finding (p < 0.001).

Cardiovascular magnetic resonance also has the potential to be effective in the noninvasive evaluation of human atherosclerotic plaques. With CMR, Yonemura et al. (71) investigated the effects of 20-mg versus 5-mg atorvastatin on thoracic and abdominal aortic plaques in 40 hypercholesterolemic patients who were randomized to receive either dose. Treatment effects were evaluated as changes in vessel wall thickness and vessel wall area of atherosclerotic lesions from baseline to 12 months of treatment as assessed by CMR. The 20-mg dose induced a greater low-density lipoprotein (LDL) cholesterol reduction than did the 5-mg dose (–47% vs. –34%, p < 0.001). Notably, the degree of plaque regression in thoracic aorta correlated with LDL cholesterol (r = 0.64) and CRP (r = 0.49) reductions. They concluded that one-year 20-mg atorvastatin treatment induced regression of thoracic aortic plaques with marked LDL cholesterol reduction and resulted in only retardation of plaque progression in abdominal aorta.

	Congenital heart disease

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David Sahn, MD.   Long-term results after primary one-stage repair of transposition of the great arteries and aortic arch obstruction
Two European groups reported on long-term results for the one-stage repair of transposition of the great arteries and aortic arch obstruction (72). All coronary patterns were dealt with, and in 97% of the cases, ventricular septal defect was repaired. The aortic arch was enlarged, both with a patch and autologous fixed pericardium in most patients. Nine hospital deaths occurred in the first 24 months. Ten-year survival was 76%, and 89% of those surviving required no other interventions. Re-coarctation occurred in 3 of the 29 survivors and was treated by catheter intervention. Complex coronary patterns associated with side by side great arteries in these patients and severe pulmonary hypertension were other risk factors. The results show that a primary one-stage repair of severe aortic arch obstruction in transposition is feasible and, especially for the operations being performed more than 15 years ago, the results are impressive.

Assessment late after the arterial switch operation for transposition of the great arteries
Simone et al. (73) looked for evidence of overt fibrocellular intimal thickening in twenty-two asymptomatic children who were enrolled a median of 8.6 years after an arterial switch procedure and operated at a median age of 47 days. Of the 22 children enrolled, 37 coronary arteries were studied by IVUS. Intimal index in percentage was a mean of 11.7% in the most narrowed segment and a mean of 5% for the osteal. Thirty percent of the arteries had moderate to severe vessel wall abnormalities and a 6.4% mean reduction in volume of the arteries. Intimal thickening was most often eccentric. Early findings of these coronary artery IVUS studies suggest a need to continue to follow this population of post arterial switch population for their fibrocellular intimal proliferation reaction and perhaps begin to consider CAD risk factor control strategies in this population.

A study in the same population looked at the vasomotor function of the epicardial coronary arteries in nineteen asymptomatic patients five to eight years after arterial switch using a Doppler flow wire during follow-up catheterization and coronary angiography (74). Coronary artery size did not differ between the two groups, but the diameter changes measured during nitroglycerin bolus were blunted in the post-arterial switch group. Also during acetylcholine administration, coronary flow reserve was lower in the arterial switch patients. The arterial switch group had larger coronary arteries and showed limited flow reserve as a function of less dilation.

Impact of re-coarctation after the Norwood operation on survival in the balloon angioplasty era
Another important surgical study followed re-coarctation patients after the Norwood procedure for hypoplastic left heart syndrome performed from 1986 through 2001 (75). Of the 954 patients who underwent Norwood, 633 survived more than 48 h. Re-coarctation occurred in 58%. The median age of suspected obstruction was of 6.6 months; 35 underwent balloon angioplasty for recurrent coarctation, thirty-one after the Norwood, and the other 4 after their completion of cavopulmonary anastomosis. Of the 35 balloon angioplasty, 32 yielded satisfactory results, reducing the residual grade into an average of 3.9 mm. Six patients had further recurrence and underwent re-dilation; freedom from re-obstruction was 79% one in five years after the angioplasty. The success rate for dealing with this not uncommon complication of the Norwood procedure suggests that the occurrence of obstruction at the aortic arch is common in the first year and can be dealt with adequately by balloon angioplasty.

Resynchronization therapy in pediatric and congenital heart disease patients: an international multicenter study
The important area of resynchronization treatment for patients manifesting heart failure was studied by Dubin et al. (76). A total of 103 patients were reviewed who were either <21 years of age or who had congenital heart disease. At 4.5 months of follow-up, mean QRS duration in these patients decreased from 166 to 124 ms and ejection fraction increased by a mean of 13% to 40 ± 15%. There was no relationship between ejection fraction and QRS duration and ejection fraction improvement. The congenital heart disease group responded as well as the cardiomyopathy patients. There were two adverse events. In this study, pronounced hemodynamic benefit as well as favorable electrical and mechanical changes in heart function were found in this diverse group, most of whom underwent resynchronization for congenital heart disease. It is a very different substrate from the adult population, and more organized prospective studies are to be very much anticipated.

Detection of LV asynchrony in patients with right bundle branch block after repair of tetralogy of Fallot using tissue Doppler imaging derived strain
Tissue Doppler imaging derived strain was used to study LV contraction in 25 patients who had undergone tetralogy of Fallot repair and, as a result of surgery, had right bundle branch block (77). In tetralogy patients, the strain was statistically lower than in the normal patients in all of the LV segments, and the peak strain was most significantly delayed in the mid-septal segment. The study conclusion is that LV asynchrony in patients with tetralogy of Fallot and right bundle branch block is associated with decreased global measures of LV function.

Effects of long-term bosentan in children with pulmonary arterial hypertension
An important long-term study of bosentan in congenital heart patients was published (78). Data on Bosentan therapy in children before this study were extremely limited. This was an open label study involving 19 children with the safety and efficacy compared with adult patients from recent studies. In 12 to 25 months, 36 patients improved by at least one class, 5 by two functional classes, 34 patients remained in the same functional class, and 8 worsened. The improvement was more pronounced for those who started bosentan without a concomitant prostanoid therapy. Fatigue led to discontinuation of bosentan in 2 patients and there were (asymptomatic) increases in liver transaminases in 10 patients. The data suggest that an oral endothelin receptor antagonist with or without prostanoid therapy can be safe and efficacious in pulmonary artery hypertension in children. An accompanying editorial by Ian Adatia (79) concludes that these results show the effect of bosentan when administered to children in a dedicated pulmonary hypertension center but questions whether this can be reproduced in centers that are less organized and experienced.

Long-term outcome of transcatheter secundum-type ASD closure using Amplatzer septal occluders
Long-term follow-up of secundum ASDs closed with Amplatzer septal occluders was reported from Masura et al. (80) in 151 patients. There were no deaths, perforations, embolizations, or malposition thrombus formation or significant arrhythmias in the follow-up period ranging from 56 to 108 months. Thirty-one patients had immediately detectable shunts on transesophageal color Doppler echocardiography, of which 7 remained at one month. There was no evidence of encroachment on mitral or tricuspid valves, pulmonary veins, or coronary sinus. All patients were maintained on the infective endocarditis prophylaxis for six months and aspirin 5 mg/kg/day. The group chosen to go to the cath lab was selected from 190 patients consecutively found to have secundum ASD and therefore implantation was successful in 79% of the ASD patients encountered during this period. The authors stress precise selection of patients, based on ASD size compared with devices available as well as attention to detail and the use of transesophageal echocardiography during implantation.

	Anterior MI

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Ori Ben-Yehuda, MD.   Whereas data support the superiority of primary PCI over thrombolytic therapy for ST-segment elevation MI, the past year has seen a renewed emphasis on reducing door to balloon times. A pivotal study by Bradley et al. (81) examined how 11 top-performing hospitals (based on data from the National Registry of Myocardial Infarction) achieved door to balloon times of <90 min over a four-year period. They identified pre-hospital ECG performed by paramedics in the field (allowing emergency physicians to activate the catheterization laboratory) as well as collaboration between different departments in the hospital as pivotal to the success of top-performing hospitals. Once patients with AMI are admitted, new data show the continued implementation of guideline-based standardized care can help ensure better outcome. The American College of Cardiology’s own Guidelines Applied in Practice projects in Michigan demonstrated (82) that embedding AMI guidelines reduced mortality compared with historical controls by 21% to 26% even after multivariate adjustment. This remarkable benefit extended to 30-day and 1-year data.

A particularly vexing problem has been the patient with AMI complicated by cardiogenic shock, with historical mortality rates of 60% to 70%. Although the SHOCK (SHould we emergently revascularize Occluded Coronaries for cardiogenic Shock) trial demonstrated a reduction in mortality to 51% at three months with revascularization, it remained unclear whether the quality of life of survivors was adequate. Sleeper et al (83) conducted interviews with surviving SHOCK study patients. They demonstrated that, whereas survival at one year with emergency revascularization was only 46%, close to 90% of patients were in New York Heart Association (NYHA) functional class I or II and emergency revascularization patients had less functional deterioration than patients assigned to medical stabilization. The findings emphasize the importance of early revascularization to improve not only mortality but also quality of life (84).

Whereas the aforementioned studies presented data up to one year after the event, the passing of several decades since the institution of modern reperfusion therapy has allowed Domburg et al. (85) to present 20-year follow-up data on 533 patients enrolled from 1981 to 1985 in a study of reperfusion (intracoronary streptokinase with some patients also receiving intravenous streptokinase and/or angioplasty for severe residual stenosis) versus conventional treatment. The authors demonstrated significant long-term survival advantage to reperfusion therapy with the cumulative 10-, 15-, and 20-year survival being 69%, 48%, and 37%, respectively, for the reperfusion group compared with 59%, 38%, and 27% for the conventional therapy group.

Metabolic syndrome
The metabolic syndrome continued to be a focus of multiple studies. With the obesity and diabetes epidemic now extending into an ever younger age group, an important question is whether the presence of the metabolic syndrome in young adults is also associated with increased atherosclerosis. Tzou et al. (86) reported data from the Bogalusa Heart Study, a study of atherosclerosis in the young. With ultrasound carotid intima-media thickness measurements, the authors showed that among asymptomatic subjects the presence of the metabolic syndrome (defined either by the National Cholesterol Education Program Adult Treatment Panel III or the World Health Organization criteria) predicted composite carotid intima-media thickness in the upper quartile. Moreover, the higher the number of components of the metabolic syndrome, the higher the composite carotid intima-media thickness (r = 0.997, p_trend < 0.001).

How common is the metabolic syndrome in patients with MI? Does the influence of the metabolic syndrome extend to the post-MI period? With data from the GISSI-Prevenzione trial from Italy, Levantesi et al. (87) examined the effects of the metabolic syndrome in 11,323 patients with prior MI enrolled in the trail. They found that 29% met criteria for the metabolic syndrome. Death and cardiovascular events were more common in the patients with metabolic syndrome, with a 29% and 23% increased risk, respectively.

Inflammation and CAD
Inflammation and inflammatory markers, particularly CRP, continued to be the subject of many reports this year in the Journal. Inflammation plays a role in the pathogenesis of the atherosclerotic plaque but also in plaque rupture (i.e., in the pathogenesis of ACS). While previous studies documenting increased inflammatory markers from the non-infarct coronary arteries suggest that inflammation in ACS is a diffuse process, direct histopathological data has been lacking. Mauriello et al. (88), with multiple coronary artery segments from autopsy specimens of 16 patients with AMI, 5 patients with stable angina, and 9 patients without cardiac cause of death, divided plaques into culprit lesions, vulnerable plaques, and stable plaques, using the American Heart Association atherosclerosis classification. They found an average of 6.8 ± 0.5 vulnerable plaques per patient in the AMI group compared with an average of 0.8 ± 0.3 and 1.4 ± 0.3 in the stable angina group and noncardiac patients, respectively. Moreover, on immunohistochemical staining, the AMI group showed more inflammatory infiltrates not only in the culprit lesion and the vulnerable plaques but also in the stable plaques. In the same issue, Tanaka et al. (89) reported on IVUS evidence of multiple plaque rupture. They studied 45 infarct-related and 84 non–infarct-related arteries in 45 patients with first AMI. Intravascular ultrasound detected an additional 17 plaque ruptures in 11 patients (24%). Moreover, high sensitivity (hs)-CRP levels correlated with the number of plaque ruptures. The results of these studies highlight the importance of systemic therapies (such as lipid lowering) aimed at plaque stabilization in patients with AMI, a point emphasized in an accompanying editorial by Peter Libby (90).

What happens to ruptured plaques that are not the culprit lesions in ACS? With coronary angioscopy, Takano et al. (1) followed 50 such plaques in 30 patients over 13 ± 9 months. They demonstrated slow healing (23% at 1 year) with increasing stenosis. Interestingly, serum CRP levels were lower in patients with healed plaques. In another study, Inoue et al. (92) measured serum hs-CRP just proximal and distal to the culprit lesion. They thus demonstrated local release of CRP into the coronary circulation from vulnerable plaques. Moreover, they demonstrated a rise in the trans-coronary gradient of hs-CRP after stenting. If indeed CRP plays a direct role in plaque instability and the inflammatory reactions after stenting, it may end up being not only a marker of risk but a direct target of therapy.

Given the evidence that hs-CRP levels are of prognostic importance both for development of CAD and recurrence of events after MI, it is of interest to ascertain which therapies and which risk factors are associated with increased hs-CRP levels. In a Focus Issue dedicated to studies from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction (PROVE IT-TIMI) 22 trial, Ray et al. (93) reported on a cross-sectional study of 2,885 patients from the study who were evaluated four months after enrollment. They found the CRP levels were associated with increasing age, female gender, body mass index, smoking, persistent elevated LDL 70 mg/dl, glucose >110 mg/dl, low high-density lipoprotein, elevated triglycerides, and the intensity of statin therapy.

In the PROVE IT-TIMI 22 study, patients who achieved the lowest LDL levels (as well as the lowest CRP levels) had the lowest event rate. Is there any evidence of danger associated with low LDL levels? In another paper in the Focus Issue, Wiviott et al. (94) present very reassuring data for patients who lower LDL levels (patients were divided into groups with on-treatment LDL levels of <40, 40 to 60, 61 to 80, 81 to 100, and >100 mg/dl). Patients with the lowest LDL levels had the lowest event rates without any increase in muscle, liver, or retinal abnormalities. The authors conclude that in patients with ACS who achieve very low LDL levels, there is no need to lower the doses of the statins to elevate these very low LDL levels.

Aspirin and anti-platelet therapies
The issues surrounding aspirin, clopidogrel, and anti-platelet therapies continued to generate multiple submissions to the Journal. Ferrari et al. (95) in an Express Publication alerted us to the risk of withdrawing aspirin after stenting. Among 1,236 patients hospitalized with ACS, they identified 51 patients in whom aspirin withdrawal occurred within 30 days of ACS presentation. ST-segment elevation myocardial infarction was more common in these patients compared with the non–aspirin-withdrawal patients. Moreover, 20% of the aspirin-withdrawal ACS patients had stent thrombosis, and all of these were BMS patients with an average time since stenting of 15.5 ± 6.5 months.

Aspirin and clopidogrel resistance has emerged as an important topic in cardiovascular medicine. Given the widely varying estimates of aspirin resistance (and multiple tests used to assess resistance) the field is a controversial one. Tantry et al. (96), with assays that employ arachidonic acid as the agonist (aspirin inhibits the cyclooxygenase enzyme that acts on arachidonic acid to ultimately produce thromboxane A₂), found that among 223 patients compliant with aspirin, only 1 patient (0.4%) was resistant to aspirin therapy.

A similar situation exists with clopidogrel. Most studies have defined clopidogrel resistance as inadequate inhibition of adenosine diphosphate-induced platelet aggregation. Clopidogrel mainly blocks the P2Y12 receptor that is involved in stabilization of platelet aggregates. Labarthe et al. (97) therefore compared various platelet function tests in their ability to assess platelet aggregation stability. They demonstrated that when platelet aggregation stabilization was measured rather than platelet peak aggregation (a function of the P2Y1 receptor), most patients were identified as responders, especially when the test was performed in hirudin/PPACK (6% to 12% incidence of nonresponsiveness).

Further studies, particularly linking the various test results to clinical outcomes, will be necessary to fully solve the aspirin resistance and clopidogrel resistance controversies.

	Heart failure

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Barry H. Greenberg, MD.   One of the more vexing problems for clinicians is the management of mitral regurgitation in heart failure patients. Defining whether mitral regurgitation is the cause or consequence of heart failure is rarely straight-forward, and decisions about whether to attempt surgical correction are often difficult to make. There has been growing enthusiasm for performing mitral valve annuloplasty (MVA) for heart failure patients who are considered to have secondary mitral regurgitation based on reports that this procedure improves hemodynamics and symptoms; however, effects of MVA on survival are uncertain. In a report from the University of Michigan, which has been a strong proponent of MVA, Wu et al. (98) retrospectively analyzed the clinical course of a large cohort of consecutive patients with significant mitral regurgitation and LV systolic dysfunction who were treated at their institution. Of the 682 patients identified, 419 were considered to be surgical candidates, and of these, 126 underwent MVA. Overall, 41% non-MVA and 49% MVA patients reached a component of the composite end point of death, LV assist device implantation, or UNOS status 1-cardiac transplantation. With Cox regression analysis that included MVA as a time-dependent covariate and propensity scoring to adjust for differing probabilities of undergoing MVA, the investigators found that CAD (hazard ratio 1.80, blood urea nitrogen (hazard ratio 1.01), cancer (hazard ratio 2.77), and digoxin (hazard ratio 1.66) were associated with this composite end point. Angiotensin-converting enzyme inhibitors (hazard ratio 0.65), beta-blockers (hazard ratio 0.59), mean arterial pressure (hazard ratio 0.98), and serum sodium (hazard ratio 0.93) were all associated with a reduction in risk. Mitral valve annuloplasty failed to predict clinical outcome, a finding that led the investigators to conclude that there is no clearly demonstrable mortality benefit conferred by MVA for significant mitral regurgitation with severe LV dysfunction. In an accompanying editorial, Mehra and Griffith (99) raised the pivotal question of whether these results were a consequence of the lack of efficacy of the surgical approach or whether a different surgical approach is needed and whether annuloplasty alone is sufficient. They were in agreement with the investigators that this question was still unsettled and that it needs to be addressed by well-designed clinical trials assessing various surgical approaches.

An issue that is fundamental to surgical repair of the mitral valve in heart failure patients is whether or not the mitral valve in patients with severe LV dysfunction and secondary mitral regurgitation is structurally normal. To determine if this was the case, Grande-Allen et al. (100) assessed the pathology in what were considered to be normal mitral valves from 37 heart failure patients (23 dilated, 14 ischemic) who underwent cardiac transplantation. They found that these mitral valves had up to 78% more DNA (p < 0.03), 59% more glycosaminoglycans (p < 0.02), and 15% more collagen (p < 0.007) but 7% less water (p < 0.05) than normal. Derangements in biochemical measures were associated with the absence of anterior leaflet redundancy (p < 0.03), leaflet thickness and DNA concentration (+, p = 0.003), annular diameter and chordal collagen (+, p = 0.03), and water concentration and both left atrial diameter (–, p = 0.008) and LV collagen concentration (–, p = 0.04). The presence of the biochemical abnormalities in these mitral valves suggested that the extracellular matrix had been influenced by the altered cardiac dimensions and were not entirely functional in nature. The presence of structural changes such as those described in this study could provide an explanation for the failure of MVA annuloplasty alone to alter survival in heart failure patients with secondary mitral regurgitation.

Many patients with end stage renal disease develop heart failure associated with a reduced LV ejection fraction (LVEF). Wali et al. (101) assessed the effect of kidney transplantation on LVEF in end stage renal disease patients with heart failure. A total of 103 renal transplant recipients with LVEF 40% and evidence of heart failure underwent radionuclide ventriculography 12 months after transplant. Overall, mean ejection fraction increased from 31.6 ± 6.7% to 52.2 ± 12.0% (p = 0.002) at 12 months after transplantation. In nearly 70% of the patients, the ejection fraction had normalized after renal transplantation. A shorter duration of pre-transplant dialysis was a significant predictor of recovery of cardiac function. Moreover, after renal transplantation, an ejection fraction above 50% was the only significant factor associated with a lower risk of death or heart failure hospital stay. These results suggest that end-stage renal disease patients who develop the onset of heart failure due to LV systolic dysfunction should be counseled for kidney transplantation as soon as the diagnosis of systolic heart failure is established.

Although the mechanism(s) responsible for the recovery of cardiac function after renal transplant was not evaluated, Sheppard et al. (102) evaluated the role of apoptosis for predicting myocardial recovery in recent-onset cardiomyopathy. In a group of 20 patients with recent-onset heart failure, the mean LVEF improved from 0.28 at baseline to 0.40 after six months. Overall, these investigators found that the highest expression of genes associated with apoptosis (e.g., Fas and tumor necrosis factor receptor type 1) was associated with a reduced likelihood of recovery of cardiac function, suggesting that apoptosis limits myocardial recovery. Thus, apoptotic pathways represent potential therapeutic targets to help potentiate recovery of cardiac function in patients with recent-onset cardiomyopathy. Of interest is the fact that these findings could also relate to recovery of systolic function after renal transplantation where perhaps dialysis through as yet undefined pathways initiates apoptosis in cardiac myocytes.

An issue of great concern is the lack of support for heart failure programs within a medical system. Most hospitals use cross sectional accounting methods based on direct reimbursement fees, an approach favoring procedure-oriented specialties but failing to take into account the incremental revenues generated by the recruitment of heart failure patients to system. To address this issue, Gregory et al. (103) computed cumulative recurrent rates of utilization, cost, and reimbursement for hospital services as functions of time using reliability models in 82 heart failure patients referred for cardiac transplant evaluation at an academic medical center compared with those not transplanted. They found that mean hospital stays and outpatient encounters per patient at the end of the first year for those transplanted were 2.1 and 11.9, respectively, compared with 1.1 and 6.0 for those not transplanted. The mean revenue and direct cost per patient were $194,470 and $146,623, respectively, for transplanted patients and $43,587 and $33,424, respectively, for non-transplanted patients. Overall, the first-year contribution margins per patient were $47,847 for transplanted and $10,163 for non-transplanted patients. This analysis provides evidence that newly evaluated patients for cardiac transplantation generate substantial incident demands for inpatient and outpatient services over a two-year follow-up, regardless of whether transplant was performed.

	Electrophysiology

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Gregory K. Feld, MD.   The use of automatic implantable defibrillators (ICDs) for prevention of sudden death has increased dramatically in the past several years. The indications for implantation of ICDs have been tightly regulated however, including the requirement for a QRS duration >120 ms for reimbursement. Thus, a number of studies have been undertaken to determine the most robust predictors of risk for subsequent sudden or arrhythmic death to more precisely identify patients who will benefit from ICD implantation. Two such studies were published in the Journal in 2005. The first, published by Gehi et al. (104), was a meta-analysis of 19 studies involving 2,608 subjects who underwent microvolt T-wave alternans (MTWA) testing for exercise-induced MTWA. This analysis demonstrated that an abnormal MTWA test was associated with a significantly increased risk of developing subsequent ventricular arrhythmia events, with positive predictive value of 51% for a secondary event (in patients with a history of previous ventricular arrhythmia) and 15% for a primary event. Among patients evaluated for prediction of a primary event, in those with congestive heart failure an abnormal MTWA test had a positive predictive value of 20.9%, whereas in those who were post-MI an abnormal MTWA test had a positive predictive value of only 6.0%. Among those with ischemic or non-ischemic etiology of congestive heart failure, there was no difference in positive predictive value (29.7% vs. 21.3%). The negative predictive value was high in all populations studied (86% to 99.4%). Relative risk ranged from 2.51 to 4.74 across all groups. Indeterminate MTWA tests were included in the data in some studies but not others and did not provide a clear predictive value. They conclude that a positive MTWA test had significant predictive value for subsequent ventricular arrhythmic events, with a nearly four-fold relative risk compared with a negative test. The authors suggested that further study of the combined predictive value of several methods of risk stratification was warranted.

In the second study on risk stratification of patients for ICD implantation, Buxton et al. (105) retrospectively analyzed data from the PainFreeRx II study, a randomized, 12-month follow-up study comparing efficacy of anti-tachycardia pacing versus shock therapy for ventricular tachycardia/ventricular fibrillation in patients receiving ICDs. This sub-study consisted of 431 of the 634 patients who had CAD and a standard 12-lead ECG suitable for analysis. Approximately one-half had an ICD for primary prevention and the other half for secondary prevention, of whom 76% and 87%, respectively, had prior MI. The mean ejection fraction was 30% in both primary and secondary prevention groups. The principal finding was that during follow-up, neither the time to occurrence nor the frequency of arrhythmic events identified by ICD interrogation differed significantly between patients with a QRS duration < or >120 ms, independent of whether the indication was for primary or secondary arrhythmia prevention. Patients with left bundle branch block, despite QRS duration >120 ms, were actually less likely to experience arrhythmia than patients with QRS duration <120 ms (9% vs. 23%, p = 0.02). The authors did find, however, that total mortality was greater in patients with QRS duration >120 ms (15% vs. 9%, p = 0.047), although the cause of deaths was not determined in several cases. Furthermore, the overall positive predictive value of QRS duration for arrhythmic events gradually increased from 23% with QRS duration 80 ms to 50% with QRS duration 190 ms. Nonetheless, the authors concluded that there was no argument for basing ICD implantation on QRS duration of > or <120 ms, as is currently recommended by Medicare guidelines. The authors acknowledged several limitations of the study, including its retrospective nature, the short duration of follow-up, and lack of patients with advanced congestive heart failure, any of which could have affected study outcome.

Atrial fibrillation can cause stroke and congestive heart failure, is a major risk for mortality especially with congestive heart failure, and accounts for increasingly large national health care costs. In 2005, several articles of interest were published on the role of inflammation in development of AF and the role of angiotensin receptor blockers and beta receptor blockers in the prevention of AF. Malouf et al. (106) reported on their study of 67 patients with AF or atrial flutter undergoing cardioversion, in whom hs-CRP levels were measured just before cardioversion. Patients with recent infection, ACS, or surgery were excluded. Patients with successful cardioversion were then followed for up to one month for evidence of arrhythmia recurrence documented by ECG. They observed that arrhythmia recurrence was associated with a significantly higher CRP level (odds ratio 1.84, p = 0.013), even after adjusting for age, gender, and arrhythmia duration. On multivariate analysis, CRP level was the only independent predictor of AF or atrial flutter recurrence (odds ratio 2.19, p = 0.036). The authors concluded that inflammation was a risk factor for AF/atrial flutter and anti-inflammatory interventions may help maintain normal sinus rhythm after cardioversion.

An alternative, novel pharmacological approach to prevent AF was provided in a study by Wachtell et al. (107), who analyzed data from the Losartan Intervention for Endpoint reduction in hypertension (LIFE) study in a subset of 8,851 patients with hypertension and ECG-documented LV hypertrophy and no AF history. Patients were randomized to treatment with once-daily losartan versus atenolol-based antihypertensive therapy. After follow-up of up to a mean of 4.8 years, it was determined that losartan therapy was associated with a 33% lower rate of new-onset AF, as identified on annual in-study ECGs, independent of other risk factors determined by univariate analysis, including age, male gender, systolic blood pressure, and LV hypertrophy on ECG. Development of AF during this study was associated with significantly increased risk of cardiovascular events, fatal and non fatal stroke, and rate of hospital stay for congestive heart failure. The authors propose that the mechanism by which losartin prevents new-onset AF is by a reduction in LV hypertrophy, which was shown in previous LIFE sub-studies to be associated with increased left atrial size and risk of AF and stroke.

In another study of alternative pharmacological approaches to prevention of AF, McMurray et al. (108) reported data from a sub-study of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) study, in which 1,959 patients with reduced LV systolic function after AMI (98% of whom were treated with an angiotensin-converting enzyme inhibitor) were randomized to either placebo or carvedilol treatment 3 to 21 days after AMI. After an average of 1.3 years follow-up, the incidence of AF/atrial flutter and ventricular arrhythmias were determined by review of reported adverse events, however without ECG documentation. The authors noted a significantly lower reported incidence of AF/atrial flutter in the carvedilol-treated group compared with the placebo treatment group (2.3% vs. 5.4%, p = 0.0003). The authors concluded from this study that beta-blocker therapy may play a significant role, in addition to angiotensin-converting enzyme inhibitor therapy, in prevention of AF/atrial flutter after AMI.

Radiofrequency catheter ablation has been extensively studied recently as a minimally invasive curative treatment of AF; however, there is controversy over the most effective and safest ablation techniques. Because pulmonary vein isolation (PVI) may be associated with PVI stenosis, alternative methods have been proposed and tested, including the so-called left atrial linear ablation and left atrial circumferential ablation techniques. The original basis for such an approach was provided by Cox et al. (109) in their description of the first surgical operation called the MAZE procedure, wherein the right and left atrium were surgically compartmentalized into areas too small to sustain AF. In 2005, there appeared two reports in the Journal that raised a somewhat controversial notion that linear left atrial ablation alone, without necessarily isolating the pulmonary veins, could prevent recurrence of AF.

In the first report, Tanner et al. (110) demonstrated in a population of 129 patients undergoing intra-operative left atrial linear ablation, that after 3.6 ± 0.4 years follow-up, seven-day continuous ECG monitoring in 30 patients revealed the occurrence of atrial ectopic beats in all patients and atrial runs in 83% of patients but AF in only 13% of patients. The authors concluded that elimination of the triggers of AF, which predominately arise from the pulmonary veins, was not essential for prevention of AF but could also be accomplished by elimination of the reentrant substrate required for maintenance of AF.

In a similar approach, Lemola et al. (111) studied 60 consecutive patients with paroxysmal (39 patients) or chronic (21 patients) AF and performed percutaneous left atrial circumferential ablation with radiofrequency energy. The ablation lesions included encircling lesions around the right and left pulmonary veins, a line between the circles, and a line from the mitral valve annulus to the left circle. After left atrial linear ablation, pulmonary vein conduction was assessed to determine the percentage of pulmonary veins isolated by the linear ablation technique. After left atrial circumferential ablation, in 48 (80%) patients one or more pulmonary veins remained electrically connected to the left atrium. Despite this, at 11 ± 1 months follow-up there was no difference in the recurrence rate of AF, with 10 of 12 (83%) with complete PVI and 39 of 48 (81%) with incomplete PVI free of AF. Freedom from AF was not related to the number of pulmonary veins isolated either. The principal drawback of left atrial circumferential ablation is the occurrence of left atrial flutter, with reentry through gaps in the line, in 17% of patients, independent of PVI. Many left atrial flutters require repeat ablation. The authors of this study also concluded that PVI may not be necessary to prevent recurrence of AF but that left atria linear ablation modifies the substrate responsible for maintaining AF, thus preventing its recurrence. It is not clear from these studies whether a combination of left atrial linear ablation plus PVI will provide better long-term suppression of AF, as these studies were not prospective and randomized.

Ventricular arrhythmias in the absence of structural heart disease have generally been considered benign. Two recent reports in the Journal however, have brought to light a more malignant potential for some idiopathic ventricular arrhythmias. In a study by Noda et al. (112), 16 patients with a history of spontaneous ventricular fibrillation and/or polymorphic ventricular tachycardia initiated by ventricular ectopy with a left bundle branch block morphology and inferior axis consistent with a right ventricular outflow tract origin were evaluated among an overall population of 101 patients in whom radiofrequency catheter ablation was being performed for idiopathic RVOT tachycardia. The authors found that 5 patients presented with spontaneous ventricular fibrillation and 11 had prior syncopal episodes. Ambulatory ECG recordings revealed frequent isolated ventricular extrasystoles with a morphology similar to those initiating ventricular fibrillation or polymorphic ventricular tachycardia. The history of syncope was higher in patients with ventricular fibrillation/polymorphic ventricular tachycardia, the QRS duration of the ventricular ectopic beats was longer, and the cycle length of tachycardias was shorter. Ablation of the origin of the triggering foci in the RVOT eliminated syncopal episodes and ventricular fibrillation episodes in all 16 patients over a mean follow-up of 54 ± 39 months. The authors concluded that not all idiopathic ventricular ectopy is benign, but that in a small percentage of patients with ventricular fibrillation/polymorphic ventricular tachycardia, an idiopathic focus may be the trigger and can be cured by radiofrequency catheter ablation. This is a novel and unexpected observation that expands our knowledge of this syndrome.

In another study of patients with idiopathic ventricular ectopy of RVOT origin, Takemoto et al. (113) demonstrated that a small percentage of patients developed unexpected LV dysfunction. They observed 45 consecutive patients who underwent radiofrequency catheter ablation for frequent monomorphic premature ventricular contractions originating from the RVOT. These patients underwent echocardiographic evaluation and ambulatory ECG monitoring at baseline, one day, and 6 or 12 months after radiofrequency catheter ablation. The patients were grouped by percent premature ventricular contractions (<10%, 10% to 20%, >20% of total beats); LVEF, LV end-diastolic and end-systolic dimensions, and NYHA functional class were evaluated for each of these subgroups. The authors found a significant correlation between percent premature ventricular contractions and LVEF (r = 0.56, p = 0.0002) and a significantly lower LVEF and higher LV end-diastolic and end-systolic dimensions and NYHA functional class (p < 0.05) in patients with >20% premature ventricular contractions. The LVEF, LV end-systolic and end-diastolic dimensions, and NYHA functional lass were also noted to normalize after successful radiofrequency catheter ablation but continued to deteriorate in those with unsuccessful ablation. The authors concluded that idiopathic RVOT ectopy, generally considered benign, may be associated with significant ventricular dysfunction and symptoms that could ultimately to heart failure in some patients. This is a finding that physicians should be aware of when evaluating a patient with heart failure, because it may be a curable cause.

Finally, bi-ventricular pacing or cardiac resynchronization therapy has become an important intervention in patients with refractory congestive heart failure. Whereas there are many controversial issues in biventricular pacing, the role of atrial pacing has received less attention. One article published in the Journal in 2005 addressed the issue of atrial pacing site with optimal atrioventricular delay. In a report by Bernheim et al. (114), 17 patients who underwent cardiac resynchronization therapy were studied a mean of 10 months (1 to 46 months) after implantation to determine the effects of right atrial pacing with the dual-chamber mode compared with no atrial pacing in the single-chamber mode. After optimizing atrioventricular delay by timing LV contraction properly at the end of atrial contraction, the acute hemodynamic effects were assessed by Doppler echocardiography. The authors demonstrated that single-chamber mode pacing improved intra-ventricular dyssynchrony measured by septal-to-posterior wall motion delay (single-chamber mode 106 ± 83 ms vs. dual-chamber mode 145 ± 95 m, p = 0.001), whereas inter-ventricular mechanical delay was not different. In addition, single-chamber mode pacing significantly prolonged rate-corrected LV filling period (single-chamber mode 458 ± 123 ms vs. dual-chamber mode 371 ± 94 ms, p = 0.001) and improved myocardial performance index (single-chamber mode 0.60 ± 0.18 vs. dual-chamber mode 0.71 ± 0.23, p < 0.01). The authors concluded that avoidance of right atrial pacing results in better LV resynchronization and hemodynamic improvement and thus the single-chamber mode seems superior to dual-chamber mode pacing in patients undergoing cardiac resynchronization therapy.

	General cardiology research

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Wilbur Y. W. Lew, MD.   Erythropoietin (EPO), the hematopoietic cytokine that regulates erythropoiesis, has been shown in recent preclinical studies to reduce injury from myocardial ischemia-reperfusion. It is unknown if this novel cardioprotective effect of EPO occurs in humans. Namiuchi et al. (115) studied 101 patients who had successful PCI within 12 h of their first AMI. Patients with high versus low serum EPO levels (above vs. below median values, respectively) had smaller infarcts as measured by peak creatine kinase levels and cumulative creatine kinase release. Serum EPO, along with preinfarction angina and TIMI flow grade 2 after PCI were identified as independent predictors of cumulative creatine kinase release in a stepwise multiple regression analysis. Although preinfarction angina was more common in the high EPO group and was associated with smaller infarct size (a potential confounding factor), serum EPO level was also an independent predictor of cumulative creatine kinase release in patients without preinfarction angina. This study does not distinguish whether elevated endogenous EPO reduced infarct size owing to cardioprotective effects or whether this association merely represents an epiphenomenon; however, these results set the stage for future clinical studies to determine whether EPO has cardioprotective effects that may be useful for treating patients with ischemic heart disease.

Statins reduce infarct size after ischemia-reperfusion, which has been attributed to the pleiotropic effect of activation of phosphatidylinositol-3 kinase (PI3K) /Akt, a cell survival signaling pathway. Mensah et al. (116) used a rat model to demonstrate that one or three days of 20 mg/kg atorvastatin before ischemia-reperfusion reduced infarct size, but this protective effect was lost after one or two weeks of pretreatment. Chronic atorvastatin treatment increased PTEN (phosphatase and tensin homolog deleted on chromosome 10), a major inhibitor of PI3K; however, the loss of cardioprotection with chronic therapy could be recovered by acute treatment with 40 mg/kg of atorvastatin. This is clinically relevant because many patients who would benefit from the cardioprotective effects of statins are likely to be already receiving chronic statin therapy. Schulz (117), in an accompanying editorial comment, discusses the cell signaling pathways that are differentially activated by acute versus chronic statin therapy and how their interaction determines whether or not there is cardioprotection. There is evidence that statins reduce infarct size in patients, but some of the benefits may be related to a reduction in plaque volume and/or plaque stabilization that decreases the extent of coronary microembolization. Future clinical studies are needed to determine if patients on chronic statin therapy will benefit from acute statin therapy.

Endothelial progenitor cells (EPC) have been postulated to repair vascular injuries to prevent endothelial dysfunction and the progression of atherosclerosis. Two studies in the Journalexamine whether EPC are altered in conditions associated with endothelial dysfunction and vascular disease. In the first study, Heiss et al. (118) compared 20 young with 20 older (average age 20 and 61 years, respectively) healthy individuals without cardiovascular risk factors. There was no difference in the number of circulating EPC, but the older group had diminished EPC function (measured by in vitro survival, migration, and proliferation) in association with impaired brachial artery endothelium-dependent flow-mediated dilation. Endothelial progenitor cell proliferation and migration were independent predictors of flow-mediated dilation. This suggests that endothelial dysfunction with aging may be related to reduced EPC function.

In the second study, with 51 subjects, Fadini (119) found a 40% to 50% reduction in circulating EPC levels in patients with peripheral vascular disease or type 2 diabetes mellitus compared with a healthy control group. The EPC levels were even lower in patients with both diseases. The authors hypothesized that vascular disease in diabetes mellitus may be related to a reduction in EPC.

Goldschmidt-Clermont et al. (120) in an accompanying editorial comment, review the evidence that bone marrow derived EPC are recruited to repair arterial injuries; this concept has caused a paradigm shift in vascular biology. They propose that the inflammatory factors, cytokines, and growth factors that recruit EPC can exacerbate arterial damage and cause progression of atherosclerosis when the EPC response is inadequate, such as with a senescent bone marrow. Current methodological limitations in identifying EPC from surface markers makes it difficult to interpret studies with disparate methods and difficult to discern how cells with specific markers function in the arterial repair process; however, there are rapid technological breakthroughs in this nascent field that may lead to novel therapeutic approaches that target EPC. This may have an impact on the approach to common clinical cardiovascular conditions (e.g., aging, diabetes mellitus, and vascular disease), as suggested by the studies in this Journal.

	Preclinical research

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Geoffrey S. Ginsburg, MD, PhD.   Stem cell therapy and paracrine factors
Encouraging results from both animal and human studies suggest that stem cell therapy may be a viable means of myocardial repair after MI. One potential major limitation of this strategy is the viability of the transplanted cells. Genetically engineering stem cells before implantation has been explored as an option to enhance their survival, proliferative capacity, and function. Tang et al. (121) engineered adult bone marrow derived mesenchymal stem cells with the heme oxygenase 1 (HO-1) gene, a gene whose product is known to have cardioprotective properties via its antioxidant properties preventing heme from causing oxidative injury, inflammation, and apoptosis. These cells were injected into mice one h after MI; their survival was enhanced five-fold at seven days, and myocardial function and remodeling was enhanced at two weeks compared with animals that received non-modified mesenchymal stem cells. This study not only has evolved the methods for effective myocardial regeneration and repair, it lends support to a growing body of evidence that paracrine factors (e.g., HO-1) from mesenchymal stem cells may be in part responsible for the reparative process.

Diabetes and angiogenesis
Type II diabetic patients suffer a number of abnormalities of angiogenesis, including enhanced vessel growth in the retina and the walls of atherosclerotic blood vessels, possibly leading to plaque destabilization. The hearts of diabetic patients with chronic coronary heart disease exhibit decreased collateral circulation; however, paradoxically circulating levels of vascular endothelial growth factor are increased. Sasso et al. (122) examined the expression and function of vascular endothelial growth factor in diabetic and non-diabetic patients undergoing coronary artery bypass surgery and found that vascular endothelial growth factor levels in the myocardium of diabetic patients was significantly increased whilst the expression levels of vascular endothelial growth factor receptors (Flt-1 and Flk-1) were decreased. Moreover, activation signaling downstream of the vascular endothelial growth factor receptors was markedly reduced, as were a number of downstream effectors, such as endothelial nitric oxide synthase. Thus, this report provides key data that begin to explain the seemingly paradoxical augmented vascular endothelial growth factor levels and pro-angiogenic effects in some tissues but the defective signaling and reduced angiogenesis in the myocardium. Moreover, it focuses the therapeutic direction into the cell and perhaps at specific pathway targets for the treatment of diabetic patients with chronic cardiovascular disease.

EPO and neovascularization
A number of cytokine growth factors are being investigated for their salutary myocardial effects. Erythropoietin has been long known to be expressed both inside and outside the hematopoietic system, including in endothelial cells and cardiomyocytes. Van der Meer et al. (123) studied the role of early, early and late, and late erythropoietin treatment of rats with and without MI. The results revealed a striking reduction in infarct size and improvement in myocardial function in rats treated early and salutary effects on LV performance in animals treated late. Possible mechanisms include a reduction in cardiomyocyte loss due to EPO’s anti-apoptotic effects as well as an increase in myocardial capillary density and an increased capillary-to-myocyte ratio that was more pronounced in the EPO-treated animals. Thus, this study is among the first to have shown a pronounced and significant salutary effect of EPO on the myocardium after infarction and suggests that further studies of EPO are warranted.

Chocolate, flavonoids, and endothelial dysfunction
Is it possible that chocolate might acutely reverse some of the noxious cardiovascular effects of smoking? It is well known that cigarette smoking causes a decrease in the bioactive nitric oxide (NO) in plasma and that this is associated with endothelial dysfunction as measured by flow mediated dilation. Some studies have suggested that diets rich in flavonol might increase bioactive NO in plasma. Heiss et al. (124) studied the effects of a flavonol-rich cocoa preparation on the circulating plasma NO and flow-mediated dilation in smokers and showed a dose response between flavonol content and acute increase in circulating NO and flow-mediated dilation after oral ingestion of the cocoa drink. Thus, there may be some health benefits of flavonol-rich foods such as cocoa (91).

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