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Genetic factors play an important role in nonischemic dilated cardiomyopathy (NIDC). However, prime opportunities remain for genetic discovery and prognostic understanding. TITIN gene truncating variant mutations (TTNtv) are of interest because of their frequent appearance in NIDC series. We sought to discover known and novel TTNtv mutations in a NIDC cohort and assess 5-year outcomes. Patients with NIDC entered into the INSPIRE Registry with ≥3 years of follow-up were studied. Whole exome sequencing (WES) was performed using an Illumina Novaseq platform. Genetic analysis used Sentieon software and the GRCh38 human reference genome. Variant calls were annotated with ClinVar. Five-year outcomes were determined by functional assessment and ejection fraction (EF) as recovered (EF ≥50%), persistent (EF 21% to 49%), or progressive (left ventricular assist device, transplant, heart failure [HF] or arrhythmic death, or EF ≤20%). The study comprised 229 NIDC patients (age = 50 ± 15 years, 58% men). TTNtv's were discovered in 27 patients with 22 unique mutations; (7 known, 15 novel). TTNtv+ patients more frequently presented with severe NIDC (EF ≤20%) (p = 0.032). By 5-year, outcomes were worse in TTNtv+ patients (p = 0.027), and patients less often recovered (11% vs. 30%). Prognosis was similar with known and novel mutations. Nongenetic (e.g., environmental) cocausal risk factors for HF were frequently present, and these factors frequently appeared to act in concert with genetic variants to precipitate clinical HF. In conclusion, our study expands the library of likely pathogenic TTN mutations and increases our understanding of their clinical impact in association with other HF risk factors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Atherosclerotic cardiovascular disease (ASCVD) is the most important cause of morbidity and mortality nationally and internationally. Improving ASCVD risk prediction is a high clinical priority. We sought to determine which of 3 ASCVD risk scores best predicts the need for revascularization and incident major adverse coronary events (MACE) in symptomatic patients at low-to-intermediate primary ASCVD risk referred for regadenoson-stress positron emission tomography (PET). Risk scores included the standard ASCVD pooled cohort equation (PCE), the multiethnic study of atherosclerosis (MESA) risk equation, and the coronary artery calcium score (CACS), obtained by PET. All qualifying patients in our institution at primary ASCVD risk referred for PET-stress tests in whom PCE, MESA, and CAC scores could be calculated were studied. CACS categories were: 0, 1 to 10, 11 to 299, 300 to 999, and 1000+. MESA and PCE scores were divided into quartiles. Logistic regression modeling was used to predict clinical/PET-driven early revascularization (within 90 days) and 1-year MACE (death, myocardial infarction, or any-time revascularization). A total of 981 patients (54% men, age 67 ± 10 years) qualified and were studied. Scores including CAC (MESA, CACS) performed better than PCE for predicting overall 1-year MACE (MESA p <0.001, CACS p = 0.012 vs PCE), which was driven by early revascularization. In conclusion, in a large population of patients at primary ASCVD risk referred for PET-stress testing, risk scores including CAC (CACS, MESA), which better predicted early revascularization and 1-year MACE, may be particularly useful in primary coronary risk assessment when considering whom to refer for PET-stress testing., (Copyright © 2019. Published by Elsevier Inc.)

The neutrophil to lymphocyte ratio (NLR) has been proposed as a simple and routinely obtained marker of inflammation. This study sought to determine whether the NLR on admission as well as NLR trajectory would be complementary to the Get with the Guidelines Heart Failure (GWTG-HF) risk score in patients hospitalized with acute heart failure with preserved ejection fraction (HFpEF).Using the Stanford Translational Research Database, we identified 443 patients between January 2002 and December 2013 hospitalized with acute HFpEF and with complete data of NLR both on admission and at discharge. The primary endpoint was all-cause mortality. Mean age was 77 ± 16 years, 58% were female, with a high prevalence of diabetes mellitus (35.4%), coronary artery disease (58.2%), systemic hypertension (96.6%) and history of atrial fibrillation (57.5%). Over a median follow-up of 2.2 years, 121 (27.3%) patients died. The median NLR on admission was 6.5 (IQR 3.6 - 11.1); a majority of patients decreased their NLR during the course of hospitalization. On multivariable Cox modeling, both NLR on admission (HR 1.18 95% CI (1.00 - .38), p = 0.04) and absolute NLR trajectory (HR 1.26 95% CI (1.10 - 1.45), p = 0.001) were shown to be incremental to GWTG-HF risk score (p < 0.05) for outcome prediction. Adding the NLR or absolute NLR trajectory to the GWTG-HF risk score significantly improved the area under the operator-receiver curve and the reclassification up to 3 years after admission.This simple, readily available marker of inflammation may be useful when stratifying the risk of patients hospitalized with HFpEF., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Stroke prevention in atrial fibrillation (AF) is guided by clinical factors with inadequate predictive power. Most thrombi observed in AF are observed in the left atrial appendage (LAA). This study was designed to determine (1) the association between LAA and the incidence of AF-related stroke and (2) the power of LAA to predict stroke. Patients (n = 48) with a history of AF and stroke were compared with control subjects (n = 48) with a history of AF but no history of stroke. Magnetic resonance images from both case and control populations were manually segmented to determine LAA volume. Patients with a history of stroke had larger LAA mean volumes than control subjects (28.8 ± 13.5 cm(3) vs 21.7 ± 8.27 cm(3), p = 0.002). Stroke risk is highest in patients with a LAA volume >34 cm(3) (multivariable OR 7.11, p = 0.003). In conclusion, larger LAA volume is associated with stroke in the setting of AF, and this measure can potentially improve risk stratification for stroke risk management in AF patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Lipoprotein(a) (Lp[a]) has gained attention as a heritable coronary artery disease (CAD) risk factor and therapeutic target. Two genetic variants in the LPA gene have been reported to influence Lp(a) levels and increase CAD risk. The aim of this study was to prospectively test these variants for their associations with Lp(a) and CAD risk. Participants (n = 1,400) in the Intermountain Heart Collaborative Study Registry who had Lp(a) cholesterol levels determined at coronary angiography were genotyped for rs3798220 and rs1045587 in LPA. Variants were detected by Taqman polymerase chain reaction. Chi-square and linear and logistic regression tests were used as appropriate among genotypes for Lp(a) and angiographic CAD. Age averaged 63 years; 65% were men; and severe CAD was present in 57%, mild CAD in 12%, and no CAD in 31%. Minor allele frequencies were 0.023 for rs3798220 and 0.090 for rs10455872. In multivariate modeling, only rs10455872 (odds ratio [OR] 2.33, 95% confidence interval [CI] 1.67 to 3.33, p = 1.75 × 10⁻⁹) and rs3798220 (OR 1.99, 95% CI 0.99 to 4.00, p = 0.065) contributed to the prediction of elevated Lp(a) cholesterol. Lp(a) cholesterol was weakly associated with CAD (OR 1.17, 95% CI 1.00 to 1.37, p = 0.055). Rs10455872 strongly predicted prevalent CAD (per allele OR 1.43, 95% CI 1.07 to 1.91, p = 0.0172); the effect size for the rare rs3798220 variant was similar (dominant OR 1.47, 95% CI 0.81 to 2.67, p = 0.20), but power was limited to demonstrate significance. The combined genotype explained only a small percentage (≤4%) of variability in Lp(a) cholesterol and prevalence of angiographic CAD. In conclusion, heritable contributions of LPA rs10455872 and rs3798220 to Lp(a) cholesterol levels and to angiographic CAD were prospectively assessed in this study. The percentage of intersubject variability in Lp(a) cholesterol and the percentage of prevalent CAD explained were small., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Previously we discovered that routine periodic fasting was associated with a lower prevalence of coronary artery disease (CAD). Other studies have shown that fasting increases longevity in animals. A hypothesis-generating analysis suggested that fasting may also associate with diabetes. This study prospectively tested whether routine periodic fasting is associated with diabetes mellitus (DM). Patients (n = 200) undergoing coronary angiography were surveyed for routine fasting behavior before their procedure. DM diagnosis was based on physician reports of current and historical clinical and medication data. Secondary end points included CAD (physician reported for ≥ 1 lesion of ≥ 70% stenosis), glucose, and body mass index (BMI). Meta-analyses were performed by evaluation of these patients and 448 patients from a previous study. DM was present in 10.3% of patients who fasted routinely and 22.0% of those who do not fast (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.17 to 0.99, p = 0.042). CAD was found in 63.2% of fasting and 75.0% of nonfasting patients (OR 0.42, CI 0.21 to 0.84, p = 0.014), and in nondiabetics this CAD association was similar (OR 0.38, CI 0.16 to 0.89, p = 0.025). Meta-analysis showed modest differences for fasters versus nonfasters in glucose concentrations (108 ± 36 vs 115 ± 46 mg/dl, p = 0.047) and BMI (27.9 ± 5.3 vs 29.0 ± 5.8 kg/m(2), p = 0.044). In conclusion, prospective hypothesis testing showed that routine periodic fasting was associated with a lower prevalence of DM in patients undergoing coronary angiography. A reported fasting association with a lower CAD risk was also validated and fasting associations with lower glucose and BMI were found., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Vitamin D recently has been proposed to play an important role in a broad range of organ functions, including cardiovascular (CV) health; however, the CV evidence-base is limited. We prospectively analyzed a large electronic medical records database to determine the prevalence of vitamin D deficiency and the relation of vitamin D levels to prevalent and incident CV risk factors and diseases, including mortality. The database contained 41,504 patient records with at least one measured vitamin D level. The prevalence of vitamin D deficiency (≤30 ng/ml) was 63.6%, with only minor differences by gender or age. Vitamin D deficiency was associated with highly significant (p <0.0001) increases in the prevalence of diabetes, hypertension, hyperlipidemia, and peripheral vascular disease. Also, those without risk factors but with severe deficiency had an increased likelihood of developing diabetes, hypertension, and hyperlipidemia. The vitamin D levels were also highly associated with coronary artery disease, myocardial infarction, heart failure, and stroke (all p <0.0001), as well as with incident death, heart failure, coronary artery disease/myocardial infarction (all p <0.0001), stroke (p = 0.003), and their composite (p <0.0001). In conclusion, we have confirmed a high prevalence of vitamin D deficiency in the general healthcare population and an association between vitamin D levels and prevalent and incident CV risk factors and outcomes. These observations lend strong support to the hypothesis that vitamin D might play a primary role in CV risk factors and disease. Given the ease of vitamin D measurement and replacement, prospective studies of vitamin D supplementation to prevent and treat CV disease are urgently needed., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Plasma renin activity (PRA) is a measure of renin-angiotensin system activity and is associated with cardiovascular outcomes in patients with heart failure (HF). We conducted a prospective analysis to assess whether elevated baseline PRA is associated with cardiovascular outcomes in 1,165 patients with coronary artery disease (> or =70% stenosis on the coronary angiogram) enrolled in the Intermountain Heart Collaborative Study. The exclusion criteria included previous myocardial infarction (MI) or HF, ejection fraction < or =45%, and a discharge diagnosis of MI/beta-blocker treatment. Baseline PRA measurements were evaluated as risk categories (< or =0.50, 0.51 to 2.30, and >2.30 ng/ml/h) and as tertiles (< or =0.40, 0.41 to 1.90, and > or =1.90 ng/ml/h). Predefined cardiovascular outcomes were assessed for a minimum follow-up of 3 years (mean 6.4 +/- 3.2, maximum 14.6) using Cox regression analysis to adjust for the baseline characteristics. The mean patient age was 64.4 years; most patients were men (73.1%) and hypertensive (63.2%). Elevated baseline PRA (high vs low category; >2.30 vs < or =0.50 ng/ml/h) was associated with a significantly increased risk of 3-year cardiac morbidity/mortality (hazard ratio 1.96; p = 0.004), MI (hazard ratio 2.41; p = 0.02), HF hospitalization (hazard ratio 4.39; p = 0.03), and all-cause death (hazard ratio 1.80; p = 0.01). Elevated baseline PRA was also associated with longer-term HF hospitalization (hazard ratio 2.12; p = 0.004) and all-cause death (hazard ratio 1.56; p = 0.002). Similar results were observed for the PRA tertiles. The association of PRA with outcomes was observed after correction for hypertension, hyperlipidemia, diabetes, a family history of cardiovascular events, smoking, renal failure, and the use of statins. In conclusion, elevated baseline PRA is associated with cardiac morbidity and mortality in patients with coronary artery disease but normal left ventricular function and no previous MI or HF., (Copyright 2010 Elsevier Inc. All rights reserved.)

Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation appears to be associated with increased mortality. However, the determination of which patients are at greater risk of developing postoperative RVF remains controversial and relatively unknown. We sought to determine the preoperative risk factors for the development of RVF after LVAD implantation. The data were obtained for 175 consecutive patients who had received an LVAD. RVF was defined by the need for inhaled nitric oxide for >/=48 hours or intravenous inotropes for >14 days and/or right ventricular assist device implantation. An RVF risk score was developed from the beta coefficients of the independent variables from a multivariate logistic regression model predicting RVF. Destination therapy (DT) was identified as the indication for LVAD implantation in 42% of our patients. RVF after LVAD occurred in 44% of patients (n = 77). The mortality rates for patients with RVF were significantly greater at 30, 180, and 365 days after implantation compared to patients with no RVF. By multivariate logistic regression analysis, 3 preoperative factors were significantly associated with RVF after LVAD implantation: (1) a preoperative need for intra-aortic balloon counterpulsation, (2) increased pulmonary vascular resistance, and (3) DT. The developed RVF risk score effectively stratified the risk of RV failure and death after LVAD implantation. In conclusion, given the progressively growing need for DT, the developed RVF risk score, derived from a population with a large percentage of DT patients, might lead to improved patient selection and help stratify patients who could potentially benefit from early right ventricular assist device implantation., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: Some components of the complete blood count and basic metabolic profile are commonly used risk predictors. Many of their components are not commonly used, but they might contain independent risk information. This study tested the ability of a risk score combining all components to predict all-cause mortality., Methods: Patients with baseline complete blood count and basic metabolic profile measurements were randomly assigned (60%/40%) to independent training (N = 71,921) and test (N = 47,458) populations. A third population (N = 16,372) from the Third National Health and Nutrition Examination Survey and a fourth population of patients who underwent coronary angiography (N = 2558) were used as additional validation groups. Risk scores were computed in the training population for 30-day, 1-year, and 5-year mortality using age- and sex-adjusted weights from multivariable modeling of all complete blood count and basic metabolic profile components., Results: Area under the curve c-statistics were exceptional in the training population for death at 30 days (c = 0.90 for women, 0.87 for men), 1 year (c = 0.87, 0.83), and 5-years (c = 0.90, 0.85) and in the test population for death at 30 days (c = 0.88 for women, 0.85 for men), 1 year (c = 0.86, 0.82), and 5 years (c = 0.89, 0.83). In the test, the Third National Health and Nutrition Examination Survey, and the angiography populations, risk scores were highly associated with death (P <.001), and thresholds of risk significantly stratified all 3 populations., Conclusion: In large patient and general populations, risk scores combining complete blood count and basic metabolic profile components were highly predictive of death. Easily computed in a clinical laboratory at negligible incremental cost, these risk scores aggregate baseline risk information from both the popular and the underused components of ubiquitous laboratory tests.

Bisphosphonates comprise the most common treatment for patients with osteoporosis and fracture risk. Large randomized trials have shown that these therapies may increase the risk of atrial fibrillation (AF). Controversy over the arrhythmia risk prompted the Federal Drug Administration to recently pursue an ongoing safety review to determine the cardiac risk across the entire drug class. Study patients came from 2 large prospective databases (ongoing registry of consecutive patients who underwent coronary angiography and the Intermountain Healthcare health plans database). Medical details regarding bisphosphonate use and cardiovascular risk factors were abstracted from the records. End points included AF, myocardial infarction, and death. In the angiographic database (n = 9,623), patients treated with bisphosphonates were older and more likely to have hypertension, a previous myocardial infarction, heart failure, and osteoporosis. Over 1,481 +/- 1,024 days we found no increased risk of AF in the drug-treated group (hazard ratio 0.90, 95% confidence interval 0.48 to 1.68, p = 0.74). In the Intermountain Healthcare health plans database (n = 37,485), patients treated with bisphosphonates were older and were more likely to have hyperlipidemia and osteoporosis. Over 1,667.5 +/- 557.0 days, there was no increased risk of AF (hazard ratio 0.82, 95% confidence interval 0.66 to 1.01, p = 0.63). In the 2 databases there was no statistical difference in long-term rates of myocardial infarction or mortality. In conclusion, in a long-term study of >47,000 patients, we were unable to find an association between bisphosphonate therapy and AF. However, patients who received bisphosphonates were older and had more cardiovascular disease that we suspect accounts for the increased arrhythmia risk reported in other trials.

Cardiopulmonary disease has been associated with particulate matter (PM) air pollution. There is evidence that exposure to elevated PM concentrations increases risk of acute ischemic heart disease events, alters cardiac autonomic function, and increases risk of arrhythmias. It is plausible, therefore, that PM exposure may exacerbate heart failure (HF). A case-crossover study design was used to explore associations between fine PM (PM(2.5): particles with an aerodynamic diameter < or =2.5 microm) and 2,628 HF hospitalizations. Patients lived on Utah's Wasatch Front and were drawn from those hospitalized at Intermountain Healthcare facilities with a primary diagnosis of HF. A 14-day lagged cumulative moving average of 10 microg/m(3) PM(2.5) was associated with a 13.1% (95% confidence interval 1.3 to 26.2) increase in HF admissions. The strongest PM(2.5)-HF associations were for elderly patients who had previously been admitted for HF and who required only a short period of hospitalization. HF hospitalizations are associated with lagged cumulative exposure to PM(2.5) of approximately 2 weeks. In conclusion, particulate air pollution may play a role in precipitating acute cardiac decompensation in otherwise well-managed patients with HF, perhaps through effects of PM on myocardial ischemia, cardiac autonomic function, and/or arrhythmic effects.

Coronary artery disease (CAD) is common and multifactorial. Members of the Church of Jesus Christ of Latter-day Saints (LDS, or Mormons) in Utah may have lower cardiac mortality than other Utahns and the US population. Although the LDS proscription of smoking likely contributes to lower cardiac risk, it is unknown whether other shared behaviors also contribute. This study evaluated potential CAD-associated effects of fasting. Patients (n(1) = 4,629) enrolled in the Intermountain Heart Collaborative Study registry (1994 to 2002) were evaluated for the association of religious preference with CAD diagnosis (> or = 70% coronary stenosis using angiography) or no CAD (normal coronaries, <10% stenosis). Consequently, another set of patients (n(2) = 448) were surveyed (2004 to 2006) for the association of behavioral factors with CAD, with routine fasting (i.e., abstinence from food and drink) as the primary variable. Secondary survey measures included proscription of alcohol, tea, and coffee; social support; and religious worship patterns. In population 1 (initial), 61% of LDS and 66% of all others had CAD (adjusted [including for smoking] odds ratio [OR] 0.81, p = 0.009). In population 2 (survey), fasting was associated with lower risk of CAD (64% vs 76% CAD; OR 0.55, 95% confidence interval 0.35 to 0.87, p = 0.010), and this remained after adjustment for traditional risk factors (OR 0.46, 95% confidence interval 0.27 to 0.81, p = 0.007). Fasting was also associated with lower diabetes prevalence (p = 0.048). In regression models entering other secondary behavioral measures, fasting remained significant with a similar effect size. In conclusion, not only proscription of tobacco, but also routine periodic fasting was associated with lower risk of CAD.

Atrial fibrillation (AF) is the most common rhythm disturbance seen in clinical practice. Evidence emerged that suggested inflammation was associated with risk of AF. Helicobacter pylori causes gastric and esophageal inflammation, as well as systemic and vascular inflammation. These local and systemic inflammatory effects may increase the risk of AF. Study patients were consecutive patients who underwent angiography for suspicion of coronary artery disease. Patients' AF status was determined by a search of hospital discharge summaries for diagnostic International Classification of Diseases, Ninth Revision codes for AF, assessment of previous electrocardiograms at the index and previous admissions to LDS Hospital (Salt Lake City, Utah), and search of the electrocardiographic database of LDS Hospital. In addition to routine laboratory studies, serum was analyzed to determine H pylori serostatus and index C-reactive protein (CRP) level. A total of 943 patients with known AF status were studied. Those with AF tended to be older (70.9 +/- 9.5 vs 63.9 +/- 10.7 years; p <0.001) and had a higher prevalence of congestive heart failure (28% vs 11%; p <0.001). In addition, patients with AF were more likely to be seropositive for H pylori in comparison to the seronegative group (65% vs 55%; p = 0.049). Mean CRP was similar between those with and without AF (2.2 +/- 2.7 vs 2.3 +/- 2.4 mg/dl; p = 0.79). There was no apparent association between H pylori serostatus and CRP. Multivariate predictors of AF included age (hazard ratio [HR] 1.07 per year, 95% confidence interval [CI] 1.04 to 1.10, p <0.0001) and heart failure (HR 2.87, 95% CI 1.59 to 5.18, p <0.0001). H pylori added to the model was marginally associated with AF (HR 1.53, 95% CI 0.95 to 2.47, p = 0.08) when not accounting for age. However, younger patients (<50 years) who were H pylori seropositive had a higher relative risk of AF (8%) versus those who were seronegative (0%). In comparison, older patients seropositive for H pylori had only a modest increased risk of AF (17.5% vs 15.4%; p = 0.11). In conclusion, these data showed a general association of H pylori and AF in patients with multiple cardiovascular risk factors. The association did not persist after accounting for other risk factors. Although older age was highly associated with AF risk in this population, H pylori was additive across 3 distinct age groups, with the highest risk conveyed in the younger cohort.

Diabetes mellitus is a strong risk factor for atherosclerosis and is often characterized by dyslipidemia. Besides acting on traditional lipids, statins and fibrates may also exert beneficial effects on various pro- and antiatherogenic lipid subparticles. This analysis was undertaken to evaluate combination therapy on lipid subparticles in the Diabetes and Combined Lipid Therapy Regimen (DIACOR) study. Patients with type 2 diabetes mellitus and no histories of coronary heart disease were evaluated (n = 498). Eligible patients underwent a 6- to 8-week washout period of all lipid-lowering medications and were enrolled if they demonstrated mixed dyslipidemia (having >or=2 of the following 3 lipid parameters: low-density lipoprotein [LDL] cholesterol >or=100 mg/dl, triglycerides >or=200 mg/dl, and high-density lipoprotein cholesterol <40 mg/dl). Patients were randomized to simvastatin 20 mg, fenofibrate 160 mg, or combined simvastatin 20 mg and fenofibrate 160 mg. Lipid subparticles were assessed 12 weeks after randomization by the Vertical Auto Profile II method. A total of 300 patients (mean age 61.6 +/- 11.5 years, 55% men) were randomized. Combination therapy was superior in lowering LDL cholesterol pattern B (-33.9 mg/dl) and dense very low-density lipoprotein cholesterol (-10.0 mg/dl) and increasing high-density lipoprotein3 (+2.3 mg/dl) and exerted the greatest change in altering the LDL cholesterol size profile. A potential effect on lipoprotein(a) (-0.5 mg/dl) was also found. For those with triglycerides >170 mg/dl, combination therapy was superior in lowering dense very low density lipoprotein cholesterol (-10.7 mg/dl) and LDL cholesterol pattern B (-35.8 mg/dl), the lipids that tend to be formed in the presence of elevated triglycerides. In conclusion, in this trial of mixed dyslipidemic patients with diabetes, combination therapy was more effective in changing a variety of other cardiovascular risk markers.

Management of heart failure (HF) remains complex with low 5-year survival. The Seattle Heart Failure Model (SHFM) is a recently described risk score derived predominantly from clinical trial populations that may enable the prediction of survival in patients with HF. This study sought to validate the SHFM in an independent, nonclinical trial-based HF population. Patients (n = 4,077) from the hospital-based Intermountain Heart Collaborative Study registry with a diagnosis of HF were evaluated using prospectively collected data (mean +/- SD follow-up 4.4 +/- 3.1 years). The SHFM was used to calculate a risk score for each patient. Receiver-operating characteristic area under the curve provided SHFM predictive ability for a composite end point of survival free from death, transplantation, or left ventricular assist device implantation. Addition of creatinine, serum urea nitrogen, diabetes status, and B-type natriuretic peptide (BNP) to the SHFM was also evaluated. Patient age averaged 67 +/- 13 years and 61% were men. Area under the curves were 0.70 (95% confidence interval 0.66 to 0.70), 0.67 (95% confidence interval 0.66 to 0.69), 0.67 (95% confidence interval 0.065 to 0.68), and 0.66 (95% confidence interval 0.63 to 0.67) for 1-, 2-, 3-, and 5-year survivals, respectively. Area under the curves were slightly attenuated in patients >75 years of age (n = 1,339), implantable cardioverter-defibrillator recipients (n = 693), and patients with an ejection fraction >40% (n = 1,634). BNP added significantly to the model (area under the curve +0.06). BNP was found to add additional predictive ability at 1 year (area under the curve change +0.05) and nominally at 5 years (area under the curve change +0.02). In conclusion, the SHFM predicts survival in patients with HF in a hospital-based population, with areas under the curve similar to those from data on which models were initially fit.

Although previous studies have demonstrated that various "statins" decrease levels of high-sensitivity C-reactive protein (hs-CRP), the dose-response relation for lowering hs-CRP by the clinically important drug simvastatin compared with lipid lowering is unclear. A 16-week, randomized, double-blind study was performed in patients with stable coronary artery disease and high hs-CRP levels (>3 mg/L). Subjects were randomized to placebo, 20 mg of simvastatin, or 80 mg of simvastatin for 12 weeks. Those currently on a statin first underwent a 4-week washout. Of the 107 total patients randomized, 96 completed the trial, and 89 were able to be evaluated for efficacy. Changes in hs-CRP differed across simvastatin and placebo groups (change score +1.6 vs -0.6 mg/L, p = 0.004), but no dose response was observed when comparing 80 with 20 mg/day (-0.6 vs -0.5 mg/L, respectively). A strong dose response was observed for changes in total (p <0.01) and low-density lipoprotein (p <0.001) cholesterol. hs-CRP changes did not correlate with low-density lipoprotein changes. In conclusion, this randomized trial in patients with chronic stable coronary artery disease showed a strong dose response for simvastatin for total and low-density lipoprotein cholesterol lowering but not for hs-CRP.

The complete blood cell (CBC) count is an inexpensive, frequently obtained blood test whose information content is potentially underused. We examined the predictive ability of the CBC count for incident death in 29,526 consecutive consenting patients who underwent coronary angiography. Subjects were randomly assigned to training (60%) and test (40%) groups and were followed for an average of 4.9 years. Computed and integer risk score models for all-cause death were developed for 30 days and 1, 5, and 10 years using multivariable logistic regressions applied to CBC metrics, age, and gender. The study cohort was an average age of 61 years, 62% were men, and had a 3.3% annual risk of mortality. An integer (scalar) risk score (range 0 to 18) successfully separated patient cohorts into subgroups at markedly different mortality risks (<1% to >14% at 30 days). Predictive fractions (area under risk curve) at 30 days for the CBC-only model and the age- and gender-adjusted CBC model were 0.76 and 0.78, respectively, in the training set and 0.71 and 0.75, respectively, in the test set (all p values <<0.001). The CBC model was markedly more informative than models based only on hematocrit, white blood cell count, or age and gender and was superior to models with all 7 traditional risk factors. In conclusion, in a large, prospectively assembled database, a CBC risk model had high predictive ability for risk of incident mortality. A total CBC score is an important new addition to risk prediction, and it can be easily generated by computer for clinical use at negligible incremental cost.

Although increased cholesterol levels predict mortality in patients with coronary artery disease, it is unclear whether hypercholesterolemia is associated with adverse survival in patients with heart failure. A cohort of subjects derived from the Intermountain Heart Collaborative Study Registry (1993 to 2003) who had ejection fractions < or = 40% or clinical diagnoses of heart failure and long-term follow-up for death were studied (n = 1,646). Total cholesterol (TC) was divided into quartiles: quartile 1, < 141.3 mg/dl; quartile 2, 141.3 to 167.9 mg/dl; quartile 3, 168.0 to 201.0 mg/dl; and quartile 4, > 201.0 mg/dl. Multivariate Cox regression models were used to evaluate the associations of cholesterol, statin therapy, and C-reactive protein to mortality. The mean age was 65.5 years; 65% of the subjects were men and 65% had coronary artery disease. Although 53% were using statins, statin use was not different across TC quartiles. Average time to death was 2.4 years (maximum 10). Mortality for quartile 4 versus quartile 1 was not different (hazard ratio [HR] 1.12, p = 0.52); mortality was reduced for quartile 3 versus quartile 1 (HR 0.66, p = 0.027) and tended to be reduced for quartile 2 versus quartile 1 (HR 0.77, p = 0.14). Subanalysis of patients not using statins (n = 737, death = 20.2%) found no association between TC and survival (for quartile 3 vs quartile 1, HR 0.97, p = 0.89), but for patients using statins (n = 848, death = 16.3%), the effect was even greater for quartile 3 versus quartile 1 (HR 0.40, p = 0.002) than in the overall population. Nonsurvivors had higher levels of C-reactive protein than survivors. In conclusion, elevated TC appears to be associated with improved survival. The effect was stronger in patients receiving statin therapy, but the cause of this differential effect is uncertain.

A recent European case-control study suggested that statins increase the risk for polyneuropathy, a rare but serious neurologic condition. This risk was assessed in 272 patients with idiopathic polyneuropathy and 1,360 matched controls in the Intermountain Health Care electronic database. It was found that statin use before diagnosis was not significantly greater in patients than controls (odds ratio 1.30, 95% confidence interval 0.3 to 2.1, p = 0.27), nor were doses different between patients and controls.

Beta-blocker therapy has been shown to benefit patients who have coronary artery disease and present with acute myocardial infarction (AMI) and/or congestive heart failure (HF). However, whether beta-blocker therapy provides a similar benefit in patients who have coronary artery disease but not AMI or HF is unknown. A population of 4,304 patients who did not have HF but did have angiographically confirmed coronary artery disease (>/=1 stenosis of >/=70%) without AMI at hospital presentation was evaluated. Baseline demographics, cardiac risk factors, clinical presentation, therapeutic procedures, and discharge medications were recorded. Patients were followed for a mean of 3.0 +/- 1.9 years (range 1 month to 6.9 years) for outcomes of all-cause death or AMI. Patients' average age was 65 +/- 11 years and 77% were men. Overall, 10% died and 5% had a nonfatal AMI. Discharge beta-blocker prescription was associated with an increased event-free AMI survival rate for all-cause death (no beta blocker 88.3%, beta blocker 94.5%, p <0.001) and death/AMI (no beta blocker 83.4%, beta blocker 89.2%, p <0.001) but not non-fatal AMI (no beta blocker 93.6%, beta blocker 94.1%, p = 0.60). After adjustment for 16 covariates, including statin prescription, angiotensin-converting enzyme inhibitor prescription, and type of baseline therapy, the effect of beta blockers on the combination end point of death/AMI was eliminated. However, the effect of beta blockers on death remained (hazard ratio 0.66, 95% confidence interval 0.47 to 0.93, p = 0.02). Thus, beta blockers are clearly indicated for most patients who have HF or AMI, and our results suggest that patients who have coronary artery disease without these conditions have approximately the same protective benefit against death. No effect was observed on longitudinal incidence of AMI or the combination of death/nonfatal MI.

A medium-sensitivity assay for C-reactive protein (CRP) was compared with a high-sensitivity, enhanced immunoturbidimetric assay in 803 angiographically studied patients. Different absolute CRP values were found by the assays, but there was a high correlation by quartile rank and similar predictive values for death and myocardial infarction. This suggests that the conclusions of previous studies performed using the medium-sensitivity assay are still valid but that cross-study comparisons should use percentile rank.

Inflammation has been implicated in the pathogenesis of cardiovascular diseases. C-reactive protein (CRP), a marker of systemic inflammation, predicts the risk of coronary events and stroke. Atrial fibrillation (AF) is associated with atrial structural changes that may have an inflammatory basis. We tested the hypothesis that CRP is a risk factor for AF. Subjects were those included in the database registry of the Intermountain Heart Collaborative Study from 1994 to 2001. Patients who had >or=1 electrocardiogram that demonstrated AF formed the disease group (n = 347), and those who had neither electrocardiographic nor clinical evidence for AF comprised the control group (n = 2,449). Logistic regression assessed the quartile (Q) of CRP and 13 other clinical and angiographic predictors of AF. Average age was 63 +/- 12 years, 33% were women, and 61% had advanced coronary artery disease. Patients who had AF were older (by 7 years) and more frequently had a history of heart failure than did controls (41% vs 9%). CRP was higher in patients who had AF than in controls (p <0.001). Q-CRP was a univariable predictor of AF (odds ratio 1.39/Q, 95% confidence interval 1.25 to 1.55, p <0.001). Adjusting for age and heart failure decreased the predictive value of Q-CRP to 1.20/Q (95% confidence 1.07 to 1.34, p = 0.002), whereas further adjustment for 11 other variables had little additional effect (odds ratio 1.19/Q, 95% confidence interval 1.06 to 1.33, p = 0.003). Thus, high levels of CRP independently predicted an increased risk of AF among a large, prospectively studied patient cohort that was assessed angiographically. Increased CRP is a new risk marker for AF propensity, and testing therapies that target inflammation should be considered.

Statins improve survival in patients with coronary artery disease, especially those with elevated C-reactive protein (CRP). Although some randomized studies have shown a delay in statin-related survival advantage of up to 2 years, recent studies demonstrated early (<2 months) survival benefit in certain patient groups. We hypothesized that this early benefit relates to baseline CRP concentration. Patients (n = 2,924) with significant, angiographically defined coronary artery disease (>/=70% stenosis in >/=1 coronary artery) were followed for an average of 2.4 years after discharged on a statin prescription. CRP was divided into tertiles (<1.2, 1.2 to 1.7, >1.7 mg/dl), and Kaplan-Meier methods were used to determine timing of statin benefit in both the overall population and a propensity score-matched subgroup. Cox regressions (multivariable and propensity score approaches) were used to predict mortality. Statins were prescribed for 28.4% of patients. In the first CRP tertile, no early statin benefit was observed (adjusted hazard ratio 0.69, 95% confidence interval [CI] 0.30 to 1.6, p = 0.39), and survival curves separated after >2 years. However, in the second and the third tertiles, statin survival curves separated much earlier ( approximately 3 months and 1 week, respectively) and statins predicted improved survival (second tertile: hazard ratio 0.63, 95% CI 0.32 to 1.2, p = 0.17; third tertile: hazard ratio 0.35, 95% CI 0.18 to 0.67, p = 0.002). Propensity score analysis confirmed both statin benefit and early timing. Thus, statin use in patients with high CRP provides not only a larger but also a significantly earlier absolute survival benefit than statin use in patients with lower CRP. This provides further evidence of an anti-inflammatory effect of statins.

Purpose: To determine whether sex and age affect serum C-reactive protein level and its prognostic value in patients with coronary artery disease., Methods: In a consecutive series of 2254 patients with angiographically defined coronary artery disease, baseline C-reactive protein and predictive value for incident death or nonfatal myocardial infarction by sex and age (<55 and > or =55 years) were compared. C-reactive protein levels were measured by fluorescence polarization immunoassay with use of a medium-sensitivity method. Patients were followed for a mean (+/-SD) of 3.1 +/- 2.2 years. Comparisons used ln-transformed C-reactive protein and linear and time-to-event regression analyses, adjusting for confounders., Results: Overall, women had higher geometric mean C-reactive protein levels than did men (1.47 vs. 1.30 mg/dL, P <0.001), even after adjustment for age, hyperlipidemia, diabetes, prior myocardial infarction, body mass index, and heart failure (P = 0.002). High C-reactive protein levels were associated with increased mortality or myocardial infarction among men (adjusted hazard ratio [HR] = 1.9; 95% confidence interval [CI]: 1.5 to 2.3) but not among women (HR = 1.0; 95% CI: 0.69 to 1.4). Among patients aged <55 years, C-reactive protein level was similarly predictive in men and women (HR = 2.2 vs. 2.7), whereas in patients > or =55 years of age, it remained predictive for men (HR = 1.8; 95% CI: 1.5 to 2.3) but not women (HR = 0.93; 95% CI: 0.63 to 1.4)., Conclusion: We found that the prognostic value of C-reactive protein in coronary artery disease patients varied by sex and age. This sex-age interaction may have important implications for C-reactive protein-based secondary risk assessment and requires further investigation.

Purpose: In 1998, the Food and Drug Administration mandated the fortification of food products with folic acid. The effect of this rule on mortality associated with homocysteine levels in patients with coronary artery disease is unknown., Methods: We studied 2481 consecutive patients with coronary artery disease who underwent coronary angiography between 1994 and 1999, and who had baseline homocysteine measurements and at least 2 years of follow-up. Patients were divided into prefortification (1994 to 1997, n = 1595) and postfortification (1998 to 1999, n = 886) groups, as well as classified based on baseline homocysteine levels (normal to low, intermediate, and high). Homocysteine levels were measured by fluorescence polarization immunoassay. Mortality was determined by telephone survey or from a national Social Security database or hospital records., Results: After implementation of the fortification rule, median homocysteine levels declined from 13.8 to 12.3 micromol/L (P <0.001), and the proportion of patients with high homocysteine levels (>15 micromol/L) decreased from 41% (n = 650) to 28% (n = 249) (P <0.001). Overall, homocysteine was a modest risk factor for mortality (adjusted relative risk [RR] = 1.03 per micromol/L; 95% confidence interval [CI]: 1.01 to 1.05; P = 0.006). There was no significant interaction between fortification status and homocysteine category with mortality (P for interaction = 0.85). Two-year mortality was reduced minimally (7.8% [n = 124] to 7.2% [n = 64]; RR = 0.93; 95% CI: 0.68 to 1.27; P = 0.63; adjusted RR = 0.97; 95% CI: 0.68 to 1.40), but was consistent with the expectation of a modest reduction in homocysteine levels., Conclusion: Homocysteine is an independent, graded risk factor for mortality. Homocysteine levels decreased modestly after the fortification of food with folic acid, but the effects on mortality were minor and likely attributable to other factors, indicating the need for more aggressive measures to reduce homocysteine-associated cardiovascular risk.

We investigated the association between Helicobacter pylori (H. pylori) infection and coronary artery disease (CAD) in 2 study populations: (1) a cross-sectional study to determine risk of having CAD, and (2) a longitudinal study to determine risk of acute myocardial infarction (AMI) or death over a mean follow-up period of 3 years in patients with angiographically documented CAD. Blood samples were tested for serum immunoglobulin G antibodies to H. pylori and C-reactive protein (CRP) levels. Study 1: Of 391 patients (62% men, mean age 57 years), 41% had antibodies to H. pylori. CAD prevalence was 70% in H. pylori seropositive patients and 59% in seronegative patients (p = 0.03). Elevated CRP levels (>0.5 mg/dl) were significantly higher in patients with than without CAD (p = 0.02). By univariate analysis, CAD prevalence significantly increased stepwise depending on H. pylori seropositivity and elevated CRP levels (p = 0.008). Significance was lost after adjustment for traditional risk factors. Further analyses revealed that age was the critical confounder. Study 2: Of 929 patients (77% men, mean age 65 years), 56% had antibodies to H. pylori. By univariate analysis, the incidence of AMI or death was 22% in H. pylori seropositive patients and 18% in seronegative patients (p = 0.1). The adjusted hazard ratio of AMI or death for H. pylori seropositivity was 1.12 (95% confidence interval 0.81 to 1.54). Our data suggest that prior infection with H. pylori is not a major factor determining either risk of CAD, AMI, or death in patients with CAD.

High-sensitivity C-reactive protein (CRP), proposed as a new coronary risk marker, may reflect either an acute phase reaction or the level of chronic inflammation. Thus, CRP may be less predictive of long-term outcomes when measured after acute myocardial infarction (AMI) than after unstable angina pectoris (UAP) or stable angina pectoris (SAP). A total of 1,360 patients with severe coronary artery disease (>/=1 stenosis >/=70%) had CRP levels obtained at angiography. Presenting diagnoses were SAP (n = 599), UAP (n = 442), or AMI (n = 319). During follow-up (mean 2.8 years), death or nonfatal AMI (D/AMI) occurred in 19.5%, 16.1%, and 17.2% (p = NS) with SAP, UAP, and AMI, respectively. Corresponding median CRP levels were 1.31, 1.27, and 2.50 mg/dl (p <0.001). For the overall cohort, increasing age, low ejection fraction, revascularization, and elevated CRP were the strongest of 6 independent predictors for D/AMI. Among those presenting with SAP, CRP levels above the first tertile were associated with an adjusted hazard ratio of 1.8 (95% confidence interval [CI] 1.2 to 2.8, p <0.009) for D/AMI. After UAP, the hazard ratio was 2.7 (95% CI 1.4 to 5.0, p <0.002). However, when measured during hospitalization for AMI, CRP was not predictive of long-term outcome (hazard ratio 1.0 [95 % CI 0.5 to 1.7] p = 0.86). In conclusion, predischarge CRP levels are higher after AMI than after UAP or SAP. However, whereas CRP is strongly predictive of long-term D/AMI for patients presenting with SAP or UAP, it is not predictive shortly after AMI, suggesting that measurements should be delayed until the acute phase reaction is over and levels have returned to baseline.