Cardiac geometry, function and mechanics in left ventricular non-compaction cardiomyopathy with preserved ejection fraction.

BACKGROUND: Left ventricular non-compaction (LVNC) cardiomyopathy in adults has primarily been studied with a phenotypic expression of low ejection fraction (EF) and dilated cardiomyopathy; however, data on LVNC with preserved EF is scarce. The present study aimed to evaluate cardiac geometry and mechanics in LVNC patients with preserved EF. METHODS: A retrospective cohort study of patients diagnosed with LVNC and a preserved EF between 2008 and 2019 was performed. LVNC was defined according to the presence of established transthoracic 2D echocardiographic (TTE) criteria as follows: (1) prominent LV trabeculations with deep recesses; (2) bi-layered myocardial appearance; and, (3) systolic non-compacted:compacted ratio≥ 2. Subjects were matched 1:1 to controls without LVNC referred for routine TTE. Geometric, functional and mechanics parameters were analyzed in the two cohorts using 2D and speckle-tracking TTE. RESULTS: Seventeen patients with LVNC and preserved EF were identified. Compared with controls, patients with LVNC had similar LV systolic function and chamber dimensions, but a larger mass and relative wall thickness, and more abnormal LV geometry (76% vs. 18%, p = 0.002), LA remodeling, and pulmonary hypertension. Global longitudinal strain was significantly decreased (-15.4 ± 3.2 vs. -18.9 ± 2.8%, p = < 0.01) and the prevalence of rigid body rotation was significantly increased (57% vs. 14%, p = 0.05) in the LVNC population. The peak twist values were comparable in both cohorts. CONCLUSIONS: Impaired LV geometry and longitudinal mechanics, as well as increased myocardial stiffness as expressed by rigid body rotation, characterize LVNC with preserved EF when compared with controls.

Low-Level Cadmium Exposure and Atherosclerosis.

PURPOSE OF REVIEW: Cadmium has been recognized as a potential risk factor for cardiovascular disease (CVD). We present a review of cadmium toxicity, its effect on cellular activities, and a summary of reported association between environmental cadmium exposure and CVD. We also discuss the possible therapeutic benefit of cadmium chelation. RECENT FINDINGS: Experimental data suggest that cadmium affects several signaling pathways which may lead to endothelial dysfunction and vascular tissue damage, promoting atherosclerosis. This is further supported by epidemiological studies that have shown an association of even low-level cadmium exposure with an increased risk of clinical cardiovascular events. The Trial to Assess Chelation Therapy (TACT) provided inferential evidence for the cardiovascular benefit of treating toxic metal burden. However, at the present time, there is no direct evidence, but suggestive findings from clinical trials indicating that removal of cadmium from body stores may be associated with improved cardiovascular outcomes. An evolving body of evidence supports environmental cadmium exposure as a pro-atherosclerosis risk factor in CVD; however, the mechanisms for the proatherogenic effect of cadmium are still not completely understood. Further studies in translational toxicology are needed to fill the knowledge gaps regarding the molecular mechanisms of cadmium toxicity and the promotion of atherosclerosis.

Cellular senescence evaluated by P16INK4a immunohistochemistry is a prevalent phenomenon in advanced calcific aortic valve disease.

BACKGROUND: Fibrosis, calcification, and ossification are histopathologic hallmarks of calcific aortic valve disease (CAVD), a leading cause of morbidity and mortality in the aging population. Cellular senescence contributes to a functional decay in chronic diseases by intensifying tissue remodeling and impairing tissue regeneration. We evaluated the expression of P16INK4A and P53 as surrogate markers of senescence in CAVD. METHODS: Aortic valves from 27 individuals with severe CAVD requiring aortic valve replacement were selected for routine histologic processing. Immunohistochemical expression of P16INK4A and P53 was quantified using computerized image analysis on fields matching compartments with varying degrees of tissue remodeling. RESULTS: All aortic valves demonstrated P16INK4A and P53-positive cells. The percentage of P16INK4A -positive cells, but not of P53, was higher in areas of calcification and/or ossification (57.21%±26.31, n=40) and severe fibrosis (54.79%±27.19, n=25) than in areas with minimal to mild tissue remodeling (13.69% ± 11.88, n=16, P<.0001). P16INK4A expression was observed in interstitial valve cells within all compartments proportional to the degree of fibrosis and did not correlate with age, severity of aortic stenosis, or P53 expression. Multiple linear regression analysis by backward elimination revealed P16INK4A expression was lower among statin users (P<.01). CONCLUSIONS: P16INK4A- expression is ubiquitous in calcified aortic valves and correlates with severity of tissue remodeling, suggesting a role of cellular senescence in the progression of CAVD. Further research is needed to identify possible treatment modalities as disease modifying agents for CAVD.

Transthoracic versus intra-operative transesophageal echocardiography in right heart assessment.

METHODS: Fifty-four patients who had combined mitral and tricuspid valve surgery were included. Right heart measurements were performed in the TTE apical 4-chamber (A4C) and RV inflow views, and TEE mid-esophageal 4-chamber (ME4C) and transgastric RV inflow views at end-diastole. Spearman correlation coefficients (r) were applied to test for associations between the imaging modalities. RESULTS: The mean age was 65 years and 39% were male. All patients had ≥ moderate tricuspid regurgitation (TR), and a secondary/functional etiology was present in 89%. The median TAd and RV basal (RVd) diameters in the TTE-A4C view measured 37 mm [interquartile range (IQR), 34-44] and 43 mm (IQR, 40-51), respectively. The TTE-A4C TAd strongly correlated with the TEE-ME4C measurement (r=0.72), with an overestimation of 1 mm (IQR, -2 to 4) by TEE (P<0.01). For RVd, the TTE-A4C measurement correlated moderately with the TEE-ME4C view (r=0.61), underestimating the RVd by -1 mm (IQR, -4 to 3.3) (P<0.01). No correlation was observed between TAPSE measured by TTE and TEE (r=0.22, P=0.13). CONCLUSIONS: Intra-operative TEE may reliably quantitate TA and RV size and geometry. The current findings are best interpreted as hypothesis-generating for future validative studies.

Tricuspid regurgitation and in-hospital outcomes after transcatheter aortic valve replacement in high-risk patients.

BACKGROUND: The prognostic impact of tricuspid regurgitation (TR) following transcatheter aortic valve replacement (TAVR) is uncertain, and the management of patients with severe aortic stenosis and significant TR undergoing TAVR is unclear. METHODS: Retrospective study investigating the role of TR severity on hospital outcomes in high risk patients with severe aortic stenosis undergoing TAVR. RESULTS: A total of 174 participants were included in the present study. The median age was 84 years and 48% were women. The median (IR) STS score was 7.3 (4.7-13.6). The pre-procedural mean (SD) aortic valve area (AVA) was 0.69 (0.2) cm2 and the average (SD) peak and mean gradients were 71 [23]/42 [15] mmHg. Pre TAVR, 28.7% of patients had significant (moderate or severe) TR. Significant TR pre-TAVR increased the risk of in-hospital cardiovascular (CV) and all-cause and mortality [adjusted relative risk (RR) (95% CI): 14.67 (1.35-159.51) and 5.09 (1.14-22.72), respectively], and those with severe TR post-TAVR had longer hospital stay [median (IR): 9.9 (2.9-17.0) days]. No improvement or worsened TR (greater than mild) post-TAVR was associated with higher CV and all-cause mortality [adjusted RR (95% CI): 21.5 (1.81-255.96) and 8.19 (1.67-40.29), respectively]. Right ventricular systolic pressure (RVSP) was independently associated with TR severity pre and post TAVR. CONCLUSIONS: Significant TR was common among patients undergoing high risk TAVR, and is associated with increased in hospital mortality and longer hospital stay. Patients with elevated RVSP and persistent moderate or severe TR after TAVR are at higher risk of in hospital death.

Urinary Metal Levels after Repeated Edetate Disodium Infusions: Preliminary Findings.

Environmentally acquired lead and cadmium are associated with increased cardiovascular disease risk. In the Trial to Assess Chelation Therapy, up to 40 infusions with edetate disodium over an approximately one-year period lowered the cardiovascular disease risk in patients with a prior myocardial infarction. We assessed whether a reduction in surrogate measures of total body lead and cadmium, post-edetate disodium urine lead and pre-edetate urine cadmium, could be detected after repeated edetate disodium-based infusions compared to the baseline. Fourteen patients with coronary artery disease received multiple open-label edetate disodium infusions. The urine metals pre- and post-edetate infusion, normalized for urine creatinine, were compared to urine levels pre and post final infusion by a paired t-test. Compared with the pre-edetate values, post-edetate urine lead and cadmium increased by 3581% and 802%, respectively, after the first infusion. Compared to baseline, post-edetate lead decreased by 36% (p = 0.0004). A reduction in post-edetate urine lead was observed in 84% of the patients after the final infusion. Pre-edetate lead decreased by 60% (p = 0.003). Pre-edetate lead excretion became undetectable in nearly 40% of patients. This study suggests that edetate disodium-based infusions may decrease the total body burden of lead. However, our data suggest no significant reduction in the body burden of cadmium.

Myocardial longitudinal strain, fitness, and heart failure risk factors in young adults.

AIMS: To investigate the relationship between fitness, heart failure (HF) risk factors (age, blood pressure, and obesity), and global/regional myocardial longitudinal strain in young adults undergoing stress testing. METHODS: Individuals 25-55 years old without any significant medical history, not taking medications, and with a normal maximal stress echocardiogram were eligible. Global and regional longitudinal strain (LS) was evaluated by 2D speckle tracking echocardiography. RESULTS: One hundred and seventy patients were included, of which 60% were males. The mean age was 43 years old, 49% had optimal blood pressure, and 30% were obese. On average, patients achieved 10.5 (3) METS, and the global LS was -19.9 (3.1) %. Reduced fitness was associated with decreased global longitudinal strain (GLS). Those in the top GLS quartile walked on average 1 minute and 21 seconds longer compared with the lowest quartile (P < .001). The effect of fitness on LS was preferential to the mid and apex, such that there was an apex-to-base gradient. Obesity was also independently associated with reduced GLS. However, the reduction in LS in obese individuals was more prominent at the base and mid-walls with relative sparing of the apex. Similar to fitness, aging was also associated with an increase in the apex-to-base gradient of LS. Furthermore, diastolic filling parameters correlated distinctively with regional LS. CONCLUSIONS: In young adults without cardiovascular disease, low fitness and obesity are independently associated with reduced left ventricular longitudinal strain. There is a differential effect of HF risk factors on regional longitudinal function.

The effect of EDTA-based chelation on patients with diabetes and peripheral artery disease in the Trial to Assess Chelation Therapy (TACT).

OBJECTIVE: Approximately 1 in 7 US adults have diabetes; and over 60% of deaths in patients with diabetes have cardiac disease as a principal or contributing cause. Both coronary and peripheral artery disease (PAD) identify high-risk cohorts among patients with diabetes. We have previously demonstrated improved cardiovascular outcomes with edetate disodium-based chelation in post-MI patients with diabetes, enrolled in the Trial to Assess Chelation Therapy (TACT). In these analyses we further studied the effect size of patients with diabetes and severe disease in 2 vascular beds; coronaries, and lower extremity arteries. We questioned whether greater atherosclerotic burden would attenuate the observed beneficial effect of edetate disodium infusions. RESEARCH DESIGN AND METHODS: The multicenter TACT used a double blind, placebo controlled, 2 × 2 factorial design with 1708 participants, randomly assigned to receive edetate disodium-based chelation, or placebo and high dose oral vitamins or placebo. There were 162 (9.5% of 1708) post-MI patients with a diagnosis of diabetes mellitus and PAD for this post hoc analysis. Patients received up to 40 double-blind intravenous infusions of edetate disodium-based chelation, or placebo. The composite primary endpoint of TACT consisted of death from any cause, myocardial infarction, stroke, coronary revascularization and hospitalization for angina. RESULTS: The median age was 66 years, 15% female, 5% non-Caucasian, and BMI was 31. Insulin was used by 32% of patients. Active infusions significantly reduced the primary endpoint compared with placebo infusions (HR, 0.52; 95% CI, 0.30-0.92; P = 0.0069), with a 30% absolute risk reduction in the primary endpoint. There was a marked reduction in total mortality from 24% to 11%, although of borderline significance (P = 0.052). CONCLUSION: Atherosclerotic disease in multiple vascular beds did not attenuate the beneficial effect of edetate disodium infusions in post MI patients with diabetes. Studies now in progress will prospectively test this post hoc finding.

Echocardiographic and clinical markers of left ventricular ejection fraction and moderate or greater systolic dysfunction in left ventricular noncompaction cardiomyopathy.

BACKGROUND: Left ventricular noncompaction (LVNC) is associated with progressive LV systolic dysfunction and dilated cardiomyopathy. We aimed to investigate the echocardiographic and clinical characteristics associated with LV ejection fraction (LVEF) and moderate or greater systolic dysfunction in patients with LVNC. METHODS: Our institutional echocardiography database was retrospectively reviewed between 2008 and 2014, and 62 patients with LVNC were identified. Forty-three (69%) had moderate or greater LV systolic dysfunction (LVEF ≤ 40%) and were compared with 19 (31%) patients with preserved or mildly reduced LVEF (>40%). Linear regression analyses were utilized to identify markers associated with LVEF. RESULTS: The mean age was 63 ± 17 years and noncompacted-to-compacted ratio was 2.3 ± 0.5, and was larger in patients with LVEF ≤ 40% (2.4 vs 2.1; P = .02). Patients with LVEF ≤ 40% were older, had more congestive heart failure, significant QRS interval prolongation, and greater LV remodeling and worse mean global longitudinal strain (GLS). Multivariate regression analysis revealed increased age (standardized regression coefficient (ß) = -0.17; P = .04) and QRS duration (ß = -0.13; P = .08), congestive heart failure (ß = -0.18; P = .04), and worsened GLS (ß = -0.40; P = .001) were independently associated with decreased LVEF in the cohort (overall model fit R2  = 0.71; P < .0001). Increased age (ß = -0.49; P = .01) and QRS duration (ß = -0.50; P = .002), and worsened GLS (ß = -0.33; P = .04), were also associated with a lower LVEF in patients with LVEF > 40%. CONCLUSIONS: The independent markers associated with LVEF and moderate or greater LV systolic dysfunction in patients with LVNC, in particular GLS and QRS duration, may detect high-risk candidates for more aggressive clinical surveillance and medical therapy.

Enhanced vasculotoxic metal excretion in post-myocardial infarction patients following a single edetate disodium-based infusion.

Toxic metals have been associated with cardiovascular mortality and morbidity. We have hypothesized that enhanced excretion of vasculotoxic metals might explain the positive results of the Trial to Assess Chelation Therapy (TACT). The purpose of this study was to determine whether a single infusion of the edetate disodium- based infusion used in TACT led to enhanced excretion of toxic metals known to be associated with cardiovascular events. METHODS: Twenty six patients (post-MI, age > 50 years, serum creatinine ≤ 2.0mg/dL) were enrolled in this open-label study. Urinary levels of 20 toxic metals normalized to urinary creatinine concentrations were measured at baseline in overnight urine collections, for 6h following a placebo infusion of 500mL normal saline and 1.2% dextrose, and for 6h following a 3g edetate disodium-based infusion. Self-reported metal exposure, smoking status, food frequency, occupational history, drinking water source, housing and hobbies were collected at baseline by a metal exposure questionnaire. RESULTS: The mean age was 65 years (range 51-81 years). All patients were male. 50% had diabetes mellitus and 58% were former smokers. Mean (SD) serum creatinine was 0.95 (0.31) mg/dL. Toxic metals were detected in the baseline urine of >80% of patients. After placebo infusion there were no significant changes in total urinary metal levels. After edetate infusion, total urinary metal level increased by 71% compared to baseline (1500 vs. 2580µg/g creatinine; P<0.0001). The effect of edetate was particularly large for lead (3835% increase) and cadmium (633% increase). CONCLUSIONS: Edetate disodium-based infusions markedly enhanced the urinary excretion of lead and cadmium, toxic metals with established epidemiologic evidence and mechanisms linking them to coronary and vascular events.

Tumor necrosis factor-alpha and vascular angiotensin II in estrogen-deficient rats.

Alterations in the vascular angiotensin II system may play a role in the pathophysiology of vascular disease after menopause. In previous studies we have shown that an increase in tumor necrosis factor (TNF)-alpha levels in aging rats because of estrogen deficiency may result in vascular dysfunction. In this study we investigated the effect of TNF-alpha inhibition in angiotensin II modulation of vascular function in aging female animals. Female rats approaching reproductive senescence (12 to 15 months old) were ovariectomized and treated with placebo, estrogen, or a selective TNF-alpha inhibitor (etanercept) for 4 weeks. Expression of angiotensin II in mesenteric arteries was evaluated by immunofluorescence, and the expression of angiotensin-converting enzyme and angiotensin type I receptor (AT(1)R) was investigated by Western immunoblot. Vascular function was assessed in mesenteric arteries using the myograph system, and the role of endogenous angiotensin II on adrenergic vasoconstriction was evaluated in vitro by selective AT(1)R blockade (Candesartan; 10 micromol/L). Our data demonstrate that estrogen-depleted rats have higher serum levels of TNF-alpha and greater sensitivity to phenylephrine vasoconstriction compared with estrogen-replaced animals, which was attenuated by AT(1)R blockade. In vivo TNF-alpha inhibition or estrogen replacement reduced phenylephrine constriction of mesenteric arteries and decreased the modulation of this vasoconstriction by candesartan. These functional changes were accompanied by a reduction in the vascular expression of angiotensin II, angiotensin-converting enzyme, and AT(1)R. These observations indicate that upregulation of TNF-alpha during estrogen deficiency may contribute to enhance vascular constriction by altering the vascular angiotensin II system.

Estrogen improves cardiac recovery after ischemia/reperfusion by decreasing tumor necrosis factor-alpha.

BACKGROUND: Estrogen has cardioprotective effects on ischemia/reperfusion (I/R). Tumor necrosis factor alpha (TNFalpha) is an inflammatory cytokine with depressor effects on myocardial function and has been suggested to mediate I/R injury. Whether cardiac TNFalpha levels are influenced by estrogen status is unknown. We investigated the effect of estrogen on TNFalpha levels and TNFalpha receptors in the ischemic heart and its role in estrogen modulation of I/R injury. METHODS: Hearts were isolated from ovariectomized Sprague-Dawley female rats that were treated with either estrogen or placebo for 4 weeks. Working heart preparations were subjected to global, no-flow ischemia (25 min) followed by reperfusion (40 min). RESULTS: I/R increased TNFalpha levels in coronary effluent and in the left ventricle (LV) of estrogen-deficient rats, which were decreased by estrogen replacement. Moreover, estrogen improved functional recovery (55.0+/-5.0% vs. 22.0+/-7.0%, P<0.05), decreased LV apoptosis, and reduced myocardial necrosis. To further evaluate the role of TNFalpha in I/R injury, a selective TNFalpha inhibitor (etanercept) was used in vitro before the ischemic insult. TNFalpha inhibition improved functional recovery (39+/-4.4% vs. 22.0+/-7.0%, P<0.05) and reduced apoptosis and myocardial necrosis in estrogen-deficient animals but did not have a summative protective effect in the hearts of estrogen-replaced animals. CONCLUSIONS: These data indicate that estrogen modulates cardiac expression of TNFalpha and TNFalpha receptors. Moreover, the cardioprotective effects of estrogen are in part mediated by regulation of TNFalpha levels in the ischemic heart.

Preeclampsia: current understanding of the molecular basis of vascular dysfunction.

Preeclampsia is a pregnancy-specific disorder characterised by hypertension and proteinuria occurring after the 20th week of gestation. Delivery of the placenta results in resolution of the condition, implicating the placenta as a central culprit in the pathogenesis of preeclampsia. In preeclampsia, an inadequate placental trophoblast invasion of the maternal uterine spiral arteries results in poor placental perfusion, leading to placental ischaemia. This could result in release of factors into the maternal circulation that cause widespread activation or dysfunction of the maternal endothelium. Factors in the maternal circulation might induce oxidative stress and/or elicit an inflammatory response in the maternal endothelium, resulting in the altered expression of several genes involved in the regulation of vascular tone. This review addresses the potential circulating factors and the molecular mechanisms involved in the alteration of vascular function that occurs in preeclampsia.

Age-associated impairment in vasorelaxation to fluid shear stress in the female vasculature is improved by TNF-alpha antagonism.

Aging is associated with alterations in vascular homeostasis, including a reduction in flow-mediated vasodilation, which in women is related to the onset of menopause. We previously found that in female animals, aging is associated with an increase in TNF-alpha. Thus we investigated the role of in vivo TNF-alpha inhibition on vascular responses to shear stress in aging female rats. Mesenteric arteries (approximately 150 microm) were isolated from young (3 mo) and ovariectomized Sprague-Dawley female rats approaching reproductive senescence (12 mo) treated with either placebo or a TNF-alpha inhibitor (etanercept; 0.3 mg/kg) and were mounted on a pressure myograph system. Vessels were equilibrated at an intraluminal pressure of 60 mmHg and then preconstricted with phenylephrine at approximately 70% of their initial diameter. Perfusate flow was increased in steps from 0 to 150 microl/min. Compared with young vessels, aged vessels have a decrease in flow-mediated dilation [maximal dilation (means +/- SE): 52 +/- 4 vs. 24 +/- 15%; P < 0.05], which was improved by TNF-alpha inhibition. Moreover, in aged vessels maximal dilation to flow was achieved at higher levels of shear stress compared with young vessels. In all groups, flow-mediated dilation was abolished by either endothelial removal or nitric oxide synthase inhibition with N(G)-nitro-L-arginine methyl ester. However, the modulation by N(G)-nitro-L-arginine methyl ester was reduced in vessels from aged animals compared with young animals but was improved in the etanercept-treated aged animals. In vivo chronic TNF-alpha inhibition improves flow-mediated arterial dilation in resistance arteries of aged female animals.