Association of serum calcium and phosphorus with measures of left ventricular structure and function: The ARIC study.

BACKGROUND AND AIMS: Elevated serum calcium and phosphorus have been associated with increased risk of cardiovascular disorders. We evaluated whether abnormal calcium and high serum phosphorus are associated cross-sectionally with echocardiographic measures of left ventricular (LV) structure and function, as doing so may provide insight into the etiology of cardiac disorders. METHODS AND RESULTS: Included in the analysis were 5213 Atherosclerosis Risk in Communities Study (ARIC) participants who in 2011-2013 had echocardiography and serum calcium and phosphorus measurements. We evaluated the association of serum calcium (corrected for albumin) and phosphorus quintiles with measures of LV structure and function, after adjusting for other cardiovascular risk factors. Participants were on average 75.3 years old; 59.1% were female and 19.8% were African American. Mean (±SD) concentrations of calcium and phosphorus were 9.33 ± 0.38 and 3.46 ± 0.45 mg/dL, respectively. Higher calcium was associated with lower LV end-diastolic diameter (LVEDD) but greater prevalence of concentric remodeling (p-trend: 0.005 and 0.004 respectively). We observed association between high phosphorus and high septal E/e' (p-trend: 0.02). Likewise, higher serum phosphorus was associated with higher left atrial volume index (p-trend: 0.001) and LV hypertrophy prevalence (p-trend: 0.04). CONCLUSIONS: In conclusion, higher calcium was associated with more concentric remodeling but lower LVEDD, suggesting complex associations between calcium and cardiac function. Serum phosphorus was related to worse indices of LV diastolic function and LV hypertrophy, but not to LV systolic function. However, the magnitudes of association were modest, so clinical implications of these findings may be limited.

Choline Diet and Its Gut Microbe-Derived Metabolite, Trimethylamine N-Oxide, Exacerbate Pressure Overload-Induced Heart Failure.

BACKGROUND: Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite of dietary choline and other trimethylamine-containing nutrients, is both elevated in the circulation of patients having heart failure and heralds worse overall prognosis. In animal studies, dietary choline or TMAO significantly accelerates atherosclerotic lesion development in ApoE-deficient mice, and reduction in TMAO levels inhibits atherosclerosis development in the low-density lipoprotein receptor knockout mouse. METHODS AND RESULTS: C57BL6/J mice were fed either a control diet, a diet containing choline (1.2%) or a diet containing TMAO (0.12%) starting 3 weeks before surgical transverse aortic constriction. Mice were studied for 12 weeks after transverse aortic constriction. Cardiac function and left ventricular structure were monitored at 3-week intervals using echocardiography. Twelve weeks post transverse aortic constriction, myocardial tissues were collected to evaluate cardiac and vascular fibrosis, and blood samples were evaluated for cardiac brain natriuretic peptide, choline, and TMAO levels. Pulmonary edema, cardiac enlargement, and left ventricular ejection fraction were significantly (P<0.05, each) worse in mice fed either TMAO- or choline-supplemented diets when compared with the control diet. In addition, myocardial fibrosis was also significantly greater (P<0.01, each) in the TMAO and choline groups relative to controls. CONCLUSIONS: Heart failure severity is significantly enhanced in mice fed diets supplemented with either choline or the gut microbe-dependent metabolite TMAO. The present results suggest that additional studies are warranted examining whether gut microbiota and the dietary choline → TMAO pathway contribute to increased heart failure susceptibility.

Emodin protects against diabetic cardiomyopathy by regulating the AKT/GSK-3ß signaling pathway in the rat model.

Diabetes mellitus (DM) has been recognized as a major health problem. Emodin (Emo) has been reported to exhibit protective effects against diabetic nephropathy. However, little has been known about the effect of Emo on diabetic cardiomyopathy (DCM). A type 2 DM model was induced in rats by low dose streptozotocin (STZ) combined with high energy intake. We found that Emo-treated groups displayed significantly higher body weight (BW) and lower heart weight (HW)/BW. Furthermore, Emo could significantly decrease blood glucose, total cholesterol (TG) levels, and triglyceride (TC) levels in diabetic rats. Moreover, the Emo-treated group showed a marked increase in heart rate (HR) and showed lower left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular posterior wall thickness (LWPWT), and interventricular septal diastolic wall thickness (IVSD). Emo induced a significant increase in phosphorylation of Akt and GSK-3ß in myocardium. These results suggest that Emo may have great therapeutic potential in the treatment of DCM by Akt/GSK-3ß signaling pathway.

Electrophysiological and haemodynamic effects of vernakalant and flecainide in dyssynchronous canine hearts.

AIMS: About one-third of patients with mild dyssynchronous heart failure suffer from atrial fibrillation (AF). Drugs that convert AF to sinus rhythm may further slowdown ventricular conduction. We aimed to investigate the electrophysiological and haemodynamic effects of vernakalant and flecainide in a canine model of chronic left bundle branch block (LBBB). METHODS AND RESULTS: Left bundle branch block was induced in 12 canines. Four months later, vernakalant or flecainide was administered using a regime, designed to achieve clinically used plasma concentrations of the drugs, n = 6 for each drug. Epicardial electrical contact mapping showed that both drugs uniformly prolonged myocardial conduction time. Vernakalant increased QRS width significantly less than flecainide (17 ± 13 vs. 34 ± 15%, respectively). Nevertheless, both drugs equally decreased LVdP/dtmax by ∼15%, LVdP/dtmin by ∼10%, and left ventricular systolic blood pressure by ∼5% (P = n.s. between drugs). CONCLUSIONS: Vernakalant prolongs ventricular conduction less than flecainide, but both drugs had a similar, moderate negative effect on ventricular contractility and relaxation. Part of these reductions seems to be related to the increase in dyssynchrony.

Early detection and prediction of cardiotoxicity in chemotherapy-treated patients.

As breast cancer survival increases, cardiotoxicity associated with chemotherapeutic regimens such as anthracyclines and trastuzumab becomes a more significant issue. Assessment of the left ventricular (LV) ejection fraction fails to detect subtle alterations in LV function. The objective of this study was to evaluate whether more sensitive echocardiographic measurements and biomarkers could predict future cardiac dysfunction in chemotherapy-treated patients. Forty-three patients diagnosed with breast cancer who received anthracyclines and trastuzumab therapy underwent echocardiography and blood sampling at 3 time points (baseline and 3 and 6 months during the course of chemotherapy). The LV ejection fraction; peak systolic myocardial longitudinal, radial, and circumferential strain; echocardiographic markers of diastolic function; N-terminal pro-B-type natriuretic peptide; and high-sensitivity cardiac troponin I were measured. Nine patients (21%) developed cardiotoxicity (1 at 3 months and 8 at 6 months) as defined by the Cardiac Review and Evaluation Committee reviewing trastuzumab. A decrease in longitudinal strain from baseline to 3 months and detectable high-sensitivity cardiac troponin I at 3 months were independent predictors of the development of cardiotoxicity at 6 months. The LV ejection fraction, parameters of diastolic function, and N-terminal pro-B-type natriuretic peptide did not predict cardiotoxicity. In conclusion, cardiac troponin plasma concentrations and longitudinal strain predict the development of cardiotoxicity in patients treated with anthracyclines and trastuzumab. The 2 parameters may be useful to detect chemotherapy-treated patients who may benefit from alternative therapies, potentially decreasing the incidence of cardiotoxicity and its associated morbidity and mortality.

Oestradiol supplement minimises coronary occlusion-induced myocardial infarction and ventricular dysfunction in oophorectomised female rats.

BACKGROUND: Endogenous oestrogen deficiency after menopause is associated with high risk of acute cardiac events and the protection of exogenous oestrogen supplements remains uncertain. This study investigates whether oestrogen therapy protects the heart from ischemic injury in oophorectomised rats. METHODS: Sexually mature female Sprague-Dawley rats (6 for each group) with bilateral oophorectomy underwent selective ligation (occlusion) of left coronary artery for 4 weeks. 17ß-oestradiol (E2) supplements (10 µg, i.m., every other day) were started before (preventive-therapeutic supplement) or after coronary occlusion (therapeutic supplement). RESULTS: In oophorectomised rats plasma levels of E2 declined from 1301 ± 80 to 196 ± 48 pmol/L (p<0.01) and cardiac expression of oestrogen receptors (ER) decreased by ∼60%. E2 supplements recovered the ER expression. Selective ligation of left coronary led myocardial infarction in the left ventricle, with an increase in plasma cardiac troponin I (cTn-I), decrease in systolic blood pressure (SBP), and reduction of left ventricular pressures. Preventive-therapeutic but not therapeutic E2 supplement reduced cTn-I levels (from 21.9 ± 2.0 to 6.0 ± 0.3 ng/mL, p<0.01), minimised infarction (from 37.0 ± 1.2% to 18.1 ± 2.3%, p<0.05), increased SBP (from 82 ± 4.2 to 97 ± 4.4mm Hg, p<0.05), and improved left ventricular end pressures in the oophorectomised rats following coronary occlusion. CONCLUSION: Postmenopausal (ooporectomised) oestrogen supplement commenced before establishment of myocardial ischemia minimises myocardial infarction and ventricular dysfunction following the coronary artery occlusion. Cellular and molecular mechanisms underlying the cardiac protection of oestrogen therapy remain unclear, in which activation of cardiac ER expression and increasing in circulating CD90(+) stem cells may be involved.

Myocardial dysfunction due to hypocalcemia.

Hypocalcemia is a curable cause of myocardial dysfunction and clinical congestive cardiac failure, with only stray reports available in literature. We describe 15 infants presenting with severe left ventricular dysfunction, who were found to have hypocalcemia with or without hypomagnesemia. Vitamin D deficiency was identified as the main cause of hypocalcemia. These children improved on supplementation of vitamin D and calcium.

Regulation of circulating progenitor cells in left ventricular dysfunction.

BACKGROUND: Reductions in numbers of circulating progenitor cells (CD34+ cell subsets) have been demonstrated in patients at risk for, or in the presence of, cardiovascular disease. The mediators of these reductions remain undefined. To determine whether neurohumoral factors might regulate circulating CD34+ cell subsets in vivo, we studied complementary canine models of left ventricular (LV) dysfunction. METHODS AND RESULTS: A pacing model of severe LV dysfunction and a hypertensive renal wrap model in which dogs were randomized to receive deoxycorticosterone acetate (DOCA) were studied. Circulating CD34+ cell subsets including hematopoietic precursor cells (HPCs: CD34+/CD45(dim)/VEGFR2-) and endothelial progenitor cells (EPCs: CD34+/CD45-/VEGFR2+) were quantified. Additionally, the effect of mineralocorticoid excess on circulating progenitor cells in normal dogs was studied. The majority of circulating CD34+ cells expressed CD45dimly and did not express VEGFR2, consistent with an HPC phenotype. HPCs were decreased in response to pacing, and this decrease correlated with plasma aldosterone levels (Spearman rank correlation=-0.67, P=0.03). In the hypertensive renal wrap model, administration of DOCA resulted in decreased HPCs. No changes were seen in EPCs in either model. Normal dogs treated with DOCA exhibited a decrease in HPCs in peripheral blood but not bone marrow associated with decreased telomerase activity. CONCLUSIONS: This is the first study to demonstrate that mineralocorticoid excess, either endogenous or exogenous, results in reduction in HPCs. These data suggest that mineralocorticoids may induce accelerated senescence of progenitor cells, leading to their reduced survival and decline in numbers.

Atorvastatin enhances interleukin-10 levels and improves cardiac function in rats after acute myocardial infarction.

LV (left ventricular) remodelling is the basic mechanism of HF (heart failure) following MI (myocardial infarction). Although there is evidence that pro-inflammatory cytokines [including TNF-alpha (tumour necrosis factor-alpha) and IL-6 (interleukin-6)] are involved in the remodelling process, only little is known about the role of anti-inflammatory cytokines, such as IL-10. As accumulating evidence has revealed that statins possess anti-inflammatory properties, the aim of the present study was to elucidate the effect of atorvastatin on the modulation of the anti-inflammatory cytokine IL-10 and its effect on LV function in rats with HF subsequent to MI. Rats with MI, induced by permanent LAD (left anterior descending) branch coronary artery ligation, were treated for 4 weeks with atorvastatin (10 mg x kg(-1) of body weight x day(-1) via oral gavage) starting on the first day after induction of MI. Cardiac function was assessed by echocardiography and cardiac catheterization 4 weeks after MI induction. Membrane-bound and soluble fractions of TNF-alpha, IL-6 and IL-10 protein, the TNF-alpha/IL-10 ratio, serum levels of MCP-1 (monocyte chemoattractant protein-1) as well as myocardial macrophage infiltration were analysed. Treatment with atorvastatin significantly improved post-MI LV function (fractional shortening, +120%; dP/dt(max), +147%; and LV end-diastolic pressure, -27%). Furthermore atorvastatin treatment markedly decreased the levels of TNF-alpha, IL-6 and MCP-1, reduced myocardial infiltration of macrophages and significantly increased myocardial and serum levels of the anti-inflammatory cytokine IL-10. Thus the balance between pro-inflammatory and anti-inflammatory cytokines was shifted in the anti-inflammatory direction, as shown by a significantly decreased TNF-alpha/IL-10 ratio. Atorvastatin ameliorated early LV remodelling and improved LV function in rats with HF subsequent to MI. Our study suggests that the modulation of the balance between pro- and anti-inflammatory cytokines towards the anti-inflammatory cytokine IL-10 is one salutary mechanism underlying how atorvastatin influences post-MI remodelling and thus improves LV function.

Limited cardiotoxicity after extensive thoracic surgery and intraoperative hyperthermic intrathoracic chemotherapy with doxorubicin and cisplatin.

BACKGROUND: Recently, pleural mesothelioma has been treated by cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy with doxorubicin and cisplatin. The well-established cardiotoxicity of doxorubicin and distressing data from an animal study raised concern about its impact on cardiac function. In the present study, early cardiotoxicity of this treatment modality was prospectively analyzed. PATIENTS AND METHODS: In 13 pleural mesothelioma patients, cardiotoxicity was monitored by clinical examination, electrocardiography, Troponin levels, cardiac ultrasonography, and estimation of left ventricular ejection fraction (LVEF) by radionuclide ventriculography before and during the first 6 months after cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy with doxorubicin (25-54 mg/m(2)) and cisplatin (65-120 mg/m(2)). RESULTS: No clinical cardiac failure or treatment-related death was observed. In two patients transient atrial fibrillation was noted; one associated with pulmonary emboli. Early posttreatment Troponin release was not of predictive value. Ultrasonography did not reveal significant alterations. LVEF decreased significantly (mean 0.07 or 11%, P = .001) during the first 3 months and remained stable thereafter. In univariate analysis, the degree of LVEF reduction was statistically related to maximal intrathoracic doxorubicin concentration (P = .031) and total cisplatin dose (P = .029). Direct exposure of the heart to the drugs as a result of partial pericardectomy was not associated with greater LVEF decrease. On the contrary, partial pericardectomy seemed to be associated with a smaller LVEF decline than when the pericardium remained intact (P = .045). In this small series, no statistically significant correlation between other treatment or pharmacokinetic parameters and LVEF decline was found. Notably, higher doxorubicin plasma concentrations and exposure were not associated with increased LVEF reduction. CONCLUSIONS: Early cardiotoxicity is limited after this treatment modality using substantial doses of doxorubicin and cisplatin. Hence, this study suggests that intrathoracic chemotherapy with doxorubicin and/or cisplatin may be used for primary and secondary pleural malignancies, even immediately after extensive thoracic surgery, without concern of severe early cardiotoxicity.

Left ventricular function and calcium phosphate plasma levels in uraemic patients.

UNLABELLED: BACKGROUND. Recent investigations have focused on the pathogenetic role of disturbances of calcium phosphate metabolism in causing cardiovascular morbidity and mortality in haemodialysis patients. The aim of the present study was to assess left ventricular function and its relationship to phosphate and calcium plasma levels in stable uraemic patients on haemodialysis treatment. METHODS: Twenty uraemic patients (mean age 51+/-13 years) on maintenance haemodialysis and free from overt cardiac dysfunction, and 20 healthy volunteers underwent standard echocardiography, tissue Doppler-derived early (E(m)) and late (A(m)) diastolic velocities, tissue characterization with cyclic variations of integrated backscatter (CV-IBS), and serum biochemistry. RESULTS: With respect to tissue Doppler imaging (TDI), uraemic patients showed a lower E(m) peak, a higher A(m) peak, and a reduced E(m)/A(m) ratio of both interventricular septum and lateral wall (0.01>P<0.001) than controls. CV-IBS of both septum and posterior wall was significantly smaller in uraemic patients than in the control subjects (P<0.001). Moreover, the E(m)/A(m) ratio of septum and lateral wall were negatively related to serum phosphorus and to calcium phosphate product (P<0.001 for all). Accordingly, an inverse relationship was also found between CV-IBS of septum and lateral wall and calcium phosphate product and phosphorus (P<0.05 for all). CONCLUSIONS: These results showed early cardiac impairment of diastolic myocardial function evaluated by TDI and IBS analysis, and a close relationship between these changes and the calcium-phosphate plasma levels. These findings are well in keeping with the important role of hyperphosphataemia as a risk factor for cardiovascular damage, and justify the effort for optimal control of calcium phosphate metabolism in uraemic patients.

N-acetylcysteine treatment normalizes serum tumor necrosis factor-alpha level and hinders the progression of cardiac injury in hypertensive rats.

BACKGROUND: Studies in isolated cardiomyocytes showed that replenishment in cellular glutathione, achieved with the glutathione precursor N-acetylcysteine (NAC), abrogated deleterious effects of tumor necrosis factor-alpha (TNF-alpha). METHODS AND RESULTS: We examined the ability of NAC to limit the progression of cardiac injury in the rat model of hypertension, induced by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) (50 mg/kg per day SC) and high-salt diet (HS) (8% NaCl). Four-week HS/L-NAME administration induced hypertension (193+/-8 versus 122+/-4 mm Hg for low-salt diet [LS] group) and left ventricular (LV) dysfunction, revealed by echocardiography and characterized by decreased LV shortening fraction (38+/-2% versus 49+/-4% for LS group; P<0.05) and decreased LV posterior wall thickening (49+/-3% versus 70+/-4% for LS group; P<0.05). LV dysfunction worsened further after 6-week HS/L-NAME administration. Importantly, increase in serum TNF-alpha level was strongly correlated with shortening fraction decrease and cardiac glutathione depletion. NAC (75 mg/d) was given as a therapeutic treatment in a subgroup of HS/L-NAME animals during weeks 5 and 6 of HS/L-NAME administration. NAC treatment, which replenished cardiac glutathione, had no effect on hypertension but reduced LV remodeling and dysfunction, normalized serum TNF-alpha level, and limited activation of matrix metalloproteinases -2 and -9 and collagen deposition in LV tissues. CONCLUSIONS: These findings suggest that glutathione status determines the adverse effects of TNF-alpha in cardiac failure and that TNF-alpha antagonism may be achieved by glutathione supplementation.

Coronary revascularization: a procedure in transition from on-pump to off-pump? The role of glucose-insulin-potassium revisited in a randomized, placebo-controlled study.

OBJECTIVE: To investigate an optimized glucose-insulin-potassium (GIK) solution regimen as an alternate myocardial protective strategy in off-pump coronary artery bypass graft (OP-CAB) surgery and as a supplement to conventional coronary artery bypass graft (CABG) surgery using cardiopulmonary bypass (CPB). DESIGN: Prospective, randomized, placebo-controlled. SETTING: Single institution, cardiothoracic specialty hospital. PARTICIPANTS: Forty-four patients scheduled for elective multivessel coronary artery surgery using either conventional CPB (n = 22) or OP-CAB techniques (n = 22). INTERVENTIONS: Preischemic, ischemic, and postischemic administration of GIK solution was carried out, optimally dosed to ensure nonesterified fatty acid (NEFA) suppression, and supplemented with magnesium, a glycolytic enzymatic cofactor. MEASUREMENTS AND MAIN RESULTS: GIK solution therapy reduced plasma NEFA levels (p < 0.001) in OP-CAB surgery and CPB groups but failed to affect the incidence of non-Q wave perioperative myocardial infarction, incidence of postoperative atrial fibrillation, incidence of postoperative infection, reduction in creatinine clearance, or duration of postoperative intensive care unit or hospital length of stay. After adjusting for GIK solution therapy, OP-CAB surgery resulted in significantly less ischemic injury (troponin I >15 microg/L, 19.0% v 91.3%; p = 0.0001) and reduced postoperative infections (14.3% v 43.5%; p = 0.049). CONCLUSION: GIK solution therapy achieved NEFA suppression and an insignificant trend toward reduced biochemical parameters of ischemic injury in OP-CAB surgery and CPB groups, but no major clinical benefit (perioperative myocardial infarction, intensive care unit length of stay, or hospital length of stay) was shown after elective CABG surgery in low-risk patients. Compared with CPB, OP-CAB surgery significantly reduced ischemic injury and postoperative infections.