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Purpose Obesity is a major public health concern in the United States, affecting nearly 79 million people. There have been promising results performing microvascular breast reconstruction in patients with obesity; however, the definition of obesity is often poorly defined or does not extend above a body mass index (BMI) of 35. Our goal was to examine outcomes of microvascular breast reconstruction in this questionably more risky population. Methods A retrospective review from 2013 to 2016 was performed of 2 surgeons' experience with abdominally based microvascular breast reconstructions. Women were categorized by BMI into the following groups: normal (18.5-24.9 kg/m), overweight (25.1-29.0 kg/m), class I (30.0-34.9 kg/m), class II (35.0-39.9 kg/m), and class III (>40 kg/m). Demographics included history of tobacco use, breast cancer diagnosis, adjuvant care, and comorbidities. Complications evaluated included donor site (delayed wound healing, fat necrosis, dehiscence, infection, abdominal hernia/bulge, and seroma), recipient site (delayed wound healing and fat necrosis), and need for reoperation. Statistical analyses were performed using analysis of variance and χ test. Results A total of 90 women (117 breasts) underwent microsurgical breast reconstruction using abdominal tissue. Twenty-seven women (48 breasts) met criteria for class II and class III obesity (BMI 35-53). Mean follow-up was 24 months. No statistically significant difference was found in demographics among all groups. There was a trend toward variability in overall complications across the BMI groups (P = 0.149). Donor site complications had a significant variation across the different BMI groups (P = 0.016). The rate of donor site complications was similar in class II (8/14) and class III (7/13) obese women. Recipient site complications were similar across the BMI groups. Conclusions We found obese women to have a higher rate of abdominal donor site complications; however, this risk seems to level off at class I or II obesity. We have modified our surgical technique of managing the abdominal donor site to optimize our outcomes in the morbidly obese patient population.

Background The optimal level of sodium intake remains controversial. Objectives This study sought to determine whether examination of left ventricular longitudinal strain (LS), circumferential strain, and e′ velocity can provide insight into thresholds for the detrimental effects of estimated sodium intake (ESI) on subclinical cardiovascular disease. Methods We performed speckle-tracking analysis on HyperGEN (Hypertension Genetic Epidemiology Network) study echocardiograms with available urinary sodium data (N = 2,996). We evaluated the associations among ESI and LS, circumferential strain, and e′ velocity using multivariable-adjusted linear mixed-effects models (to account for relatedness among subjects) with linear splines (spline 1: ESI ≤3.7 g/day, spline 2: ESI >3.7 g/day based on visual inspection of fractional polynomial plots of the association between ESI and indices of strain and e′ velocity). We performed mediation analysis to understand the indirect effects of systolic blood pressure and serum aldosterone on the relationship between ESI and strain and e′ velocity. Results Mean age of participants was 49 ± 14 years, 57% were female, 50% were African American, and 54% had hypertension. The median ESI was 3.73 (interquartile range: 3.24, 4.25) g/day. ESI >3.7 g/day was associated with larger left atrial and left ventricular dimensions (p 3.7 g/day was associated with both strain parameters and e′ velocity (p 0.05 for all comparisons). There were significant interactions by potassium excretion for circumferential strain. Mediation analysis suggested that systolic blood pressure explained 14% and 20% of the indirect effects between ESI and LS and e′ velocity, respectively, whereas serum aldosterone explained 19% of the indirect effects between ESI and LS. Conclusions ESI >3.7 g/day is associated with adverse cardiac remodeling and worse systolic strain and diastolic e′ velocity.

We sought to evaluate whether unbiased machine learning of dense phenotypic data (“phenomapping”) could identify distinct hypertension subgroups that are associated with the myocardial substrate (i.e., abnormal cardiac mechanics) for heart failure with preserved ejection fraction (HFpEF). In the HyperGEN study, a population- and family-based study of hypertension, we studied 1273 hypertensive patients utilizing clinical, laboratory, and conventional echocardiographic phenotyping of the study participants. We used machine learning analysis of 47 continuous phenotypic variables to identify mutually exclusive groups constituting a novel classification of hypertension. The phenomapping analysis classified study participants into 2 distinct groups that differed markedly in clinical characteristics, cardiac structure/function, and indices of cardiac mechanics (e.g., phenogroup #2 had a decreased absolute longitudinal strain [12.8 ± 4.1 vs. 14.6 ± 3.5%] even after adjustment for traditional comorbidities [p

Background Several large epidemiologic studies and clinical trials have included echocardiography, but images were stored in analog format and these studies predated tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE). We hypothesized that digitization of analog echocardiograms, with subsequent quantification of cardiac mechanics using STE, is feasible, reproducible, accurate, and produces clinically valid results. Methods In the NHLBI HyperGEN study (N = 2234), archived analog echocardiograms were digitized and subsequently analyzed using STE to obtain tissue velocities/strain. Echocardiograms were assigned quality scores and inter-/intra-observer agreement was calculated. Accuracy was evaluated in: (1) a separate second study (N = 50) comparing prospective digital strain versus post hoc analog-to-digital strain, and (2) in a third study (N = 95) comparing prospectively obtained TDI e’ velocities with post hoc STE e’ velocities. Finally, we replicated previously known associations between tissue velocities/strain, conventional echocardiographic measurements, and clinical data. Results Of the 2234 HyperGEN echocardiograms, 2150 (96.2%) underwent successful digitization and STE analysis. Inter/intra-observer agreement was high for all STE parameters, especially longitudinal strain (LS). In accuracy studies, LS performed best when comparing post hoc STE to prospective digital STE for strain analysis. STE-derived e’ velocities correlated with, but systematically underestimated, TDI e’ velocity. Several known associations between clinical variables and cardiac mechanics were replicated in HyperGEN. We also found a novel independent inverse association between fasting glucose and LS (adjusted β = −2.4 [95% CI −3.6, −1.2]% per 1-SD increase in fasting glucose; P < 0.001). Conclusions Archeological echocardiography, the digitization and speckle tracking analysis of archival echocardiograms, is feasible and generates indices of cardiac mechanics similar to contemporary studies.

BACKGROUND: Indices of cardiac mechanics are sensitive markers of subclinical myocardial dysfunction. Improved understanding of the clinical correlates and heritability of cardiac mechanics could result in novel insight into the acquired and genetic risk factors. Therefore, we sought to determine the clinical correlates and heritability of indices of cardiac mechanics in whites and African Americans (AAs). METHODS: We examined 2058 participants stratified by race (1104 whites, 954 AA) in the Hypertension Genetic Epidemiology Network (HyperGEN), a population- and family-based study, and performed digitization of analog echocardiograms with subsequent speckle-tracking analysis. We used linear mixed effects models to determine the clinical correlates of indices of cardiac mechanics (longitudinal, circumferential, radial strain; early diastolic strain rate; and early diastolic tissue velocities). Heritability estimates for cardiac mechanics were calculated using maximum-likelihood variance component analyses in Sequential Oligogenic Linkage Analysis Routine (SOLAR), with adjustment for clinical and echocardiographic covariates. RESULTS: Several clinical characteristics and conventional echocardiographic parameters were found to be associated with speckle-tracking traits of cardiac mechanics. Male sex, blood pressure, and fasting glucose were associated with worse longitudinal strain (LS) (P

Objectives The purpose of this study was to determine the relationship between albuminuria and cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). Background Albuminuria, a marker of endothelial dysfunction, has been associated with adverse cardiovascular outcomes in HFpEF. However, the relationship between albuminuria and cardiac structure/function in HFpEF has not been well studied. Methods We measured urinary albumin-to-creatinine ratio (UACR) and performed comprehensive echocardiography, including tissue Doppler imaging and right ventricular (RV) evaluation, in a prospective study of 144 patients with HFpEF. Multivariable-adjusted linear regression was used to determine the association between UACR and echocardiographic parameters. Cox proportional hazards analyses were used to determine the association between UACR and outcomes. Results The mean age was 66 ± 11 years, 62% were female, and 42% were African American. Higher UACR was associated with greater left ventricular mass, lower preload-recruitable stroke work, and lower global longitudinal strain. Higher UACR was also significantly associated with RV remodeling (for each doubling of UACR, RV wall thickness was 0.9 mm higher [95% confidence interval: 0.05 to 0.14 mm; p = 0.001, adjusted p = 0.01]) and worse RV systolic function (for each doubling of UACR, RV fractional area change was 0.56% lower [95% confidence interval: 0.14 to 0.98%; p = 0.01, adjusted p = 0.03]. The association between UACR and RV parameters persisted after the exclusion of patients with macroalbuminuria (UACR >300 mg/g). Increased UACR was also independently associated with worse outcomes. Conclusions In HFpEF, increased UACR is a prognostic marker and is associated with increased RV and left ventricular remodeling and longitudinal systolic dysfunction. (Classification of Heart Failure With Preserved Ejection Fraction; NCT01030991 )

Background— Left atrial (LA) enlargement is associated with adverse events in heart failure with preserved ejection fraction (HFpEF). However, the role of LA mechanics (ie, LA strain measures) in HFpEF has not been well studied. We hypothesized that in HFpEF, reduced (worse) LA strain is a key pathophysiologic abnormality and is a stronger correlate of adverse events than left ventricular or right ventricular longitudinal strain. Methods and Results— We evaluated baseline LA function in 308 patients with HFpEF who were followed up longitudinally for adverse outcomes. All patients underwent speckle-tracking echocardiography for measurement of left ventricular longitudinal strain, right ventricular free wall strain, and LA booster, conduit, and reservoir strains. The clinical and prognostic significance of left ventricular, right ventricular, and LA strain measures was assessed by regression analyses. The mean age was 65±13 years, 64% were women, 26% had atrial fibrillation, and LA enlargement was present in the majority of patients (67%). Decreased LA reservoir strain was associated with increased pulmonary vascular resistance ( P P =0.0001). Of the left ventricular, right ventricular, and LA strain measures, LA reservoir strain was the strongest correlate of adverse events and was independently associated with the composite outcome of cardiovascular hospitalization or death (adjusted hazard ratio per 1-SD decrease in LA strain, 1.54; 95% CI, 1.15–2.07; P =0.006). Conclusions— Abnormal indices of LA mechanics (particularly LA reservoir strain) are powerful clinical and prognostic factors in HFpEF. Unloading the LA and augmentation of LA function may be important future therapeutic targets in HFpEF. Registration Information— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01030991.

The optimal level of sodium intake remains controversial.This study sought to determine whether examination of left ventricular longitudinal strain (LS), circumferential strain, and e' velocity can provide insight into thresholds for the detrimental effects of estimated sodium intake (ESI) on subclinical cardiovascular disease.We performed speckle-tracking analysis on HyperGEN (Hypertension Genetic Epidemiology Network) study echocardiograms with available urinary sodium data (N = 2,996). We evaluated the associations among ESI and LS, circumferential strain, and e' velocity using multivariable-adjusted linear mixed-effects models (to account for relatedness among subjects) with linear splines (spline 1: ESI ≤3.7 g/day, spline 2: ESI3.7 g/day based on visual inspection of fractional polynomial plots of the association between ESI and indices of strain and e' velocity). We performed mediation analysis to understand the indirect effects of systolic blood pressure and serum aldosterone on the relationship between ESI and strain and e' velocity.Mean age of participants was 49 ± 14 years, 57% were female, 50% were African American, and 54% had hypertension. The median ESI was 3.73 (interquartile range: 3.24, 4.25) g/day. ESI3.7 g/day was associated with larger left atrial and left ventricular dimensions (p 0.05). After adjusting for speckle-tracking analyst, image quality, study site, age, sex, smoking status, alcohol use, daily blocks walked, diuretic use, estimated glomerular filtration rate, left ventricular mass, ejection fraction, and wall motion score index, ESI3.7 g/day was associated with both strain parameters and e' velocity (p 0.05 for all comparisons), but ESI ≤3.7 g/day was not (p0.05 for all comparisons). There were significant interactions by potassium excretion for circumferential strain. Mediation analysis suggested that systolic blood pressure explained 14% and 20% of the indirect effects between ESI and LS and e' velocity, respectively, whereas serum aldosterone explained 19% of the indirect effects between ESI and LS.ESI3.7 g/day is associated with adverse cardiac remodeling and worse systolic strain and diastolic e' velocity.

Rationale: Substantial variation in the prevalences of obstructive lung disease exist between Hispanic/Latino heritage groups. Experimental studies have posited biological mechanisms linking serum lipids and lipid-lowering medications with obstructive lung disease. The aim of this study is to examine the associations of serum lipid levels with the prevalences of asthma and chronic obstructive pulmonary disease in the Hispanic Community Health Study/ Study of Latinos and how these associations vary by Hispanic/Latino heritage group. Methods: The Hispanic Community Health Study/Study of Latinos is a population-based probability sample of 16,415 self-identified Hispanic/Latino persons aged 18-74 years recruited between 2008 and 2011 from randomly selected households in four US field centers. The baseline clinical examination included comprehensive biological testing (fasting serum lipid levels), behavioral and socio-demographic assessments, medication inventory including inhalers, and respiratory data including questionnaires for asthma and standardized spirometry with post-bronchodilator measures for identification of obstructive lung disease. Measurements and main results: Hispanic/Latinos with current asthma had lower age- and statin-use-adjusted mean serum total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels than their non-asthmatic counterparts. In analysis adjusted for age plus gender, ethnicity, cigarette smoking, alcohol intake, body mass index, lipid/cholesterol-lowering medications, age at immigration, health insurance status, and use of oral corticosteroids, increasing serum levels of total cholesterol and low-density lipoprotein cholesterol were associated with lower odds of current asthma in the estimated population. Unlike asthma, Hispanic/Latinos with chronic obstructive pulmonary disease had lower mean high-density lipoprotein than their non- chronic obstructive pulmonary disease counterparts. In the fully adjusted analysis no significant associations were found between lipid levels and prevalent chronic obstructive pulmonary disease. Conclusions: We showed a modest inverse relationship between serum lipid levels and current asthma. These results highlight some important differences in Hispanics/Latinos and certain serum lipids may be factors or markers of obstructive lung disease.

Background— Albuminuria is a marker of endothelial dysfunction and has been associated with adverse cardiovascular outcomes. The reasons for this association are unclear but may be attributable to the relationship between endothelial dysfunction and intrinsic myocardial dysfunction. Methods and Results— In the Hypertension Genetic Epidemiology Network (HyperGEN) Study, a population- and family-based study of hypertension, we examined the relationship between urine albumin-to-creatinine ratio (UACR) and cardiac mechanics (n=1894, all of whom had normal left ventricular ejection fraction and wall motion). We performed speckle-tracking echocardiographic analysis to quantify global longitudinal, circumferential, and radial strain, and early diastolic (e′) tissue velocities. We used E/e′ ratio as a marker of increased left ventricular filling pressures. We used multivariable-adjusted linear mixed effect models to determine independent associations between UACR and cardiac mechanics. The mean age was 50±14 years, 59% were female, and 46% were black. Comorbidities were increasingly prevalent among higher UACR quartiles. Albuminuria was associated with global longitudinal strain, global circumferential strain, global radial strain, e′ velocity, and E/e′ ratio on unadjusted analyses. After adjustment for covariates, UACR was independently associated with lower absolute global longitudinal strain (multivariable-adjusted mean global longitudinal strain [95% confidence interval] for UACR Quartile 1 = 15.3 [15.0–15.5]% versus UACR Q4 = 14.6 [14.3–14.9]%, P for trend P =0.003). The association between UACR and global longitudinal strain was present even in participants with UACR < 30 mg/g ( P Conclusions— Albuminuria, even at low levels, is associated with adverse cardiac mechanics and higher E/e′ ratio.

Rabies virus infection remains a serious public health threat in the developing world, where cost-concerns make wide-scale public health interventions impractical. The development of novel and inexpensive ELISA diagnostic antigens is critical in early detection and prevention of complications. The transmembrane glycoprotein (G) of rabies virus (RV) contains an external domain capable of inducing the synthesis of anti-rabies, virus-neutralizing antibodies, in infected or immunized hosts. In our study, the external G domain was synthesized and fused in-frame with a polyhistidine-tag coding sequence present in the expression plasmid. Soluble truncated recombinant G was secreted in Hansenula polymorpha (H. polymorpha) using H. polymorpha-derived calnexin (HpCNE1) overproduction and found to be correctly N-glycosylated. The truncated recombinant G was purified from cell culture supernatant by Ni-agarose affinity chromatography and when compared with the full-length glycoprotein, found to be similarly immunogenic in vaccinated rabbits. These results subsequently led us to explore the potential of truncated recombinant G as a diagnostic antigen in ELISA. Our results show that the truncated recombinant G can detect antibodies directed to both whole virion and native glycoprotein. More sophisticated applications of truncated recombinant G would profit from the correctly N-glycosylated and soluble monomer.

Background— Central obesity, defined by increased waist circumference or waist:hip ratio (WHR), is associated with increased cardiovascular events, including heart failure. However, the pathophysiological link between central obesity and adverse cardiovascular outcomes remains poorly understood. We hypothesized that central obesity and larger WHR are independently associated with worse cardiac mechanics (reduced left ventricular strain and systolic [s′] and early diastolic [e′] tissue velocities). Methods and Results— We performed speckle-tracking analysis of echocardiograms from participants in the Hypertension Genetic Epidemiology Network (HyperGEN) study, a population- and family-based epidemiological study (n=2181). Multiple indices of systolic and diastolic cardiac mechanics were measured. We evaluated the association between central obesity and cardiac mechanics using multivariable-adjusted linear mixed-effects models to account for relatedness among participants. The mean age of the cohort was 51±14 years, 58% were women, and 47% were black. Mean body mass index was 30.8±7.1 kg/m 2 , waist circumference was 102±17 cm, WHR was 0.91±0.08, and 80% had central obesity based on waist circumference and WHR criteria. After adjusting for multiple potential confounders (including age, sex, race, physical activity, body mass index, heart rate, smoking status, systolic blood pressure, fasting glucose, total cholesterol, antihypertensive medication use, glomerular filtration rate, left ventricular mass index, wall motion abnormalities, and ejection fraction), central obesity and WHR remained associated with worse global longitudinal strain, early diastolic strain rate, s′ velocity, and e′ velocity ( P Conclusions— In this cross-sectional study of participants with multiple comorbidities, central obesity was found to be associated with adverse cardiac mechanics.

Introduction: A genetic predisposition to abnormal cardiac mechanics may explain the familial predisposition to heart failure (HF). We hypothesized that indices of cardiac mechanics (speckle-tracking strain parameters and tissue velocities) are heritable traits. Methods: We performed speckle-tracking analysis on echocardiograms and measured global longitudinal, circumferential, and radial strain (GLS, GCS, GRS), early diastolic strain rate, and e’ velocities in the HyperGEN study, a family- and population-based study of hypertension (N=2058 [54% African American (AA)]). Additive genetic heritability estimates for cardiac mechanics were calculated by maximizing the likelihood variance components in SOLAR (ver.6) adjusted for age, sex, race, height, weight, systolic blood pressure (SBP), left ventricular (LV) mass, ejection fraction, reader, image quality, and institution. Results: Mean age was 51±14 years and HF risk factors were common: hypertension (56%), obesity (47%), and diabetes (16%). Clinical and conventional echocardiographic characteristics, including male gender, hypertension, elevated fasting glucose, higher body-mass index, and LV hypertrophy were all significantly associated with increased absolute GLS and septal e’ velocity (P Conclusions: Echocardiographic measures of cardiac mechanics, particularly GLS and e’ velocity, are heritable traits, even after adjustment for clinical and cardiac structural factors (e.g., SBP and LV mass, respectively) that are known to be heritable and associated with cardiac mechanics. These data support the exploration of genetics of cardiac mechanics, which may provide insight into the molecular pathogenesis of LV dysfunction and HF.

Background Comorbidities are common in heart failure ( HF ), and the number of comorbidities has been associated with poor outcomes in HF patients. However, little is known about the effect of multiple comorbidities on cardiac mechanics, which could impact the pathogenesis of HF . We sought to determine the relationship between comorbidity burden and adverse cardiac mechanics. Methods and Results We performed speckle‐tracking analysis on echocardiograms from the HyperGEN study (n=2150). Global longitudinal, circumferential, and radial strain, and early diastolic (e') tissue velocities were measured. We evaluated the association between comorbidity number and cardiac mechanics using linear mixed effects models to account for relatedness among subjects. The mean age was 51±14 years, 58% were female, and 47% were African American. Dyslipidemia and hypertension were the most common comorbidities (61% and 58%, respectively). After adjusting for left ventricular ( LV ) mass index, ejection fraction, and several potential confounders, the number of comorbidities remained associated with all indices of cardiac mechanics except global circumferential strain (eg, β=−0.32 [95% CI −0.44, −0.20] per 1‐unit increase in number of comorbidities for global longitudinal strain; β=−0.16 [95% CI −0.20, −0.11] for e' velocity; P ≤0.0001 for both comparisons). Results were similar after excluding participants with abnormal LV geometry ( P Conclusions Higher comorbidity burden is associated with worse cardiac mechanics, even in the presence of normal LV geometry. The deleterious effect of multiple comorbidities on cardiac mechanics may explain both the high comorbidity burden and adverse outcomes in patients who ultimately develop HF .

Background —Albuminuria is a marker of endothelial dysfunction and has been associated with adverse cardiovascular outcomes. The reasons for this association are unclear, but may be due to the relationship between endothelial dysfunction and intrinsic myocardial dysfunction. Methods and Results —In the HyperGEN study, a population- and family-based study of hypertension, we examined the relationship between urine albumin-to-creatinine ratio (UACR) and cardiac mechanics (N=1894, all of whom had normal left ventricular ejection fraction and wall motion). We performed speckle-tracking echocardiographic analysis to quantify global longitudinal, circumferential, and radial strain (GLS, GCS, and GRS, respectively), and early diastolic (e') tissue velocities. We used E/e' ratio as a marker of increased LV filling pressures. We used multivariable-adjusted linear mixed effect models to determine independent associations between UACR and cardiac mechanics. The mean age was 50±14 years, 59% were female, and 46% were African-American. Comorbidities were increasingly prevalent among higher UACR quartiles. Albuminuria was associated with GLS, GCS, GRS, e' velocity, and E/e' ratio on unadjusted analyses. After adjustment for covariates, UACR was independently associated with lower absolute GLS (multivariable-adjusted mean GLS [95% CI] for UACR Quartile 1 = 15.3 [15.0-15.5]% vs. UACR Q4 = 14.6 [14.3-14.9]%, P for trend

Background Diastolic wall strain (DWS), defined using posterior wall thickness (PWT) measurements from standard echocardiographic images (DWS = [PWT(systole)-PWT(diastole)]/PWT(systole)), has been proposed as a marker of left ventricular (LV) diastolic stiffness. However, the equation for DWS is closely related to systolic radial strain, and whether DWS is associated with abnormal cardiac mechanics (reduced systolic strains and diastolic tissue velocities) is unknown. We sought to determine the relationship between DWS and systolic and diastolic cardiac mechanics. Methods We calculated DWS and performed speckle-tracking analysis in a large population- and family-based study (Hypertension Genetic Epidemiology Network [HyperGEN]; N = 1907 after excluding patients with ejection fraction [EF]