Phenotypic analysis of arrhythmogenic cardiomyopathy in the Hutterite population: role of electrocardiogram in identifying high-risk desmocollin-2 carriers.

BACKGROUND: The p.Gln554X mutation in desmocollin-2 (DSC2) is prevalent in ≈10% of the Hutterite population. While the homozygous mutation causes severe biventricular arrhythmogenic right ventricular cardiomyopathy, the phenotypic features and prognosis of heterozygotes remain incompletely understood. METHODS AND RESULTS: Eleven homozygotes (mean age 32±8 years, 45% female), 28 heterozygotes (mean age 40±15 years, 50% female), and 22 mutation-negatives (mean age 43±17 years, 41% female) were examined. Diagnostic testing was performed as per the arrhythmogenic right ventricular cardiomyopathy modified Task Force Criteria. Inverted T waves in the right precordial leads on ECG were seen in all homozygotes but not in their counterparts (P<0.001). Homozygotes had higher median daily premature ventricular complex burden than did heterozygotes or mutation-negatives (1407 [IQR 1080 to 2936] versus 2 [IQR 0 to 6] versus 6 [IQR 0 to 214], P=0.0002). Ventricular tachycardia was observed in 60% of homozygotes but in none of the remaining individuals (P<0.001). On cardiac magnetic resonance imaging, homozygotes had significantly larger indexed end-diastolic volumes (right ventricular: 122±24 versus 83±17 versus 83±12 mL/m(2), P<0.0001; left ventricular: 93±18 versus 76±13 versus 80±11 mL/m(2), P=0.0124) and lower ejection fraction values compared with heterozygotes and mutation-negatives (right ventricular ejection fraction: 41±9% versus 59±9% versus 61±6%, P<0.0001; left ventricular ejection fraction: 53±8% versus 65±5% versus 64±5%, P<0.0001). Most affected individuals lacked right ventricular wall motion abnormalities. Thus, few met cardiac magnetic resonance imaging task force criteria. CONCLUSIONS: The ECG reliably identifies homozygous p.Gln554X carriers and may be useful as an initial step in the screening of high-risk Hutterites. The cardiac phenotype of heterozygotes appears benign, but further prospective follow-up of their arrhythmic risk is needed.

Accuracy and reproducibility of semi-automated late gadolinium enhancement quantification techniques in patients with hypertrophic cardiomyopathy.

BACKGROUND: The presence and extent of late gadolinium enhancement (LGE) has been associated with adverse events in patients with hypertrophic cardiomyopathy (HCM). Signal intensity (SI) threshold techniques are routinely employed for quantification; Full-Width at Half-Maximum (FWHM) techniques are suggested to provide greater reproducibility than Signal Threshold versus Reference Mean (STRM) techniques, however the accuracy of these approaches versus the manual assignment of optimal SI thresholds has not been studied. In this study, we compared all known semi-automated LGE quantification techniques for accuracy and reproducibility among patients with HCM. METHODS: Seventy-six HCM patients (51 male, age 54 ± 13 years) were studied. Total LGE volume was quantified using 7 semi-automated techniques and compared to expert manual adjustment of the SI threshold to achieve optimal segmentation. Techniques tested included STRM based thresholds of >2, 3, 4, 5 and 6 SD above mean SI of reference myocardium, the FWHM technique, and the Otsu-auto-threshold (OAT) technique. The SI threshold chosen by each technique was recorded for all slices. Bland-Altman analysis and intra-class correlation coefficients (ICC) were reported for each semi-automated technique versus expert, manually adjusted LGE segmentation. Intra- and inter-observer reproducibility assessments were also performed. RESULTS: Fifty-two of 76 (68%) patients showed LGE on a total of 202 slices. For accuracy, the STRM >3SD technique showed the greatest agreement with manual segmentation (ICC = 0.97, mean difference and 95% limits of agreement = 1.6 ± 10.7 g) while STRM >6SD, >5SD, 4SD and FWHM techniques systematically underestimated total LGE volume. Slice based analysis of selected SI thresholds similarly showed the STRM >3SD threshold to most closely approximate manually adjusted SI thresholds (ICC = 0.88). For reproducibility, the intra- and inter-observer reproducibility of the >3SD threshold demonstrated an acceptable mean difference and 95% limits of agreement of -0.5 ± 6.8 g and -0.9 ± 5.6 g, respectively. CONCLUSIONS: FWHM segmentation provides superior reproducibility, however systematically underestimates total LGE volume compared to manual segmentation in patients with HCM. The STRM >3SD technique provides the greatest accuracy while retaining acceptable reproducibility and may therefore be a preferred approach for LGE quantification in this population.

The Alberta Heart Failure Etiology and Analysis Research Team (HEART) study.

BACKGROUND: Nationally, symptomatic heart failure affects 1.5-2% of Canadians, incurs $3 billion in hospital costs annually and the global burden is expected to double in the next 1-2 decades. The current one-year mortality rate after diagnosis of heart failure remains high at >25%. Consequently, new therapeutic strategies need to be developed for this debilitating condition. METHODS/DESIGN: The objective of the Alberta HEART program (http://albertaheartresearch.ca) is to develop novel diagnostic, therapeutic and prognostic approaches to patients with heart failure with preserved ejection fraction. We hypothesize that novel imaging techniques and biomarkers will aid in describing heart failure with preserved ejection fraction. Furthermore, the development of new diagnostic criteria will allow us to: 1) better define risk factors associated with heart failure with preserved ejection fraction; 2) elucidate clinical, cellular and molecular mechanisms involved with the development and progression of heart failure with preserved ejection fraction; 3) design and test new therapeutic strategies for patients with heart failure with preserved ejection fraction. Additionally, Alberta HEART provides training and education for enhancing translational medicine, knowledge translation and clinical practice in heart failure. This is a prospective observational cohort study of patients with, or at risk for, heart failure. Patients will have sequential testing including quality of life and clinical outcomes over 12 months. After that time, study participants will be passively followed via linkage to external administrative databases. Clinical outcomes of interest include death, hospitalization, emergency department visits, physician resource use and/or heart transplant. Patients will be followed for a total of 5 years. DISCUSSION: Alberta HEART has the primary objective to define new diagnostic criteria for patients with heart failure with preserved ejection fraction. New criteria will allow for targeted therapies, diagnostic tests and further understanding of the patients, both at-risk for and with heart failure. TRIAL REGISTRATION: ClinicalTrials.gov NCT02052804.

Secondhand smoke exposure and quality of life in patients with heart failure.

BACKGROUND: Secondhand smoke (SHS) exposure is associated with an increased risk of atherosclerotic heart disease and cardiac events. We sought to assess the effect of SHS on health-related quality of life (HRQOL) in patients with heart failure. METHODS: Current nonsmokers with heart failure (N = 205) were enrolled in a cohort study. Exposure to SHS was assessed with a validated exposure questionnaire and a high-sensitivity assay for urinary cotinine level. Multidimensional HRQOL was evaluated with the RAND 36-Item Short Form Health Survey, which assesses 8 domains on a scale of 0 (worst) to 100 (best): physical functioning, bodily pain, role limitations due to physical health problems (role physical), role limitations due to emotional/personal problems (role emotional), emotional well-being, social functioning, energy/fatigue, and general health perceptions. A subset of patients (n = 75) agreed to assessment of functional status with a 6-minute walk test. RESULTS: Self-reported exposure to SHS was associated with generally lower HRQOL scores in univariate analysis, with statistically and clinically significant reductions in 3 subscale scores: role physical (22.2 points), emotional well-being (11.0 points), and role emotional (16.2 points). Even after adjustment for clinical factors, such as age, sex, New York Heart Association class of heart failure, comorbidities, and medications, exposure to SHS remained an independent predictor of HRQOL scores in these domains. When increasing quartiles of urinary cotinine level were used as the exposure measure, qualitatively similar results were obtained. CONCLUSIONS: Even low levels of SHS are associated with lower scores in several aspects of HRQOL. Physicians should advise patients with heart failure and their families to avoid SHS exposure.

Pulmonary vein stenosis following left pneumonectomy: a variant contributor to postpneumonectomy syndrome.

Postpneumonectomy syndrome is a recognized complication following pneumonectomy, resulting from mediastinal displacement into the vacated pleural space. Mediastinal displacement causes bronchial compression and dyspnea. This report describes a 47-year-old woman who presented with shortness of breath 6 months after a left pneumonectomy. She was initially hypoxic and was found to have a patent foramen ovale. Following closure of the patent foramen ovale, she was no longer hypoxic, but she continued to have dyspnea with exertion and left lateral decubitus positioning. There was no evidence of bronchial compression, but MRI and transesophageal echocardiography suggested pulmonary vein compression due to mediastinal displacement. Transthoracic echocardiography confirmed functional pulmonary vein compression that was worse in the standing and in the left lateral positions. Her symptoms improved with mediastinal repositioning using a transesophageal echocardiography-guided approach. Positional pulmonary vein compression may be an underdiagnosed complication of pneumonectomy.

Echocardiographic predictors of change in left ventricular diastolic pressure in heart failure patients receiving nesiritide.

BACKGROUND: To evaluate the usefulness of currently accepted echocardiographic parameters of diastolic function to assess the acute change in left ventricular end-diastolic pressure (LVEDP) following the administration of nesiritide in a heart failure population. METHODS: In 25 heart failure patients (15 with systolic dysfunction, 10 with preserved ejection fraction [EF]), Doppler echocardiography, right and left heart catheterization, and invasive biventricular pressure hemodynamics were obtained at baseline and 30 minutes after nesiritide infusion. RESULTS: Twenty-four patients had sufficient echocardiographic images for analysis. The mean age was 60 +/- 11 years, 48% were male, 56% had coronary artery disease, and 64% had hypertension. Right ventricular systolic pressure (RVSP) had the highest correlation with LV filling pressure: pulmonary capillary wedge pressure (PCWP), pre-A wave LV, and LVEDP (r = 0.66, P = 0.0009; r = 0.63, P = 0.002; r = 0.72, P = 0.0002, respectively). Following nesiritide administration, the mean PCWP decreased from 17.1 +/- 7.8 mmHg at baseline to 9.6 +/- 6.2 mmHg (P < 0.001). Change in RVSP had the highest correlation with change in PCWP (r =-0.67, P = 0.10) and change in LVEDP (r =-0.71, P = 0.07). CONCLUSION: Echocardiographic parameters are frequently assessed in attempts to estimate left heart diastolic pressures. In heart failure patients, RVSP appears to be the best predictor of LVEDP, outperforming tissue Doppler E/E'. RVSP was found to be the best echocardiographic predictor of change in LV filling pressure with intravenous vasodilator therapy in heart failure patients. RVSP may provide a noninvasive means of assessing response to cardiac therapy.

Nesiritide: the clinical experience.

Nesiritide is an effective therapy in decreasing symptoms and left ventricular filling pressure in patients with acute decompensated heart failure. Health Canada has recently approved this agent for the management of this patient population. The clinical trials to date using nesiritide for the management of decompensated heart failure have been summarized. The clinical experience including indications for use, contraindications, dosage and monitoring has been reviewed. The following should serve as a general guide for the clinical use of nesiritide.

The associations between tricuspid annular plane systolic excursion (TAPSE), ventricular dyssynchrony, and ventricular interaction in heart failure patients.

AIMS: Ventricular interactions may be mediated by loading conditions and biventricular timing and coordination. We sought to understand the relationships between right (RV) and left ventricular (LV) function and dyssynchrony, examine the RV correlates of LV dyssynchrony, and determine whether improved loading conditions affect inter-ventricular interaction. METHODS AND RESULTS: In 25 heart failure patients [15 with left ventricular ejection fraction (LVEF) < 40%; 10 with LVEF >/= 50%], Doppler echocardiography and invasive bi-ventricular pressure-volume haemodynamics were obtained at baseline and 30 min after infusion of the recombinant B-type natriuretic peptide vasodilator nesiritide. RV and LV intra-ventricular dyssynchrony was measured invasively using a pressure-conductance catheter. Patients with reduced LVEF had greater LV dyssynchrony (31 +/- 3 vs. 24 +/- 7%; P = 0.003) compared to those with preserved LVEF. Tricuspid annular plane systolic excursion (TAPSE) had the highest correlation with LV dyssynchrony (r = -0.52; P = 0.0002) compared to other RV echocardiographic parameters. The association between TAPSE and LV dyssynchrony was independent of RVEF and LVEF (P = 0.008). There were no acute changes in the correlations between LV dyssynchrony and TAPSE after nesiritide. CONCLUSION: TAPSE and LV dyssynchrony are strongly associated, independent of RV and LV ejection fraction. Of the RV echocardiographic parameters, TAPSE has the highest predictive value of LV dyssynchrony, and remained significant after vasodilator unloading.

Quantitative assessment of severity of mitral regurgitation by serial echocardiography in a multicenter clinical trial of percutaneous mitral valve repair.

The aims of the echocardiographic substudy of this multicenter trial were to evaluate the use of quantitative assessment of mitral regurgitation (MR) severity using serial echocardiography and to assess the efficacy of percutaneous mitral valve repair. Previous surgical repair studies did not use quantitative echocardiographic methods. Results of a percutaneous mitral valve repair clip device in a core echocardiographic laboratory were evaluated. Published parameters for quantifying MR were used in a systematic protocol to qualify patients for study entry and evaluate treatment efficacy at discharge and 6 months after clip repair. Baseline results were presented for 55 patients, and follow-up results, for 49. Ninety-eight percent of required echocardiographic studies were submitted to the core laboratory, and >85% of required measurements were possible. At baseline, mean regurgitant volume was 54.8 +/- 24 ml, regurgitant fraction was 46.9 +/-16.2%, effective regurgitant orifice area was 0.71 +/- 0.40 cm(2), and vena contracta width was 0.66 +/- 0.20 cm. Based on a severity scale of 1 to 4, mean color flow grade was 3.4 +/- 0.7, and mean pulmonary vein flow was 2.8 +/- 1.2. In patients with a clip at 6 months, all measurements of MR severity were significantly decreased versus baseline, with mean regurgitant volume decreased from 50.3 to 27.5 ml (change -22.8 ml; p <0.0001), regurgitant fraction from 44.6% to 28.9% (change -15.7%; p <0.0001), color flow grade from an average of 3.4 to 1.8 (change -1.6; p <0.0001), and pulmonary vein flow from 2.8 to 1.8 (change -1.0; p <0.0018). In conclusion, quantitative assessment of MR is feasible in a multicenter trial, and percutaneous mitral repair with the MitraClip produces a sustained decrease in MR severity to moderate or less for > or =6 months.