Background

Although the release of cardiac biomarkers after percutaneous (PCI) or surgical revascularization (CABG) is common, its prognostic significance is not known. Questions remain about the mechanisms and degree of correlation between the release, the volume of myocardial tissue loss, and the long-term significance. Delayed-enhancement of cardiac magnetic resonance (CMR) consistently quantifies areas of irreversible myocardial injury. To investigate the quantitative relationship between irreversible injury and cardiac biomarkers, we will evaluate the extent of irreversible injury in patients undergoing PCI and CABG and relate it to postprocedural modifications in cardiac biomarkers and long-term prognosis.

Methods/Design

The study will include 150 patients with multivessel coronary artery disease (CAD) with left ventricle ejection fraction (LVEF) and a formal indication for CABG; 50 patients will undergo CABG with cardiopulmonary bypass (CPB); 50 patients with the same arterial and ventricular condition indicated for myocardial revascularization will undergo CABG without CPB; and another 50 patients with CAD and preserved ventricular function will undergo PCI using stents. All patients will undergo CMR before and after surgery or PCI. We will also evaluate the release of cardiac markers of necrosis immediately before and after each procedure. Primary outcome considered is overall death in a 5-year follow-up. Secondary outcomes are levels of CK-MB isoenzyme and I-Troponin in association with presence of myocardial fibrosis and systolic left ventricle dysfunction assessed by CMR.

Discussion

The MASS-V Trial aims to establish reliable values for parameters of enzyme markers of myocardial necrosis in the absence of manifest myocardial infarction after mechanical interventions. The establishments of these indices have diagnostic value and clinical prognosis and therefore require relevant and different therapeutic measures. In daily practice, the inappropriate use of these necrosis markers has led to misdiagnosis and therefore wrong treatment. The appearance of a more sensitive tool such as CMR provides an unprecedented diagnostic accuracy of myocardial damage when correlated with necrosis enzyme markers. We aim to correlate laboratory data with imaging, thereby establishing more refined data on the presence or absence of irreversible myocardial injury after the procedure, either percutaneous or surgical, and this, with or without the use of cardiopulmonary bypass.

Coronary artery disease (CAD) is the single most common cause of death in the developed world, responsible for about 1 in every 5 deaths. The morbidity, mortality, and socioeconomic importance of this disease make timely accurate diagnosis and cost-effective management of CAD of the utmost importance. This comprehensive review of the literature highlights key elements in the diagnosis, risk stratification, and management strategies of patients with chronic CAD. Relevant articles were identified by searching the PubMed database for the following terms: chronic coronary artery disease or stable angina. Novel imaging modalities, pharmacological treatment, and invasive (percutaneous and surgical) interventions have revolutionized the current treatment of patients with chronic CAD. Medical treatment remains the cornerstone of management, but revascularization continues to play an important role. In the current economic climate and with health care reform very much on the horizon, the issue of appropriate use of revascularization is important, and the indications for revascularization, in addition to the relative benefits and risks of a percutaneous vs a surgical approach, are discussed.

Atrial fibrillation (AF) is a common disorder that significantly impacts the lives of affected patients. The restoration of sinus rhythm may prevent AF progression and reduce the occurrence of negative sequelae; however, available antiarrhythmic drugs (AADs) have largely failed to demonstrate significant benefit relative to rate control with respect to morbidity and mortality outcomes. The review commentary will address current knowledge regarding the pathologic mechanisms of AF, current trials that investigate rate and rhythm strategies, and future therapies that may change treatment approaches based on preliminary evidence suggesting a more favorable safety profile. The observed outcomes are likely a reflection of the limited efficacy plus poor safety and tolerability of available AADS. However, data from patients who attained and maintained sinus rhythm in a number of clinical studies demonstrate that the achievement of normal sinus rhythm can indeed reduce AF-associated morbidity and mortality. Furthermore, the results of trials designed to assess specific morbidity and mortality outcomes such as cardiovascular death hospitalization suggest that the development of safer AF therapies, whether pharmacologic or nonpharmacologic, can potentially improve clinical outcomes.

From bone marrow transplants 5 decades ago to the most recent stem cell—derived organ transplants, regenerative medicine is increasingly recognized as an emerging core component of modern practice. In cardiovascular medicine, innovation in stem cell biology has created curative solutions for the treatment of both ischemic and nonischemic cardiomyopathy. Multiple cell-based platforms have been developed, harnessing the regenerative potential of various natural and bioengineered sources. Clinical experience from the first 1000 patients (approximately) who have received stem cell therapy worldwide indicates a favorable safety profile with modest improvement in cardiac function and structural remodeling in the setting of acute myocardial infarction or chronic heart failure. Further investigation is required before early adoption and is ongoing. Broader application in practice will require continuous scientific advances to match each patient with the most effective reparative phenotype, while ensuring optimal cell delivery, dosing, and timing of intervention. An interdisciplinary effort across the scientific and clinical community within academia, biotechnology, and government will drive the successful realization of this next generation of therapeutic agents for the “broken” heart.

OBJECTIVE: To determine whether ethnic-specific differences in the prevalence of cardiovascular risk factors and outcomes exist worldwide among individuals with stable arterial disease.

PATIENTS AND METHODS: From December 1, 2003, to June 30, 2004, the prospective, observational REduction of Atherothrombosis for Continued Health (REACH) Registry enrolled 49,602 out-patients with coronary artery disease, cerebrovascular disease, and/or peripheral arterial disease from 7 predefined ethnic/racial groups: white, Hispanic, East Asian, South Asian, Other Asian, black, and Other (comprising any race distinct from those specified). The baseline demographic and risk factor profiles, medication use, and 2-year cardiovascular outcomes were assessed among these groups.

RESULTS: The prevalence of traditional atherothrombotic risk factors varied significantly among the ethnic/racial groups. The use of medical therapies to reduce risk was comparable among all groups. At 2-year follow-up, the rate of cardiovascular death was significantly higher in blacks (6.1%) compared with all other ethnic/racial groups (3.9%; P=.01). Cardiovascular death rates were significantly lower in all 3 Asian ethnic/racial groups (overall, 2.1%) compared with the other groups (4.5%; P<.001).

CONCLUSION: The REACH Registry, a large international study of individuals with atherothrombotic disease, documents the important ethnic-specific differences in cardiovascular risk factors and variations in cardiovascular mortality that currently exist worldwide.

Background

Between 30% and 60% of clinical cases of hypertrophic cardiomyopathy (HC) can be attributed to mutations in the genes encoding cardiac myofilament proteins. Interestingly, it appears that the likelihood of an underlying myofilament mutation can be predicted by echocardiographic assessment of left ventricular morphology. However, it is not known whether genotypically characterized HC exists as a separate entity with discrete phenotypic morphology and histology or to what extent recognized polymorphisms of the renin-angiotensin-aldosterone system (RAAS) influence this relationship. The presence of cardiac myofilament and mutations and RAAS polymorphisms will have a strong association with the severity of histologic features of HC and characteristic septal shape.

Methods

We conducted a retrospective review of histology specimens, obtained at septal myectomy among 181 patients with medically refractory symptomatic HC. All patients underwent comprehensive genetic analysis for mutations in 8 myofilament-encoding genes; a subset was genotyped for 6 known RAAS-polymorphisms. Patients underwent comprehensive echocardiography by an expert blinded to genotype and microscopic status.

Results

Microscopically, severity of myocyte hypertrophy appears to be associated with the presence of recognized HC cardiac myofilament mutations (P = .03). Other histologic features characteristic of HC were not consistently associated with myofilament mutation status. A higher burden of pro-LVH RAAS polymorphisms also appeared to predict only myocyte hypertrophy (P = .01). The presence of RAAS polymorphisms was not associated with the development of a specific septal morphology (P = .6).

Conclusion

Myofilament-positive HC does not appear to represent a distinct clinical phenotypic entity as evidenced by specific histologic characteristics and septal shape.

BACKGROUND

In most patients with stable coronary artery disease, plasma cardiac troponin T levels are below the limit of detection for the conventional assay. The distribution and determinants of very low circulating troponin T levels, as well as their association with cardiovascular events, in such patients are unknown.

METHODS

We used a new, high-sensitivity assay to determine the concentration of cardiac troponin T in plasma samples from 3679 patients with stable coronary artery disease and preserved left ventricular function. Results of the assay were analyzed in relation to the incidence of cardiovascular events during a median follow-up period of 5.2 years.

RESULTS

With the highly sensitive assay, concentrations of cardiac troponin T were at or above the limit of detection (0.001 μg per liter) in 3593 patients (97.7%) and at or above the 99th percentile for apparently healthy subjects (0.0133 μg per liter) in 407 patients (11.1%). After adjustment for other independent prognostic indicators, there was a strong and graded increase in the cumulative incidence of cardiovascular death (adjusted hazard ratio per unit increase in the natural logarithm of the troponin T level, 2.09; 95% confidence interval [CI], 1.60 to 2.74; P<0.001) and of heart failure (adjusted hazard ratio, 2.20; 95% CI, 1.66 to 2.90; P<0.001) in this study group. Increased risk associated with higher levels of troponin T was evident well below the limit of detection of conventional cardiac troponin T assays and below the 99th percentile of values in a healthy population. There was no association between troponin T levels as measured with the highly sensitive assay and the incidence of myocardial infarction (adjusted hazard ratio, 1.16; 95% CI, 0.97 to 1.40; P = 0.11).

CONCLUSIONS

After adjustment for other independent prognostic indicators, cardiac troponin T concentrations as measured with a highly sensitive assay were significantly associated with the incidence of cardiovascular death and heart failure but not with myocardial infarction in patients with stable coronary artery disease.

Background

The MASS IV-DM Trial is a large project from a single institution, the Heart Institute (InCor), University of São Paulo Medical School, Brazil to study ventricular function and coronary arteries in patients with type 2 diabetes mellitus.

Methods/Design

The study will enroll 600 patients with type 2 diabetes who have angiographically normal ventricular function and coronary arteries. The goal of the MASS IV-DM Trial is to achieve a long-term evaluation of the development of coronary atherosclerosis by using angiograms and coronary-artery calcium scan by electron-beam computed tomography at baseline and after 5 years of follow-up. In addition, the incidence of major cardiovascular events, the dysfunction of various organs involved in this disease, particularly microalbuminuria and renal function, will be analyzed through clinical evaluation. In addition, an effort will be made to investigate in depth the presence of major cardiovascular risk factors, especially the biochemical profile, metabolic syndrome inflammatory activity, oxidative stress, endothelial function, prothrombotic factors, and profibrinolytic and platelet activity. An evaluation will be made of the polymorphism as a determinant of disease and its possible role in the genesis of micro- and macrovascular damage.

Discussion

The MASS IV-DM trial is designed to include diabetic patients with clinically suspected myocardial ischemia in whom conventional angiography shows angiographically normal coronary arteries. The result of extensive investigation including angiographic follow-up by several methods, vascular reactivity, pro-thrombotic mechanisms, genetic and biochemical studies may facilitate the understanding of so-called micro- and macrovascular disease of DM.

Mechanisms underlying the triggers and maintenance of atrial fibrillation(AF) are not fully understood. One potential unproven mechanism is that gastroesophageal reflux disease(GERD) where acid reflux induces local and systemic inflammation may increase in triggered activity in the myocardium and pulmonary veins and increase AF risk. A self-report questionnaire was mailed to a random sample of 5288 Olmsted County residents aged 25-74 years to assess the presence and frequency of GERD from 1988-1994. Long-term risk of AF over a period of 11.4 ± 5.0 years was determined through review of clinical evaluations and the electrocardiogram database in those without prior AF. The average age was 53±17 years and 2571(49%) were male. Of these patients, 741 developed AF[cumulative probability of AF was 20%(95% CI 17-22%) at 18 years]. Age[HR 1.09(95% CI 1.08-1.10),p<0.001], male gender[HR 1.81(95% CI 1.53-2.14),p<0.001], hypertension[HR 1.36(95% CI 1.14-1.61),p=0.0006), and heart failure[HR 1.74(95% CI 1.16-2.60),p=0.007) were independently associated with the risk of AF. The presence of any GERD was not associated with risk of AF[HR 0.81(95% CI 0.68-0.96),p=0.014] after adjustment for other risk factors. Frequency of GERD did not significantly impact risk of AF, although patients with more frequent GERD had a slightly higher AF risk. Esophagitis increased risk of AF [HR = 1.94(95% CI 1.35-2.78),p<0.001], but the association did not persist when accounting for other risk factors(p=0.72). In conclusion, in this large population-based study of patients surveyed for GERD, we did not find an association with presence or frequency of symptoms and AF. Patients with esophagitis were more likely to develop AF, although this association requires further study.

OBJECTIVE: To compare outcomes of percutaneous coronary interventions (PCIs) at 2 community hospitals without on-site surgery (Franciscan Skemp Healthcare and Immanuel St. Joseph's Hospital) with a center with on-site surgery (Saint Marys Hospital).

PATIENTS AND METHODS: Using a matched case-control design, we studied 1842 elective and 667 nonelective PCI procedures (myocardial infarction [MI]/cardiogenic shock) performed from January 1, 1999, through December 31, 2007. The quality assurance protocol included operator volume and training, application of a risk-adjustment model, transport protocol, and database participation. We compared in-hospital mortality and/or emergent coronary artery bypass surgery after PCI at Franciscan Skemp Healthcare and Immanuel St. Joseph's Hospital, which do not have on-site surgery, with Saint Marys Hospital, a medical center with the capability to perform coronary artery bypass grafting on site.

RESULTS: Of 22 baseline variables, significant imbalances between matched groups were present in only 3 (hyperlipidemia, history of MI, American College of Cardiology/American Heart Association B2/C type lesion) in the elective group and 2 (Canadian Cardiovascular Society class III/IV angina, multivessel disease) in the nonelective group. The primary end point occurred in 0.3%, 0.1%, and 0.6% of patients undergoing elective PCI (P=.07) and 3.3%, 3.3%, and 3.7% of patients undergoing nonelective PCI (P=.65) at Immanuel St. Joseph's Hospital, Franciscan Skemp Healthcare, and Saint Marys Hospital, respectively. The in-hospital mortality rate at Immanuel St. Joseph's Hospital and Franciscan Skemp Healthcare was comparable to that at Saint Marys Hospital for both elective (0.3%, 0.1%, 0.4%; P=.24) and nonelective PCI (2.6%, 2.4%, 3.1%; P=.49). No patient undergoing elective PCI required transfer for emergency cardiac surgery. Of the 21 transfers, 20 (95%) were in the setting of MI and cardiogenic shock or left main/3-vessel disease; 18 patients (86%) survived to discharge.

CONCLUSION: Optimal outcomes with PCI have been observed at community hospitals without on-site cardiac surgical programs with application of a prospective, standardized quality assurance protocol.

In-hospital mortality and/or emergent coronary artery bypass surgery after percutaneous coronary intervention at 2 community hospitals that do not have on-site surgery was compared with a center that has the capability to perform cardiac surgery on site. Outcomes were optimal in the hospitals without on-site surgery with application of a prospective, standardized quality assurance protocol.

Background

TTN-encoded titin, CSRP3-encoded muscle LIM protein, and TCAP-encoded telethonin are Z-disc proteins essential for the structural organization of the cardiac sarcomere and the cardiomyocyte’s stretch sensor. All three genes have been established as cardiomyopathy-associated genes for both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Here, we sought to characterize the frequency, spectrum, and phenotype associated with HCM-associated mutations in these three genes in a large cohort of unrelated patients evaluated at a single tertiary outpatient center.

Methods

DNA was obtained from 389 patients with HCM (215 male, left ventricular wall thickness of 21.6 ± 6 mm) and analyzed for mutations involving all translated exons of CSRP3 and TCAP and targeted HCM-associated exons (2, 3, 4, and 14) of TTN using polymerase chain reaction (PCR), denaturing high performance liquid chromatography (DHPLC), and direct DNA sequencing. Clinical data were extracted from patient records and maintained independent of the genotype.

Results

Overall, 16 patients (4.1%) harbored a Z-disc mutation: 12 had a MLP mutation and 4 patients a TCAP mutation. No TTN mutations were detected. Seven patients were also found to have a concomitant myofilament mutation. Seven patients with a MLP-mutation were found to harbor the DCM-associated, functionally characterized W4R mutation. W4R-MLP was also noted in a single white control subject. Patients with MLP/TCAP-associated HCM clinically mimicked myofilament-HCM.

Conclusions

Approximately 4.1% of unrelated patients had HCM-associated MLP or TCAP mutations. MLP/TCAP-HCM phenotypically mirrors myofilament-HCM and is more severe than the subset of patients who still remain without a disease-causing mutation. The precise role of W4R-MLP in the pathogenesis of either DCM or HCM warrants further investigation.

Aims

Obesity has been shown to be a risk factor for first atrial fibrillation (AF), but whether it is associated with progression from paroxysmal to permanent AF is unknown.

Methods and results

In this longitudinal cohort study, Olmsted County, MN residents confirmed to have developed paroxysmal AF during 1980–2000 were identified and followed passively to 2006. The interrelationships of body mass index (BMI), left atrial (LA) size, and progression to permanent AF were analysed. Of a total of 3248 patients (mean age 71 ± 15 years; 54% men) diagnosed with paroxysmal AF, 557 (17%) progressed to permanent AF (unadjusted incidence, 36/1000 person-years) over a median follow-up period of 5.1 years (interquartile range 1.2–9.4). Adjusting for age and sex, BMI independently predicted the progression to permanent AF (hazard ratio, HR 1.04, CI 1.03–1.06; P < 0.0001). Compared with normal BMI (18.5–24.9 kg/m2), obesity (30–34.9 kg/m2) and severe obesity (≥35 kg/m2) were associated with increased risk for progression [HR 1.54 (CI 1.2–2.0; P = 0.0004) and 1.87 (CI 1.4–2.5; P < 0.0001, respectively)]. BMI remained highly significant even after multiple adjustments. In the subgroup with echocardiographic assessment (n = 744), LA volume was incremental to BMI for independent prediction of progression after multiple adjustments, and did not weaken the association between BMI and progression to permanent AF (HR 1.04; CI 1.02–1.05; P < 0.0001).

Conclusion

There was a graded risk relationship between BMI and progression from paroxysmal to permanent AF. This relationship was not weakened by LA volume, which was independent of and incremental to BMI for the prediction of progression to permanent AF.

Objectives

To examine whether sex-based differences in mortality after percutaneous coronary interventions (PCIs) have changed in the past 25 years.

Background

Women with coronary artery disease have a higher risk of adverse outcomes after PCIs than do men. Recent temporal trends in short-term and long-term mortality in women after PCIs are unknown.

Methods

We performed a retrospective cohort study of 18,885 consecutive, unique patients who underwent PCIs between 1979 and 1995 (Early group, n=7,904, 28% women) and between 1996 and 2004 (Recent group, n=10,981, 31% women). Thirty-day and long-term mortality were compared by sex.

Results

Compared with men, women undergoing PCIs were older and more likely to have diabetes mellitus, hypertension, or hypercholesterolemia. Overall, PCI was successful in 89% of women and 90% of men. In the Recent group, 30-day mortality was significantly reduced compared with the Early group in women (2.9% vs 4.4%, P=.002) and men (2.2% vs 2.8%, P=.04). However, long-term survival was similar between Early and Recent groups among both men and women. After adjustment for risk factors, there was no difference between men and women from 1994 onward for either 30-day or long-term outcomes.

Conclusions

Thirty-day mortality after PCI in men and women has decreased in the past 25 years. After accounting for baseline risks, no differences in short-term or long-term mortality were observed between men and women.

Context

Sudden cardiac death (SCD) after myocardial infarction (MI) has not recently been assessed in the community. Post-MI risk stratification for SCD commonly relies on baseline characteristics and little is known about the relationship between recurrent ischemia or heart failure (HF) and SCD.

Objective

To evaluate the risk of SCD after MI and the impact of recurrent ischemia and HF on SCD.

Design, setting, and participants

2,997 Olmsted County residents experiencing an MI between 1979 and 2005.

Main outcome measures

SCD defined as out-of-hospital death due to coronary disease. Observed survival free of SCD compared to that expected in Olmsted County.

Results

During a median follow-up of 4.7 years (25th–75th percentile 1.6–7.1, date of last follow-up 02-29-2008), 1,160 deaths occurred, 282 (24%) SCD. The 30-day cumulative incidence of SCD was 1.2% (95% confidence interval [CI] 0.8–1.6%). Thereafter, the rate of SCD was constant at 1.2%/year yielding a 5-year cumulative incidence of 6.9% (95% CI 5.9% to 7.9%). The 30-day incidence of SCD was 4-fold higher than expected (standardized mortality ratio=4.2, 95% CI 2.9 to 5.8). In the year thereafter, the risk of SCD was lower than expected (standardized mortality ratio=0.66, 95% CI 0.50 to 0.85). The risk of SCD declined over time (hazard ratio=0.62, 95% CI 0.44 to 0.88 for MIs in 1997–2005 compared to 1979–1987; p =0.03). Recurrent events, ischemia (n=842) or HF (n=365), occurred in 2,080 patients. After adjustment for baseline characteristics, recurrent ischemia was not associated with SCD (hazard ratio=1.26, 95% CI 0.96 to 1.65; p=0.09), while HF markedly increased the risk of SCD (hazard ratio= 4.20, 95% CI 3.10 to 5.69; p<0.001)

Conclusions

The risk of SCD is highest during the first month after MI and declined over time. SCD is independently associated with HF but not with recurrent ischemia.

Background

We studied the relationship between longer delays from symptom onset to hospital presentation and the use of any reperfusion therapy, door-to-balloon time, and door-to-drug time.

Methods

Cohort study of patients with ST-elevation myocardial infarction enrolled in the National Registry of Myocardial Infarction from January 1, 1995 to December 31, 2004. Delay in hospital presentation was categorized into 1 hour intervals as ≤1 hour, >1 to 2 hours, >2 to 3 hours, etc., and >11 to 12 hours. The study analyzed 3 groups: 440,398 patients for the association between delay and use of any reperfusion therapy; 67,207 patients for the association between delay and door-to-balloon time; 183,441 patients for the association between delay and door-to-drug time.

Results

In adjusted analyses, patients with longer delays between symptom onset and hospital presentation were less likely to receive any reperfusion therapy, had longer door-to-balloon times, and had longer door-to-needle times (all p<0.0001 for linear trend). For patients presenting ≤1 hour, >1 to 2 hours, and >2 to 3 hours, >9 to 10 hours, >10 to 11 hours, and >11 to 12 hours after symptom onset, the use of any reperfusion therapy were 77%, 77%, 73%, 53%, 50%, and 46% respectively; door-to-balloon times were 99, 101, 106, 123, 125, and 123 minutes respectively; door-to-drug times were 33, 34, 36, 46, 44, and 47 minutes respectively.

Conclusions

Longer delays from symptom onset to hospital presentation were associated with reduced likelihood of receiving primary reperfusion therapy, and even among those treated, late presenters had significantly longer door-to-balloon and door-to-drug times.

The MASS III Trial is a large project from a single institution, The Heart Institute of the University of Sao Paulo, Brazil (InCor), enrolling patients with coronary artery disease and preserved ventricular function. The aim of the MASS III Trial is to compare medical effectiveness, cerebral injury, quality of life, and the cost-effectiveness of coronary surgery with and without of cardiopulmonary bypass in patients with multivessel coronary disease referred for both strategies. The primary endpoint should be a composite of cardiovascular mortality, cerebrovascular accident, nonfatal myocardial infarction, and refractory angina requiring revascularization. The secondary end points in this trial include noncardiac mortality, presence and severity of angina, quality of life based on the SF-36 Questionnaire, and cost-effectiveness at discharge and at 5-year follow-up. In this scenario, we will analyze the cost of the initial procedure, hospital length of stay, resource utilization, repeat hospitalization, and repeat revascularization events during the follow-up. Exercise capacity will be assessed at 6-months, 12-months, and the end of follow-up. A neurocognitive evaluation will be assessed in a subset of subjects using the Brain Resource Center computerized neurocognitive battery. Furthermore, magnetic resonance imaging will be made to detect any cerebral injury before and after procedures in patients who undergo coronary artery surgery with and without cardiopulmonary bypass.

Clinical Trial registration information

ISRCTN59539154 Off-pump vs. on-pump surgery in patients with Stable CAD MASS III

Background

Heart failure (HF) is a disease commonly associated with coronary artery disease (CAD). Most risk models for HF development have focused on acute myocardial infarction (MI) patients. The prevention of events with angiotensin-converting enzyme inhibition (PEACE) population enabled the development of a risk model to predict HF in patients with stable CAD and preserved ejection fraction.

Methods and Results

In the 8290 PEACE patients without pre-existing HF, new-onset HF hospitalizations and fatal HF were assessed over a median follow-up of 4.8 years. Covariates were evaluated and maintained in the Cox regression multivariable model using backward selection if p<0.05. A risk score was developed and converted to an integer-based scoring system. Among the PEACE population (age 64±8, female 18%, prior MI 55%), there were 268 cases of fatal and non-fatal HF. Twelve characteristics were associated with increased risk of HF along with several baseline medications, including older age, history of hypertension, and diabetes. Randomization to trandolapril independently reduced risk of HF. There was no interaction between trandolapril treatment and other risk factors for HF. The risk score (range 0–21) demonstrated excellent discriminatory power (c-statistic 0.80). Risk of HF ranged from 1.75% in patients with a risk score of 0 to 33% in patients with risk score≥16.

Conclusion

Among patients with stable CAD and preserved EF, traditional and newer factors were independently associated with increased risk of HF. Trandolopril decreased the risk of HF in these patients with preserved EF.

Background

Mutations in myofilament proteins, most commonly MYBPC3-encoded myosin binding protein C and MYH7-encoded β-myosin heavy chain, can cause hypertrophic cardiomyopathy (HCM). Despite significant advances in structure-function relationships pertaining to the cardiac sarcomere, there is limited knowledge of how a mutation leads to clinical HCM. We therefore set out to study expression and localization of myofilament proteins in left ventricular tissue of patients with HCM.

Methods and Results

Frozen surgical myectomy specimens from 47 patients with HCM were examined and genotyped for mutations involving 8 myofilament-encoding genes. Myofilament protein levels were quantified by western blot with localization graded from immunohistochemical staining of tissue sections. Overall, 25/47 (53%) patients had myofilament-HCM including 12 with MYBPC3-HCM and 9 with MYH7-HCM. Compared to healthy heart tissue, levels of myofilament proteins were increased in patients manifesting a mutation in either gene. Patients with a frameshift mutation predicted to truncate MYBPC3 exhibited marked disturbances in protein localization as compared to missense mutations in either MYBPC3 or MYH7.

Conclusions

In this first expression study in human HCM tissue, increased myofilament protein levels in patients with either MYBPC3 or MYH7-mediated HCM suggest a poison peptide mechanism. Specifically, the mechanism of dysfunction may vary according to the genetic subgroup suggested by a distinctly abnormal distribution of myofilament proteins in patients manifesting a truncation mutation in MYBPC3.