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Background: Type D personality has been previously shown to increase the risk for mortality in patients with acquired heart disease., Objective: We aimed to compare mortality in adult patients with congenital heart disease (CHD) with and without type D., Methods: Survival was assessed using prospective data from the Dutch national Congenital Corvitia registry for adults with CHD. Patients were randomly selected from the registry and characterized at inclusion in 2009 for the presence of type D using the DS14 questionnaire., Results: One thousand fifty-five patients, with 484 (46%) males, a mean (SD) age of 41 (14) years, 613 (58%) having mild CHD, 348 (33%) having moderate CHD, and 94 (9%) having severe CHD, were included. Type D personality was present in 225 patients (21%). Type D was associated with an increased risk for all-cause mortality independent of age, sex, New York Heart Association class, number of prescribed medications, depression, employment status, and marital status (hazard ratio, 1.94; 95% confidence interval, 1.05-3.57; P = .033)., Conclusion: Type D personality was associated with an increased risk for all-cause mortality in adult patients with CHD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Rationale: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored., Objective: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA., Methods and Results: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10 -10 , OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10 -5 ). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A , which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart., Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A . Genomic and functional data support a causal role of WNT5A at the locus.

Background: The effect of angiotensin II receptor blockers on right ventricular (RV) function is still unknown. Angiotensin II receptor blockers are beneficial in patients with acquired left ventricular dysfunction, and recent findings have suggested a favorable effect in symptomatic patients with systemic RV dysfunction. The current study aimed to determine the effect of losartan, an angiotensin II receptor blocker, on subpulmonary RV dysfunction in adults after repaired tetralogy of Fallot., Methods: The REDEFINE trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) is an investigator-initiated, multicenter, prospective, 1:1 randomized, double-blind, placebo-controlled study. Adults with repaired tetralogy of Fallot and RV dysfunction (RV ejection fraction [EF] <50%) but without severe valvular dysfunction were eligible. Patients were randomly assigned between losartan (150 mg daily) and placebo with target treatment duration between 18 and 24 months. The primary outcome was RV EF change, determined by cardiovascular MRI in intention-to-treat analysis., Results: Of 95 included patients, 47 patients received 150 mg losartan daily (age, 38.0±12.4 years; 74% male), and 48 patients received placebo (age, 40.6±11.4 years; 63% male). Overall, RV EF did not change in patients allocated to losartan (n=42) (44.4±5.1% to 45.2±5.0%) and placebo (n=46) (43.2±6.3% to 43.6±6.9%). Losartan did not significantly improve RV EF in comparison with placebo (+0.51%; 95% confidence interval, -1.0 to +2.0; P =0.50). No significant treatment effects were found on secondary outcomes: left ventricular EF, peak aerobic exercise capacity, and N-terminal pro-brain natriuretic peptide ( P >0.30 for all). In predefined subgroup analyses, losartan did not have a statistically significant impact on RV EF in subgroups with symptoms, restrictive RV, RV EF<40%, pulmonary valve replacement, or QRS fragmentation. However, in a post hoc analysis, losartan was associated with improved RV EF in a subgroup (n=30) with nonrestrictive RV and incomplete remodeling (QRS fragmentation and previous pulmonary valve replacement) (+2.7%; 95% confidence interval, +0.1 to +5.4; P =0.045)., Conclusions: Losartan had no significant effect on RV dysfunction or secondary outcome parameters in repaired tetralogy of Fallot. Future larger studies may determine whether there might be a role for losartan in specific vulnerable subgroups., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02010905., (© 2017 American Heart Association, Inc.)

Background: Right ventricular (RV) function is an important prognostic marker in patients with pulmonary hypertension. The present evaluation assessed the prognostic value of RV longitudinal peak systolic strain (LPSS) in patients with pulmonary hypertension., Methods and Results: A total of 150 patients with pulmonary hypertension of different etiologies (mean age, 59±15 years; 37.3% male) were evaluated. RV fractional area change and tricuspid annular plane systolic excursion index were evaluated with 2-dimensional echocardiography. RV LPSS was assessed with speckle-tracking echocardiography. The patient population was categorized according to a RV LPSS value of -19%. Among several clinical and echocardiographic parameters, the significant determinants of all-cause mortality were evaluated. There were no significant differences in age, sex, pulmonary hypertension cause and left ventricular ejection fraction between patients with RV LPSS <-19% and patients with RV LPSS ≥-19%. However, patients with RV LPSS ≥-19% had significantly worse New York Heart Association functional class (2.7±0.6 versus 2.3±0.8; P=0.003) and lower tricuspid annular plane systolic excursion (16±4 mm versus 18±3 mm; P<0.001) than their counterparts. During a median follow-up of 2.6 years, 37 patients died. RV LPSS was a significant determinant of all-cause mortality (HR, 3.40; 95% CI, 1.19-9.72; P=0.02)., Conclusions: In patients with pulmonary hypertension, RV LPSS is significantly associated with all-cause mortality. RV LPSS may be a valuable parameter for risk stratification of these patients. Future studies are needed to confirm these results in the pulmonary hypertension subgroups.

Background: Pulmonary regurgitation (PR) late after total correction for tetralogy of Fallot may lead to progressive right ventricular (RV) dilatation and an increased incidence of severe arrhythmias and sudden death. Timing of pulmonary valve replacement (PVR) is subject to discussion, because the effect of PVR on RV function in adults is unclear. In this study, MRI was used to assess the effect of PVR on RV function and PR. Clinical improvement was established by means of the NYHA classification., Methods and Results: Twenty-six adult patients were included. Cardiac MRI was performed at a median of 5.1+/-3.4 months before and 7.4+/- 2.4 months after PVR. Mean preoperative PR was 46+/-10% (range, 25% to 64%). After PVR, 20 of 26 patients (77%) showed no residual PR, 5 patients showed mild residual PR, and 1 patient showed moderate PR. RV end-diastolic volume (RV-EDV) decreased from 305+/-87 to 210+/-62 mL (P<0.001), and RV end-systolic volume (RV-ESV) decreased from 181+/-67 to 121+/-58 mL (P<0.001). No significant change was found in RV-EF (42% versus 42%). However, RVEF corrected for regurgitations and shunting increased from 25.2+/-8.0% to 43.3+/-13.7% (P<0.001). Mean validity class improved from 2.0 to 1.3 (P<0.001)., Conclusions: In adult patients with PR and RV dilatation, late after total correction of tetralogy of Fallot, MRI measurements show remarkable hemodynamic improvement of RV function after PVR and improvement of validity. We therefore advocate a less restrictive management concerning PVR in these patients.

Background: The application of previous magnetic resonance (MR) angiography techniques has enabled noninvasive differentiation between patent and occluded coronary artery bypass grafts. However, the detection of graft stenosis remains difficult. The purpose of our study was to determine the accuracy of high-resolution navigator-gated 3-dimensional (3-D) MR angiography in detecting vein graft disease. Methods and Results- MR angiography was performed in addition to coronary angiography with quantitative coronary analysis in 56 vein grafts from 38 patients (mean age 66.6+/-9.3 years), who presented with recurrent chest pain after bypass surgery. Eighteen grafts showed a luminal stenosis >/=50%, 11 grafts a stenosis >/=70%, and 6 grafts were occluded. All MR angiograms were evaluated independently by 2 blinded observers, who scored the presence of graft occlusion and graft stenosis >/=50% and >/=70% with a confidence level of 1 to 10. MR image quality was judged as insufficient in 6 grafts and these were excluded. Receiver-operator characteristic analysis revealed an area under the curve of 0.89 and 0.89 for identifying graft occlusion, 0.81 and 0.87 for stenosis >/=50%, and 0.82 and 0.79 for stenosis >/=70% for the 2 observers, respectively. Interobserver agreement in assessing graft occlusion and stenosis >/=50% and >/=70% was 94% (kappa=0.74, r=0.81), 72% (kappa=0.40, r=0.66), and 82% (kappa=0.53, r=0.72), respectively., Conclusions: High-resolution navigator-gated 3-D MR angiography allows not only good differentiation between patent and occluded vein grafts but also the assessment of vein graft disease with a fair diagnostic accuracy. This approach offers perspective as a noninvasive diagnostic tool for patients who present with recurrent chest pain after vein graft surgery.

Background: The question of whether training-induced left ventricular hypertrophy in athletes is a physiological rather than a pathophysiological phenomenon remains unresolved. The purpose of the present study was to detect any abnormalities in cardiac function in hypertrophic hearts of elite cyclists and to examine the response of myocardial high-energy phosphate metabolism to high workloads induced by atropine-dobutamine stress., Methods and Results: We studied 21 elite cyclists and 12 healthy control subjects. Left ventricular mass, volume, and function were determined by cine MRI. Myocardial high-energy phosphates were examined by 31P magnetic resonance spectroscopy. There were no significant differences between cyclists and control subjects for left ventricular ejection fraction (59+/-5% versus 61+/-4%), left ventricular cardiac index (3.4+/-0.4 versus 3.4+/-0.4 L x min(-1) x m[-2]), peak early filling rate (562+/-93 versus 535+/-81 mL/s), peak atrial filling rate (315+/-93 versus 333+/-65 mL/s), ratio of early and atrial filling volumes (3.0+/-1.0 versus 2.6+/-0.6), mean acceleration gradient of early filling (5.2+/-1.4 versus 5.8+/-1.9 L/s2), mean deceleration gradient of early filling(-3.1 +/- 0.9 versus -3.2 +/- 0.7 L/s2), mean acceleration gradient of atrial filling (3.6+/-1.8 versus 4.5+/-1.7 L/s2), and atrial filling fraction (0.23+/-0.06 versus 0.26+/-0.04, respectively). Cyclists and control subjects showed similar decreases in the ratio of myocardial phosphocreatine to ATP measured with 31P magnetic resonance spectroscopy during atropine-dobutamine stress (1.41+/-0.20 versus 1.41+/-0.18 at rest to 1.21+/-0.20 versus 1.16+/-0.13 during stress, both P=NS)., Conclusions: Left ventricular hypertrophy in cyclists is not associated with significant abnormalities of cardiac function or metabolism as assessed by MRI and spectroscopy. These observations suggest that training-induced left ventricular hypertrophy in cyclists is predominantly a physiological phenomenon.

In general, the following three standards for myocardial viability can be used: (a) preserved coronary flow (adequate perfusion); (b) preserved wall motion (systolic wall thickening); and (c) preserved metabolism (metabolic integrity). The current magnetic resonance (MR) techniques provide a great potential to measure all three standards of viability. Adequate perfusion can be assessed by spin-echo MR imaging and/or ultrafast MR imaging, systolic wall thickening by cine MR imaging, and the presence of metabolic integrity can be determined by MR spectroscopy. These noninvasive and versatile techniques have led to an increasing interest and research in recent years. Particular strengths of the MR techniques are: the inherent three-dimensional data acquisition without radiation exposure; the intrinsic soft-tissue contrast that allows tissue characterization; the excellent spatial resolution (in the 1- to 2-mm range), which permits the evaluation of regional abnormalities; multitomographic imaging capabilities that allow acquisition of cardiac images in any plane; the inherent sensitivity to blood and wall motion; and the potential for in vivo measurement of myocardial metabolism using MR spectroscopy. This review article demonstrates that MR techniques might play a growing role in the assessment of myocardial viability.

The cardiovascular applications of nuclear magnetic resonance (MR) techniques in coronary artery disease have increased considerably in recent years. Technical advantages of MR imaging in comparison with other techniques are the excellent spatial resolution, the characterization of myocardial tissue, and the potential for three-dimensional imaging. This allows the accurate assessment of left ventricular mass and volume, the differentiation of infarcted tissue from normal myocardial tissue, and the determination of systolic wall thickening and regional wall motion abnormalities. Myocardial perfusion, metabolism, and inducible myocardial ischemia with the use of pharmacological stress also can be assessed by MR techniques. Future technical improvements in real-time imaging and development of noninvasive visualization of the coronary arteries and coronary artery bypasses will constitute a tremendous progress in clinical cardiology. Early detection and flow assessment of stenosed coronary arteries by MR angiography with the use of flow velocity measurements may outweigh the cost inherent to the MR imaging procedure. A particular strength of the MR technique is the potential to encompass cardiac anatomy, perfusion, function, metabolism, and coronary angiography in a single test. The replacement of multiple diagnostic tests with one MR test may have major effects on cardiovascular healthcare economics.

In a randomized, double-blind, cross-over, multicenter study with a placebo run-in phase, the efficacy and safety of two oral formulations of diltiazem, standard three or four times daily (t.i.d. or q.i.d.) and controlled release twice daily (b.i.d.), were compared in 49 patients with stable angina pectoris. ST-segment depression at maximum exercise 12 h after tablet intake was less frequently observed with diltiazem controlled release than with standard diltiazem (34 of 49, 69% vs. 43 of 49, 88%, p = 0.007). In patients with ST-segment depression after both treatments (n = 33), the average time to 1-mm ST-segment depression was 55.4 +/- 19.9 s longer with diltiazem controlled release than with standard diltiazem [476 +/- 195 vs. 422 +/- 163 s, p = 0.009; 95% confidence interval (CI) 14.8-96 s]. Reduction in mean number of anginal attacks and nitroglycerin (NTG) intake was not significantly different between treatment with standard diltiazem and diltiazem controlled release. The incidence of side effects was low and not different between the two treatments. Both formulations are equally effective in reducing the number of anginal attacks and are well tolerated. Diltiazem controlled release is more effective than standard diltiazem in preventing myocardial ischemia 12 h after tablet intake. Thus, diltiazem controlled release allows twice-daily intake frequency and may therefore be preferable to standard diltiazem in treatment of stable angina pectoris.

In a randomized, double-blind, multicenter study, the efficacy of diltiazem controlled-release (CR) 120 mg b.i.d. was compared with metoprolol 100 mg b.i.d. in 56 patients with stable exertional angina pectoris. Fifty-one patients (28 receiving diltiazem CR, 23 receiving metoprolol), completed a follow-up period of 8 weeks. Thirty-nine patients (20 receiving diltiazem CR, 19 receiving metoprolol), completed a follow-up period of 32 weeks. Maximal exercise testing was performed at baseline and after 8, 20, and 32 weeks of treatment. Most exercise parameters were not significantly different between the patients on diltiazem CR and those on metoprolol. However, exercise duration was longer and maximal work load was higher in patients on diltiazem CR than in patients on metoprolol, and significant differences were observed at 20 weeks of treatment (p = 0.006 and p = 0.008, respectively). At all times during treatment, heart rate at maximal exercise and rate-pressure product at maximal exercise were significantly lower in the patients treated with metoprolol. In conclusion, monotherapy with diltiazem CR is at least as effective as monotherapy with metoprolol in patients with stable angina pectoris. As compared to metoprolol, diltiazem CR has a minor depressing effect on rate-pressure product, resulting in a favorable effect on exercise duration.

In a group of 72 patients with acute myocardial infarction who underwent a maximal symptom-limited predischarge exercise test in conjunction with radionuclide angiography, 25 (35%) showed greater than 1 mm asymptomatic ST-T-segment depression during exercise. All 25 patients underwent repeated exercise radionuclide angiography 2 days later, 2 h after oral intake of 120 mg diltiazem. Double product was not significantly different before and after diltiazem both at rest and during exercise. Maximal ST-T-segment depression after diltiazem was reduced from 2.4 +/- 0.9 mm to 0.8 +/- 0.6 mm (p less than 0.01). Left ventricular ejection fraction (LVEF) at rest was (before diltiazem) 52.1 +/- 8.9% and (after diltiazem) 55.1 +/- 12.3% (NS). During exercise, LVEF improved after diltiazem from 42.8 +/- 12.1% to 49.1 +/- 10.8% (p less than 0.05). Regional wall motion score (1 = normal, 2 = hypokinetic, 3 = akinetic, 4 = dyskinetic) at rest before diltiazem was 9.9 +/- 2.3 and, after diltiazem, was 9.0 +/- 1.9 (NS). During exercise, regional wall motion score improved after diltiazem from 5.9 +/- 1.3 to 4.2 +/- 1.2 (p less than 0.02). We conclude that diltiazem has acute beneficial effects on asymptomatic ST-T-segment depression and on global and regional left ventricular function in post-infarction patients with silent ischemia.