Establishing an infrastructure to optimize the integration of genomics into research: Results from a precision health needs assessment.

Researchers across the translational research continuum have emphasized the importance of integrating genomics into their research program. To date capacity and resources for genomics research have been limited; however, a recent population-wide genomic screening initiative launched at the Medical University of South Carolina in partnership with Helix has rapidly advanced the need to develop appropriate infrastructure for genomics research at our institution. We conducted a survey with researchers from across our institution (n = 36) to assess current knowledge about genomics health, barriers, and facilitators to uptake, and next steps to support translational research using genomics. We also completed 30-minute qualitative interviews with providers and researchers from diverse specialties (n = 8). Quantitative data were analyzed using descriptive analyses. A rapid assessment process was used to develop a preliminary understanding of each interviewee's perspective. These interviews were transcribed and coded to extract themes. The codes included types of research, alignment with precision health, opportunities to incorporate precision health, examples of researchers in the field, barriers, and facilitators to uptake, educational activity suggestions, questions to be answered, and other observations. Themes from the surveys and interviews inform implementation strategies that are applicable not only to our institution, but also to other organizations interested in making genomic data available to researchers to support genomics-informed translational research.

Researchers have recognized the significance of integrating genomics into their studies across the translational research continuum. However, limited capacity and resources have hindered progress in genomics research. We conducted a survey and qualitative interviews with researchers and healthcare providers from our institution to assess their understanding of genomics in health, identify barriers, and facilitators to its adoption, and determine next steps for supporting translational research using genomics. Themes identified included different types of research, alignment with precision health, opportunities to incorporate precision health, examples of researchers in the field, barriers, and facilitators to adoption, educational recommendations, unanswered questions, and other valuable observations. The insights gathered from the surveys and interviews informed the development of implementation strategies. These strategies can benefit not only our institution but also other researchers who are interested in providing access to genomic data to support genomics-informed translational research.

Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.

BACKGROUND: Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. METHODS: An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated. RESULTS: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%; ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence. CONCLUSIONS: In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.

Management of heart failure in cardiac amyloidosis using an ambulatory diuresis clinic.

BACKGROUND: Recurrent congestion in cardiac amyloidosis (CA) remains a management challenge, often requiring high dose diuretics and frequent hospitalizations. Innovative outpatient strategies are needed to effectively manage heart failure (HF) in patients with CA. Ambulatory diuresis has not been well studied in restrictive cardiomyopathy. Therefore, we aimed to examine the outcomes of an ambulatory diuresis clinic in the management of congestion related to CA. METHODS AND RESULTS: We retrospectively studied patients with CA seen in an outpatient HF disease management clinic for (1) safety outcomes of ambulatory intravenous (IV) diuresis and (2) health care utilization. Forty-four patients with CA were seen in the clinic a total of 203 times over 6 months. Oral diuretics were titrated at 96 (47%) visits. IV diuretics were administered at 56 (28%) visits to 17 patients. There were no episodes of severe acute kidney injury or symptomatic hypotension. There was a significant decrease in emergency department and inpatient visits and associated charges after index visit to the clinic. The proportion of days hospitalized per 1000 patient days of follow-up decreased as early as 30 days (147.3 vs 18.1/1000 patient days of follow-up, P< .001) and persisted through 180 days (33.6 vs 22.9/1000 patient days of follow-up, P< .001) pre- vs post-index visit to the clinic. CONCLUSIONS: We demonstrate the feasibility of ambulatory IV diuresis in patients with CA. Our findings also suggest that use of a HF disease management clinic may reduce acute care utilization in patients with CA. Leveraging multidisciplinary outpatient HF clinics may be an effective alternative to hospitalization in patients with HF due to CA, a population who otherwise carries a poor prognosis and contributes to high health care burden.

Reader- and instrument-dependent variability in the electrocardiographic assessment of arrhythmogenic right ventricular dysplasia/cardiomyopathy.

INTRODUCTION: Despite the use of standardized definitions, widely varying prevalence estimates of electrocardiographic (ECG) features related to arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) have been reported in different cohorts. This study was aimed at examining the variability in the ECG interpretation resulting from the same reader, different readers, and using different ECG-resolutions. METHODS AND RESULTS: Blinded to other clinical data, 2 readers examined quantitative and qualitative ECG features of 20 (10 ARVD/C) randomly selected individuals. ECGs were recorded at standard-speed (SS) and double-speed-double-amplitude (DS) settings. The SS ECGs were scanned, magnified 4×, and evaluated using electronic calipers (EL). One reader repeated all measurements. For both readers, the intraclass correlation coefficient (ICC) for the measurement of QRS duration was good between conventional and electronic evaluation [DS vs EL: Reader 1--0.64 (0.52-0.73); Reader 2--0.67 (0.55-0.76)][SS vs EL: Reader 1--0.60 (0.47-0.70); Reader 2--0.60 (0.47-0.70)]. Using the same resolution, the intrareader ICC was good for SS [0.70 (0.59-0.78)], DS [0.85 (0.80-0.90)], and EL [0.70 (0.69-0.83)] resolutions, but deteriorated for interreader comparisons [0.50 (0.36-0.62), 0.75 (0.66-0.82), and 0.75 (0.66-0.82), respectively]. For qualitative parameters, the intra- and interreader agreement was inconsistent for all but 2 parameters. Both readers were in perfect agreement while interpreting right precordial T-wave inversion [κ= 1] and right bundle branch block morphology (RBBB) [κ= 0.83 (0.5-1.0)] even when using SS resolution. CONCLUSIONS: Right precordial t-wave inversion and RBBB are the only ECG parameters that can be detected consistently even using the conventionally used ECG-resolution. The substantial variability in evaluation of other parameters is not improved even with the use of higher resolutions.

Conductance catheter-based assessment of arterial input impedance, arterial function, and ventricular-vascular interaction in mice.

Global assessment of both cardiac and arterial function is important for a meaningful interpretation of pathophysiological changes in animal models of cardiovascular disease. We simultaneously acquired left ventricular (LV) and aortic pressure and LV volume (V(LV)) in 17 open-chest anesthetized mice (26.7 +/- 3.2g) during steady-state (BL) and caval vein occlusion (VCO) using a 1.4-Fr dual-pressure conductance catheter and in a subgroup of eight animals during aortic occlusion (AOO). Aortic flow was obtained from numerical differentiation of V(LV). AOO increased input impedance (Z(in)) for the first two harmonics, increased characteristic impedance (0.025 +/- 0.007 to 0.040 +/- 0.011 mmHg x microl(-1) x s, P < 0.05), and shifted the minimum in Z(in) from the third to the sixth harmonic. For all conditions, the Z(in) could be well represented by a four-element windkessel model. The augmentation index increased from 116.7 +/- 7.8% to 145.9 +/- 19.5% (P < 0.01) as well as estimated pulse-wave velocity (3.50 +/- 0.94 to 5.95 +/- 1.62 m/s, P < 0.05) and arterial elastance (E(a), 4.46 +/- 1.62 to 6.02 +/- 1.43 mmHg/microl, P < 0.01). AOO altered the maximal slope (E(max), 3.23 +/- 1.02 to 5.53 +/- 1.53 mmHg/microl, P < 0.05) and intercept (-19.9 +/- 8.6 to 1.62 +/- 13.51 microl, P < 0.01) of the end-systolic pressure-volume relation but not E(a)/E(max) (1.44 +/- 0.43 to 1.21 +/- 0.37, not significant). We conclude that simultaneous acquisition of Z(in) and arterial function parameters in the mouse, based solely on conductance catheter measurements, is feasible. We obtained an anticipated response of Z(in) and arterial function parameters following VCO and AOO, demonstrating the sensitivity of the measuring technique to induced physiological alterations in murine hemodynamics.