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Purpose To assess early subclinical coronary artery disease (CAD) burden and its relation to myocardial function in asymptomatic persons living with HIV (PLWH) who are at low risk for cardiovascular disease (CVD). Materials and Methods In this prospective, HIPAA-compliant study (ClinicalTrials.gov NCT01656564 and NCT01399385) conducted from April 2010 to May 2013, 74 adult PLWH without known CVD and 25 matched healthy controls underwent coronary MRI to measure coronary vessel wall thickness (VWT) and echocardiography to assess left ventricular function. Univariable and multivariable linear regression analyses were used to evaluate statistical associations. Results For PLWH, the mean age was 49 years ± 11 (SD), and the median Framingham risk score was 3.2 (IQR, 0.5-6.6); for matched healthy controls, the mean age was 46 years ± 8 and Framingham risk score was 2.3 (IQR, 0.6-6.1). PLWH demonstrated significantly greater coronary artery VWT than did controls (1.47 mm ± 0.22 vs 1.34 mm ± 0.18; P = .006) and a higher left ventricular mass index (LVMI) (77 ± 16 vs 70 ± 13; P = .04). Compared with controls, PLWH showed altered association between coronary artery VWT and both E/A (ratio of left ventricular-filling peak blood flow velocity in early diastole [E wave] to that in late diastole [A wave]) ( P = .03) and LVMI ( P = .04). In the PLWH subgroup analysis, coronary artery VWT increase was associated with lower E/A ( P < .001) and higher LVMI ( P = .03), indicating restricted diastolic function. In addition, didanosine exposure was associated with increased coronary artery VWT and decreased E/A ratio. Conclusion Asymptomatic low-CVD-risk PLWH demonstrated increased coronary artery VWT in association with impaired diastolic function, which may be amenable to follow-up studies of coronary pathogenesis to identify potential effects on the myocardium and risk modification strategies. Keywords: Coronary Vessel Wall Thickness, Diastolic Function, HIV, MRI, Echocardiography, Atherosclerosis Clinical trial registration nos. NCT01656564 and NCT01399385 Supplemental material is available for this article. © RSNA, 2024.

Cardiac complications have been well-described in sickle cell disease; however, it has been rare to see improvements in cardiac abnormalities following any interventions. Previous work has shown no significant structural changes after treatment with hydroxyurea. The cardiac effects of red blood cell exchange transfusion (RBCx) and hematopoietic stem cell transplantation (HSCT) have not been well described. We studied 56 patients undergoing HSCT (41 HLA-matched, 15 haploidentical), of whom 32 had RBCx within 3 months before HSCT. Echocardiograms and laboratory parameters were obtained at baseline, and at 3, 6, and 12 months following HSCT. Although hemolytic parameters and anemia improved following RBCx, there was a small increase in left ventricular volume index. Following successful HSCT, however, there were significant improvements in cardiac size, function, and diastolic filling parameters at 3 months followed by continued smaller improvements up to 1 year. There was a significant improvement in N-terminal pro B-type natriuretic peptide levels and a trend toward improvement in 6-minute walk time 1 year after HSCT. The magnitude of cardiac improvement seen following HSCT was comparable to that observed following correction of a volume overload state as seen in pregnancy or after repair of chronic valvular regurgitation. Further studies in sickle cell disease patients will help delineate which cardiac complications and what level of severity should be considered indications for HSCT.

In sickle cell disease (SCD), abnormal microvascular function combined with chronic anaemia predisposes patients to perfusion-demand mismatch. We hypothesized that skeletal muscle and myocardial perfusion, normalized to the degree of anaemia, is reduced at basal-state compared to controls, and that this defect is ameliorated by hydroxycarbamide (HC; also termed hydroxyurea) therapy. Twenty-one SCD patients, of whom 15 were treated with HC, and 27 controls underwent contrast-enhanced ultrasound (CEU) perfusion imaging of the forearm as well as the myocardium. HC treatment was associated with lower white cell and reticulocyte counts, and higher fetal haemoglobin and total haemoglobin levels. When corrected for the degree of anaemia in SCD patients, skeletal flow in HC-treated patients was significantly higher than in untreated SCD patients (217·7 ± 125·4 vs. 85·9 ± 40·2, P = 0·018). Similarly, when normalized for both anaemia and increased myocardial work, resting myocardial perfusion was also significantly higher in HC-treated patients compared with untreated SCD patients (0·53 ± 0·47 vs. 0·13 ± 0·07, P = 0·028). Haemoglobin F (HbF) levels correlated with skeletal muscle microvascular flow (r = 0·55, P = 0·01). In conclusion, patients with SCD not on HC therapy have resting flow deficits in both skeletal muscle and myocardial flow. HC therapy normalizes flow and there is a direct correlation with HbF levels. Clinical trial registration ClinicalTrials.gov Identifier: NCT01602809; https://clinicaltrials.gov/ct2/show/NCT01602809?term=sACHDEV&rank=9., (© 2017 John Wiley & Sons Ltd.)

Background: Alström syndrome (AS) is a rare monogenetic disorder with multi-organ involvement. Complex metabolic disturbances are common and cardiomyopathy is a well-recognized feature in infants as well as in older children and adults. Although the mechanism of cardiomyopathy is not known, previous reports suggest that individuals with infantile-onset cardiac disease recover completely., Methods: In this single center prospective series of 38 children and adults (age range 1.7 to 37.9years; 20 females) with AS, we evaluated cardiac manifestations in detail, in the context of specific ALMS1 mutations and multisystem involvement. All patients underwent ALMS1 sequencing, biochemical testing, electrocardiogram, and echocardiographic imaging with speckle tracking to evaluate systolic strain; 21 patients underwent cardiac magnetic resonance imaging with T1 mapping., Results: Approximately half of patients (17/38) had a previous diagnosis of cardiomyopathy. Global longitudinal strain, a measure of systolic contractile function, was abnormal in 94% of patients and correlated with body mass index (r=0.602, p=0.002) and C-reactive protein level (r=0.56, p=0.004), but only in children. Electrocardiographic abnormalities were seen in two-thirds of patients, and left ventricular dilatation and/or dysfunction was present in 4 adults and 4 children., Conclusion: AS patients with a history of resolved infantile cardiomyopathy continue to have residual impairment in cardiac function. For patients with a normal ejection fraction and no prior cardiac history, strain can be abnormal, suggesting subclinical cardiac involvement. Close cardiac screening and aggressive modification of other manifestations of AS that are risk factors for cardiac disease, including obesity, inflammation, diabetes and dyslipidemia, are essential in caring for patients with AS., (Published by Elsevier Inc.)

Context: The contiguous gene deletion syndrome (CAH-X) was described in a subset (7%) of congenital adrenal hyperplasia (CAH) patients with a TNXA/TNXB chimera, resulting in deletions of CYP21A2, encoding 21-hydroxylase necessary for cortisol biosynthesis, and TNXB, encoding the extracellular matrix glycoprotein tenascin-X (TNX). This TNXA/TNXB chimera is characterized by a 120-bp deletion in exon 35 and results in TNXB haploinsufficiency, disrupted TGF-β signaling, and an Ehlers Danlos syndrome phenotype., Objective: The objective of the study was to determine the genetic status of TNXB and resulting protein defects in CAH patients with a CAH-X phenotype but not the previously described TNXA/TNXB chimera. Design, Settings, Participants, and Intervention: A total of 246 unrelated CAH patients were screened for TNXB defects. Genetic defects were investigated by Southern blotting, multiplex ligation-dependent probe amplification, Sanger, and next-generation sequencing. Dermal fibroblasts and tissue were used for immunoblotting, immunohistochemical, and coimmunoprecipitation experiments., Main Outcome Measures: The genetic and protein status of tenascin-X in phenotypic CAH-X patients was measured., Results: Seven families harbor a novel TNXB missense variant c.12174C>G (p.C4058W) and a clinical phenotype consistent with hypermobility-type Ehlers Danlos syndrome. Fourteen CAH probands carry previously described TNXA/TNXB chimeras, and seven unrelated patients carry the novel TNXB variant, resulting in a CAH-X prevalence of 8.5%. This highly conserved pseudogene-derived variant in the TNX fibrinogen-like domain is predicted to be deleterious and disulfide bonded, results in reduced dermal elastin and fibrillin-1 staining and altered TGF-β1 binding, and represents a novel TNXA/TNXB chimera. Tenascin-X protein expression was normal in dermal fibroblasts, suggesting a dominant-negative effect., Conclusions: CAH-X syndrome is commonly found in CAH due to 21-hydroxylase deficiency and may result from various etiological mechanisms.

Background: Congenital heart disease (CHD) is estimated to affect between 3 and 5% of all newborns. Extra-cardiac malformations are observed in 7 to 50% of patients with CHD. One relatively well-known association that can occur in the context of CHD is VACTERL. Controversy still remains regarding the definition of VATER association and its expansion to VACTERL, the appropriate diagnostic criteria and the overall incidence., Methods: We conducted a description of a case series to characterize the cardiac findings present in a cohort of patients meeting the criteria for VACTERL association., Results: Forty-six of 220 were eligible for inclusion into the study, 67% (31 of 46) had CHD. The most common CHD was ventricular septal defect, present in 18 of 31 patients (58%). There was no statistically significant association between CHD severity and the presence or absence of other VACTERL component features, specifically anorectal malformation (p = 0.18) or tracheo-esophageal fistula (p = 0.72). CHD presence also did not correlate with the presence of tracheo-esophageal fistula or anorectal malformation., Conclusion: Although this study does not, by design, provide further evidence toward the questions of whether CHD is a defining feature of VACTERL association, the frequency of CHD in our cohort does lend support to it being an important medical consideration in patients with VACTERL association. Based on our experience, we strongly recommend a screening echocardiogram to evaluate for CHD in individuals with a potential diagnosis of VACTERL association., (Copyright © 2013 Wiley Periodicals, Inc.)

Context: The gene for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, CYP21A2, is flanked by the gene encoding tenascin-X (TNXB), a connective tissue extracellular matrix protein that has been linked to both autosomal dominant and autosomal recessive Ehlers-Danlos syndrome (EDS). A contiguous deletion of CYP21A2 and TNXB has been described., Objective: The objective of the study was to determine the frequency and clinical significance of TNXB haploinsufficiency in CAH patients., Design, Setting, and Participants: A total of 192 consecutive unrelated CAH patients being seen as part of an observational study at the National Institutes of Health Clinical Center (Bethesda, MD) were prospectively studied during 2006-2010. Patients were evaluated for clinical evidence of EDS, including cardiac evaluation. DNA was analyzed by PCR, multiplex ligation-dependent probe amplification, Southern blot, and TNXB sequencing. Tenascin-X expression was evaluated by Western blot analysis of fibroblasts and immunostaining of the skin. CAH patients with TNXB haploinsufficiency were compared with age-matched CAH patients with normal TNXB (controls). Phenotyping of 7 parents with TNXB haploinsufficiency was performed., Main Outcome Measures: The frequency of TNXB haploinsufficiency among CAH patients and the frequency of EDS symptomatology among CAH patients with TNXB haploinsufficiency and controls., Results: TNXB haploinsufficiency, here termed CAH-X syndrome, was present in 7% of CAH patients. Twelve of 91 patients carrying a CYP21A2 deletion (13%) carried a contiguous deletion that extended into TNXB. One patient carried a TNXB premature stop codon. Twelve of 13 patients with CAH-X had EDS clinical features. Patients with CAH-X were more likely than age-matched controls to have joint hypermobility (P < .001), chronic joint pain (P = .003), multiple joint dislocations (P = .004), a structural cardiac valve abnormality by echocardiography (P = .02), and reduced tenascin-X expression by Western blot and immunostaining. A subset of parents had clinical findings., Conclusions: Clinical evaluation for connective tissue dysplasia should be routinely performed in CAH patients, especially those harboring a CYP21A2 deletion.

Alkaptonuria is a rare metabolic disorder of tyrosine catabolism in which homogentisic acid (HGA) accumulates and is deposited throughout the spine, large joints, cardiovascular system, and various tissues throughout the body. In the cardiovascular system, pigment deposition has been described in the heart valves, endocardium, pericardium, aortic intima and coronary arteries. The prevalence of cardiovascular disease in patients with alkaptonuria varies in previous reports. We present a series of 76 consecutive adult patients with alkaptonuria who underwent transthoracic echocardiography between 2000 and 2009. A subgroup of 40 patients enrolled in a treatment study underwent non-contrast CT scans and these were assessed for vascular calcifications. Six of the 76 patients had aortic valve replacement. In the remaining 70 patients, 12 patients had aortic sclerosis and 7 patients had aortic stenosis. Unlike degenerative aortic valve disease, we found no correlation with standard cardiac risk factors. There was a modest association between the severity of aortic valve disease and joint involvement, however, we saw no correlation with urine HGA levels. Vascular calcifications were seen in the coronaries, cardiac valves, aortic root, descending aorta and iliac arteries. These findings suggest an important role for echocardiographic screening of alkaptonuria patients to detect valvular heart disease and cardiac CT to detect coronary artery calcifications., (Published by Elsevier Inc.)

Background: Noninvasively assessed pulmonary pressure elevations and left ventricular (LV) diastolic dysfunction are associated with increased mortality in adults with sickle cell disease, but their relationship to exercise intolerance has not been evaluated prospectively., Methods and Results: Echocardiography, 6-minute walk distance, hemolytic rate, and serum concentrations of ferritin and erythropoietin were evaluated in a cohort of 483 subjects with homozygous hemoglobin S in the U.S. and U.K. Walk-Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) study. Tricuspid regurgitation velocity, which reflects systolic pulmonary artery pressure, was 2.7 to <3.0 m/s (mean±SD, 2.8±0.1) in 26% of the subjects and ≥3.0 m/s (mean±SD, 3.4±0.4) in 11%. The LV lateral E/e' ratio, which has been shown to reflect LV filling pressure in other conditions but has not been studied in sickle cell disease, was significantly higher in the groups with tricuspid regurgitation velocity ≥2.7 m/s. Increased hemolysis (P<0.0001), LV lateral E/e' ratio (P=0.0001), blood urea nitrogen (P=0.0002), and erythropoietin (P=0.002) were independently associated with an increased tricuspid regurgitation velocity. Furthermore, female sex (P<0.0001), older age (P<0.0001), LV lateral E/e' ratio (P=0.014), and tricuspid regurgitation velocity (P=0.019) were independent predictors of a shorter 6-minute walk distance., Conclusions: Echocardiography-estimated elevated pulmonary artery systolic pressure and LV lateral E/e' ratio were independently associated with poor exercise capacity in a large cohort of patients with sickle cell anemia. Controlled trials investigating whether strategies to prevent or delay pulmonary hypertension and/or LV diastolic dysfunction will improve exercise capacity and long-term outcomes in sickle cell anemia should be considered. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00492531.

Background: Significant tricuspid regurgitation (TR) is occasionally associated with severe mitral stenosis and has an adverse impact on morbidity and mortality in patients undergoing mitral valve surgery. However, the effect of successful mitral balloon valvotomy (MBV) on significant TR is not fully elucidated. The aim of this study was to investigate TR after MBV in patients with severe mitral stenosis., Methods: We analyzed the data of 53 patients with significant TR (grade > or =2, on a 1 to 3 scale) from the mitral balloon valvotomy database at our hospital. Patients were evaluated by Doppler echocardiography before valvotomy and at follow-up 1 to 13 years after MBV. Patients were divided into group A (27 patients), in whom TR regressed by > or =1 scale, and group B (26 patients), in whom TR did not regress., Results: The Doppler-determined pulmonary artery systolic pressure was initially higher and decreased at follow-up more in group A (from 70.7 +/- 23.8 to 36.5 +/- 8.3 mm Hg; P < .0001) than in group B (from 48.7 +/- 17.8 to 41.6 +/- 13.1 mm Hg; P = NS). Compared with patients in group B, patients in group A were younger (25 +/-10 vs 35 +/- 11 years; P < .005), had higher prevalence of functional TR (85% vs 8%; P < .0001), and had lower incidence of atrial fibrillation (7% vs 38%; P < .005). Significant decrease in right ventricular end-diastolic dimension after MBV was noted in group A but not in group B. The mitral valve area at late follow-up was larger in group A than in group B (1.8 +/- 0.3 vs 1.6 +/- 0.3 cm2; P < .05)., Conclusions: Regression of significant TR after successful MBV in patients with severe mitral stenosis was observed in patients who had severe pulmonary hypertension. This improvement in TR occurred even in the presence of organic tricuspid valve disease.

Background: The number of patients with congenital cardiac disease reaching adulthood is increasing steadily. Many adults with such disease face both medical and surgical difficulties., Hypothesis: This retrospective study was undertaken to assess the frequency and outcome of congenital heart disease (CHD) in unoperated adults., Methods: The charts of all patients with unoperated CHD, who were admitted to a tertiary care center in Beirut, Lebanon, between 1980 and 2000 were reviewed. Of these, 206 patients (52% men, age at admittance 18-71 years [32.8 +/- 13.3 years]) with a diagnosis of CHD were evaluated. Atrial septal defect (ASD) was the most common cardiac malformation with a relative frequency of 53%, followed by ventricular septal defects (11%), tetralogy of Fallot (11%), aortic anomalies (7%), pulmonary stenosis (6%), and Ebstein anomaly (4%). Most patients were symptomatic upon presentation, with dyspnea on exertion being the most common presenting symptom. Twenty-seven patients (13%) had cyanotic CHD. Of 179 acyanotic patients, 113 (63%), and 17 of 27 cyanotic patients (63%) underwent surgical intervention. In-hospital surgical complications for the acyanotic group included cerebrovascular accident (2%) and heart block (1%). Total surgical mortality was 4 of 130 (3%). One patient with tetralogy of Fallot presented with endocarditis and died., Conclusion: Atrial septal defect is the most common defect reported in our experience; however, it occurs more frequently than that reported in the literature. Although most patients were symptomatic on presentation, their functional status was stable. Accordingly, their hospital course, whether managed medically or surgically, held a relatively low complication rate. This could be attributed to the uncomplicated nature of pathologies in our series. The surgical mortality and in-hospital complications were slighter higher than those reported for similar lesions if repaired during childhood. This study reflects the relative frequency of various cardiac malformations in selected patients with "grown up" congenital heart disease (GUCH) and their natural survival pattern.

Background: The number of people older than 80 years is increasing worldwide and many of these patients are being referred for coronary artery bypass surgery (CABG). Several recent reports from the USA and Europe have shown that CABG can be performed in octogenarians with an acceptable risk. However, data from developing countries regarding this subject is lacking. The objective of this study was to analyze the clinical characteristics and in-hospital events of octogenarian patients undergoing CABG at a tertiary referral university hospital in a developing country., Methods: The study included 28 consecutive octogenarian patients who underwent CABG at the American University of Beirut, between January 1998 and December 2000. The medical records of these patients were reviewed for demographic information, clinical and catheterization findings, operative characteristics, and in-hospital events (death, myocardial infarction, and stroke)., Results: The mean age of the study group was 82 +/- 2 years and 75% were males. Seventy-eight percent of the patients had an acute myocardial infarction or unstable angina prior to CABG. All of the patients were in NYHA class I or II and none of the operations were done on an emergent basis. The mean ejection fraction was 48 +/- 7%. Eighty-six percent of patients had multivessel disease and four patients had aortic valve replacement (AVR) concomitantly with the CABG. The in-hospital mortality was 0%. Three patients (11%) had a post-operative myocardial infarction, and one patient (4%) had a stroke. The mean post-operative stay was 9 +/- 7 days with only three patients (11%) staying for more than 14 days. The multivariate predictors of in-hospital cardiovascular events were concomitant AVR (P=0.01), and an ejection fraction <40% (P=0.03)., Conclusion: In carefully selected octogenarian patients who are clinically stable in NYHA class I or II, and where the operation is not done on an emergent basis, CABG can be performed with an acceptable risk and a low in-hospital mortality.

Fracture of the occluder disc of a low-profile Starr-Edwards prosthesis is a hitherto unrecognized complication. We describe a patient who presented with right heart failure and severe pulmonary hypertension 27 years after mitral valve replacement with a model 6520 caged-disc prosthesis. At surgery, there was a longitudinal split in the occluder disc, and organized thrombus was lodged between the split segments. This case offers a unique opportunity to study the long-term effects of wear on the polyethylene poppet and Stellite cage.