In the 15 years following the release of the first complete human genome sequences, our understanding of rare and common genetic variation as determinants of cardiovascular disease susceptibility, ...prognosis, and therapeutic response has grown exponentially. As such, the use of genomics to enhance the care of patients with cardiovascular diseases has garnered increased attention from clinicians, researchers, and regulatory agencies eager to realize the promise of precision genomic medicine. However, owing to a large burden of "complex" common diseases, emphasis on evidence-based practice, and a degree of unfamiliarity/discomfort with the language of genomic medicine, the development and implementation of genomics-guided approaches designed to further individualize the clinical management of a variety of cardiovascular disorders remains a challenge. In this review, we detail a practical approach to genetic testing initiation and interpretation as well as review the current state of cardiovascular genetic and pharmacogenomic testing in the context of relevant society and regulatory agency recommendations/guidelines.
Objectives This study sought to assess sex differences in ventricular-arterial interactions. Background Heart failure with preserved ejection fraction is more prevalent in women than in men, but the ...basis for this difference remains unclear. Methods Echocardiography and arterial tonometry were performed to quantify arterial and ventricular stiffening and interaction in 461 participants without heart failure (189 men, age 67 ± 9 years; 272 women, age 65 ± 10 years). Aortic characteristic impedance (Zc ), total arterial compliance (pulsatile load), and systemic vascular resistance index (steady load) were compared between men and women, and sex-specific multivariable regression analyses were performed to assess associations of these arterial parameters with diastolic dysfunction and ventricular-arterial coupling (effective arterial elastance/left ventricular end-systolic elastance Ea/Ees) after adjustment for potential confounders. Results Zc was higher and total arterial compliance was lower in women, whereas systemic vascular resistance index was similar between sexes. In women but not men, higher log Zc was associated with mitral inflow E/A ratio (β ± SE: −0.17 ± 0.07), diastolic dysfunction (odds ratio: 7.8; 95% confidence interval: 2.0 to 30.2) and Ea/Ees (β ± SE: 0.13 ± 0.04) (p ≤ 0.01 for all). Similarly, total arterial compliance was associated with E/A ratio (β ± SE: 0.12 ± 0.04), diastolic dysfunction (odds ratio: 0.33; 95% confidence interval: 0.12 to 0.89), and Ea/Ees (β ± SE: −0.09 ± 0.03) in women only (p ≤ 0.03 for all). Systemic vascular resistance index was not associated with diastolic dysfunction or Ea/Ees. Conclusions Proximal aortic stiffness (Zc ) is greater in women than men, and women may be more susceptible to the deleterious effects of greater pulsatile and early arterial load on diastolic function and ventricular-arterial interaction. This may contribute to the greater risk of heart failure with preserved ejection fraction in women.
Increased red blood cell distribution width (RDW), a marker of anisocytosis, has been associated with adverse outcomes in multiple settings. Whether RDW is predictive of mortality in patients with ...peripheral artery disease (PAD) is unknown. We studied 13,039 consecutive outpatients (69.5 ± 12.0 years of age, 60.9% men, 97.6% white) with PAD identified by noninvasive lower-extremity arterial testing at the Mayo Clinic from January 1997 through December 2007, with follow-up through September 2009. We defined PAD as a low (≤0.9) or high (≥1.4) ankle–brachial index (ABI). Cardiovascular risk factors and co-morbidities were ascertained using electronic medical record–based algorithms. RDW was obtained from the complete blood cell count drawn around the time of arterial evaluation. Mortality was ascertained using the Mayo electronic medical record and Accurint databases. Association of RDW with all-cause mortality was analyzed by multivariable Cox proportional hazards regression. During a median follow-up of 5.5 years, 4,039 (31.0%) deaths occurred (28.7% in low and 38.9% in high ABI subsets). After adjustment for age, gender, cardiovascular risk factors, and co-morbidities, patients in the highest quartile of RDW (>14.5%) had a 66% greater risk of mortality compared to the lowest quartile (<12.8%, p <0.0001); a 1% increment in RDW was associated with a 10% greater risk of all-cause mortality (hazard ratio 1.10, 95% confidence interval 1.08 to 1.12, p <0.0001). The adjusted hazard ratio was similar in the low (1.10, 1.08 to 1.12) and high (1.09, 1.06 to 1.12) ABI subsets. In conclusion, RDW, a routinely available measurement, is an independent prognostic marker in patients with PAD.
Abstract Objective Lower extremity peripheral arterial disease (PAD) is highly prevalent and affects millions of individuals worldwide. We developed a natural language processing (NLP) system for ...automated ascertainment of PAD cases from clinical narrative notes and compared the performance of the NLP algorithm with billing code algorithms, using ankle-brachial index test results as the gold standard. Methods We compared the performance of the NLP algorithm to (1) results of gold standard ankle-brachial index; (2) previously validated algorithms based on relevant International Classification of Diseases, Ninth Revision diagnostic codes (simple model); and (3) a combination of International Classification of Diseases, Ninth Revision codes with procedural codes (full model). A dataset of 1569 patients with PAD and controls was randomly divided into training (n = 935) and testing (n = 634) subsets. Results We iteratively refined the NLP algorithm in the training set including narrative note sections, note types, and service types, to maximize its accuracy. In the testing dataset, when compared with both simple and full models, the NLP algorithm had better accuracy (NLP, 91.8%; full model, 81.8%; simple model, 83%; P < .001), positive predictive value (NLP, 92.9%; full model, 74.3%; simple model, 79.9%; P < .001), and specificity (NLP, 92.5%; full model, 64.2%; simple model, 75.9%; P < .001). Conclusions A knowledge-driven NLP algorithm for automatic ascertainment of PAD cases from clinical notes had greater accuracy than billing code algorithms. Our findings highlight the potential of NLP tools for rapid and efficient ascertainment of PAD cases from electronic health records to facilitate clinical investigation and eventually improve care by clinical decision support.
The American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines has recently released the new cholesterol treatment guideline. This update was based on a ...systematic review of the evidence and replaces the previous guidelines from 2002 that were widely accepted and implemented in clinical practice. The new cholesterol treatment guideline emphasizes matching the intensity of statin treatment to the level of atherosclerotic cardiovascular disease (ASCVD) risk and replaces the old paradigm of pursuing low-density lipoprotein cholesterol targets. The new guideline also emphasizes the primacy of the evidence base for statin therapy for ASCVD risk reduction and lists several patient groups that will not benefit from statin treatment despite their high cardiovascular risk, such as those with heart failure (New York Heart Association class II-IV) and patients undergoing hemodialysis. The guideline has been received with mixed reviews and significant controversy. Because of the evidence-based nature of the guideline, there is room for several questions and uncertainties on when and how to use lipid-lowering therapy in clinical practice. The goal of the Mayo Clinic Task Force in the assessment, interpretation, and expansion of the ACC/AHA cholesterol treatment guideline is to address gaps in information and some of the controversial aspects of the newly released cholesterol management guideline using additional sources of evidence and expert opinion as needed to guide clinicians on key aspects of ASCVD risk reduction.
Familial hypercholesterolemia (FH), a relatively common Mendelian genetic disorder, is associated with a dramatically increased lifetime risk of premature atherosclerotic cardiovascular disease due ...to elevated plasma low-density lipoprotein cholesterol (LDL-C) levels. The diagnosis of FH is based on clinical presentation or genetic testing. Early identification of patients with FH is of great public health importance because preventive strategies can lower the absolute lifetime cardiovascular risk and screening can detect affected relatives. However, low awareness, detection, and control of FH pose hurdles in the prevention of FH-related cardiovascular events. Of the estimated 0.65 million to 1 million patients with FH in the United States, less than 10% carry a diagnosis of FH. Based on registry data, a substantial proportion of patients with FH are receiving no or inadequate lipid-lowering therapy. Statins remain the mainstay of treatment for patients with FH. Lipoprotein apheresis and newly approved lipid-lowering drugs are valuable adjuncts to statin therapy, particularly when the LDL-C-lowering response is suboptimal. Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 provide an additional approximately 60% lowering of LDL-C levels and are approved for use in patients with FH. For homozygous FH, 2 new drugs that work independent of the LDL receptor pathway are available: an apolipoprotein B antisense oligonucleotide (mipomersen) and a microsomal triglyceride transfer protein inhibitor (lomitapide). This review attempts to critically examine the available data to provide a summary of the current evidence for managing patients with FH, including screening, diagnosis, treatment, and surveillance.
Background Little is known about prevalence, awareness, and control of familial hypercholesterolemia (FH) in the United States. Objective To address these knowledge gaps, we developed an ePhenotyping ...algorithm for rapid identification of FH in electronic health records (EHRs) and deployed it in the Screening Employees And Residents in the Community for Hypercholesterolemia (SEARCH) study. Methods We queried a database of 131,000 individuals seen between 1993 and 2014 in primary care practice to identify 5992 (mean age 52 ± 13 years, 42% men) patients with low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL, triglycerides <400 mg/dL and without secondary causes of hyperlipidemia. Results Our EHR-based algorithm ascertained the Dutch Lipid Clinic Network criteria for FH using structured data sets and natural language processing for family history and presence of FH stigmata on physical examination. Blinded expert review revealed positive and negative predictive values for the SEARCH algorithm at 94% and 97%, respectively. The algorithm identified 32 definite and 391 probable cases with an overall FH prevalence of 0.32% (1:310). Only 55% of the FH cases had a diagnosis code relevant to FH. Mean LDL-C at the time of FH ascertainment was 237 mg/dL; at follow-up, 70% (298 of 423) of patients were on lipid-lowering treatment with 80% achieving an LDL-C ≤100 mg/dL. Of treated FH patients with premature CHD, only 22% (48 of 221) achieved an LDL-C ≤70 mg/dL. Conclusions In a primary care setting, we found the prevalence of FH to be 1:310 with low awareness and control. Further studies are needed to assess whether automated detection of FH in EHR improves patient outcomes.
Arterial Ultrasonography and Tonometry as Adjuncts to Cardiovascular Risk Stratification Iftikhar J. Kullo, A. Rauoof Malik Tests for early detection of vascular disease are needed to refine ...cardiovascular risk stratification. Arterial ultrasonography and tonometry can be used to obtain several measures of arterial function and structure that may provide prognostic information incremental to conventional risk factors. Standardization of methodology and establishment of quality control standards in the performance of these tests could facilitate their integration into clinical practice as adjuncts to existing risk stratification algorithms.
OBJECTIVE To create a cohort for cost-effective genetic research, the Mayo Genome Consortia (MayoGC) has been assembled with participants from research studies across Mayo Clinic with high-throughput ...genetic data and electronic medical record (EMR) data for phenotype extraction. PARTICIPANTS AND METHODS Eligible participants include those who gave general research consent in the contributing studies to share high-throughput genotyping data with other investigators. Herein, we describe the design of the MayoGC, including the current participating cohorts, expansion efforts, data processing, and study management and organization. A genome-wide association study to identify genetic variants associated with total bilirubin levels was conducted to test the genetic research capability of the MayoGC. RESULTS Genome-wide significant results were observed on 2q37 (top single nucleotide polymorphism, rs4148325; P =5.0 × 10−62 ) and 12p12 (top single nucleotide polymorphism, rs4363657; P =5.1 × 10−8 ) corresponding to a gene cluster of uridine 5′-diphospho-glucuronosyltransferases (the UGT1A cluster ) and solute carrier organic anion transporter family, member 1B1 ( SLCO1B1 ), respectively. CONCLUSION Genome-wide association studies have identified genetic variants associated with numerous phenotypes but have been historically limited by inadequate sample size due to costly genotyping and phenotyping. Large consortia with harmonized genotype data have been assembled to attain sufficient statistical power, but phenotyping remains a rate-limiting factor in gene discovery research efforts. The EMR consists of an abundance of phenotype data that can be extracted in a relatively quick and systematic manner. The MayoGC provides a model of a unique collaborative effort in the environment of a common EMR for the investigation of genetic determinants of diseases.
Objectives Our goal was to evaluate the associations of central arterial stiffness, measured by aortic pulse wave velocity (aPWV), with subclinical target organ damage in the coronary, peripheral ...arterial, cerebral, and renal arterial beds. Background Arterial stiffness is associated with adverse cardiovascular outcomes. We hypothesized that aPWV is associated with subclinical measures of atherosclerosis—coronary artery calcification (CAC) and ankle-brachial index (ABI) and arteriolosclerosis—brain white matter hyperintensity (WMH) and urine albumin-creatinine ratio (UACR). Methods Participants (n = 812; mean age 58 years; 58% women, 71% hypertensive) belonged to hypertensive sibships and had no history of myocardial infarction or stroke. aPWV was measured by applanation tonometry, CAC by electron beam computed tomography, ABI using a standard protocol, WMH volume by brain magnetic resonance, and UACR by standard methods. WMH was log-transformed, whereas CAC and UACR were log-transformed after adding 1 to reduce skewness. The associations of aPWV with CAC, ABI, WMH, and UACR were assessed by multivariable linear regression using generalized estimating equations to account for the presence of sibships. Covariates included in the models were age, sex, body mass index, history of smoking, hypertension and diabetes, total and high-density lipoprotein cholesterol, estimated glomerular filtration rate, use of aspirin and statins, and pulse pressure. Results The mean ± SD aPWV was 9.8 ± 2.8 m/s. After adjustment for age, sex, conventional cardiovascular risk factors, and pulse pressure, higher aPWV (1 m/s increase) was significantly associated with higher log (CAC + 1) (β ± SE = 0.14 ± 0.04; p = 0.0003), lower ABI (β ± SE = −0.005 ± 0.002; p = 0.02), and greater log (WMH) (β ± SE = 0.03 ± 0.009; p = 0.002), but not with log (UACR + 1) (p = 0.66). Conclusions Higher aPWV was independently associated with greater burden of subclinical disease in coronary, lower extremity, and cerebral arterial beds, highlighting target organ damage as a potential mechanism underlying the association of arterial stiffness with adverse cardiovascular outcomes.
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