Thyroid hormone receptor alpha1 downregulation in postischemic heart failure progression: the potential role of tissue hypothyroidism.

Thyroid hormone (TH) signaling is altered in response to various stresses including myocardial ischemia. The present study investigated potential implication of TH signaling in the pathophysiology of postischemic remodeling. Acute myocardial infarction was induced in rats by coronary artery ligation (AMI). After 34 weeks, 6 animals were on congestive heart failure (CHF) as indicated by measurements in lung and right ventricular weight. 7 animals were in compensated state (Non-CHF) and 8 sham-operated animals (SHAM) served as controls. Progression to congestive heart failure was characterized by marked decrease in EF% and all other functional echocardiographic parameters. Furthermore, beta-MHC expression was significantly increased in CHF. A distinct pattern of thyroid hormone receptor (TR) expression was observed in the course of postischemic remodeling; TR alpha 1 was upregulated and TR beta 1 was downregulated in Non-CHF, and TR alpha 1 expression was markedly decreased during the transition from Non-CHF to CHF resulting in tissue hypothyroidism. Circulating T3 and T4 remained unchanged. This response was associated with marked decrease in mTOR activation. A potential link between mTOR and TR alpha 1 expression was shown in a neonatal cardiomyocytes model of PE (phenylephrine)-induced pathological growth. Phenylephrine increased the expression of TR alpha 1 in nucleus and this response was abrogated in the case of mTOR inhibition by rapamycin. In conclusion, progression to congestive heart failure after myocardial infarction is associated with suppressed expression of TR alpha 1 and results in tissue hypothyroidism. This process may, at least in part, be mTOR dependent.

Thyroid hormone at supra-physiological dose optimizes cardiac geometry and improves cardiac function in rats with old myocardial infarction.

Thyroid hormone (TH) is critical in cardiac cell differentiation (regulating contractile proteins and cell geometry) and this effect could be potentially exploited therapeutically in reversing the process of de-differentiation which underlies postischemic cardiac remodeling. Acute myocardial infarction was induced in male Wistar rats by ligating left coronary artery (AMI, n=8), while sham operated animals served as control (SHAM, n=8). 13 weeks after AMI, TH was administered in a group of animals for 4 weeks (AMI-THYR, n=9). TH significantly increased beta-MHC and decreased alpha-MHC expression in the myocardium. This response was accompanied by changes in cardiac geometry: sphericity index, (SI, long to short axis ratio) was found to be 1.95 (SEM, 0.02) in SHAM, 1.51(0.03) in AMI and 1.64(0.03) in AMI-THYR, p<0.05. As a consequence, cardiac function was significantly improved: left ventricular ejection fraction (EF%) was 74.5% (SEM, 2.8) in SHAM vs 29.5% (2.1) in AMI, and 40.0% in AMI-THYR, p<0.05. Furthermore, +dp/dt and -dp/dt were 4250 (127) and 2278 (55) in SHAM vs 2737(233) and 1508 (95) in AMI vs 3866 (310) and 2137(111) in AMI -THYR, respectively, p<0.05. TH treatment partially reverses cardiac dysfunction in rats with old myocardial infarction by favorably changing cardiac chamber geometry and expression of myosin isoforms. Thyroid hormone, unlike current treatments, appears to be a paradigm of therapeutic intervention which aims at restoring cardiac geometry and may prove new effective treatment for heart failure.

Detection of coronary artery lesions and myocardial necrosis by magnetic resonance in systemic necrotizing vasculitides.

OBJECTIVE: Myocardium and coronary arteries can occasionally be affected in patients with systemic necrotizing vasculitides; however, such involvement has not been systematically assessed using cardiovascular magnetic resonance imaging (MRI). METHODS: Magnetic resonance angiography and contrast-enhanced MRI were applied for the assessment of coronary arteries (the left anterior descending [LAD], left circumflex [LCx], and right coronary artery [RCA]) and myocardium, respectively, in 39 patients with vasculitis who were asymptomatic for cardiac disease (16 with microscopic polyangiitis [MPA], 11 with Wegener's granulomatosis [WG], 9 with Churg-Strauss syndrome [CSS], and 3 with polyarteritis nodosa [PAN]). Data were compared with age-matched disease-control patients with rheumatoid arthritis (n = 20) or systemic lupus erythematosus (n = 13), and with healthy control individuals with normal coronaries (n = 40). RESULTS: Patients with MPA, WG, and PAN (but not with CSS) were found to display significantly increased maximal diameters of coronary arteries compared with healthy controls (for MPA and WG; P < 0.001 for LAD and RCA, and P < 0.01 for LCx) and with both disease-control groups (for only MPA; P < 0.01 for LAD and RCA, and P < 0.05 for LCx). Fusiform coronary aneurysms were detected in patients with MPA (4/16) and PAN (2/3), whereas coronary ectasias were evident in patients with MPA (14/16) and WG (2/11). The presence of myocardial necrosis (by assessment of late gadolinium-enhanced images) was identified only in patients with MPA (2/16) and CSS (3/8 studied). CONCLUSION: Cardiovascular MRI assessment of patients with systemic vasculitis revealed coronary ectatic disease in the majority of patients with MPA and PAN, as well as in several patients with WG. Myocardial necrosis can be detected in MPA and CSS.

Thyroid hormone modulates the responsiveness of rat aorta to alpha1-adrenergic stimulation: an effect due to increased activation of beta2-adrenergic signaling.

AIM: The ability of the thyroid hormone to increase cardiac output and to lower systemic vascular resistance may provide a novel treatment for cardiovascular diseases. Therefore, understanding the mechanisms of thyroid hormone action on the heart and peripheral vasculature could be of clinical importance. We previously found that thyroid hormone modulates the alpha1-adrenergic effect on vascular reactivity of rat aortas. In the present study we further investigated possible mechanisms of this response. METHODS: Hyperthyroidism was induced on Wistar-Kyoto male rats with L-Thyroxine, (THYR) treatment for two weeks, N.=18 while untreated rats used as controls (NORM), N.=16. The thoracic aorta was dissected and cut into rings that were suspended in an isolated organ bath with Krebs-Henseleit buffer. Maximal tension, Tmax, in g was measured in response to Potassium Chloride (KCl) and Phenylephrine (PE) in rings in the presence of Ritodrine, a beta-2 agonist (NORM-RITO, N:=8, THYR-RITO, N.=9), or in the absence of Ritodrine (THYR, N.=9, NORM, N.=8). RESULTS: With KCL, Tmax was not different between the THYR, NORM, NORM-RITO, and THYR-RITO groups. With PE, there was a difference in Tmax between NORM-RITO and NORM, 0.66 (0.056) g vs 1.00 (0.066) g, P<0.05 and THYR and NORM, 0.75 (0.055) g vs 1.00 (0.066) g, P<0.05. No significant difference was observed between THYR-RITO AND THYR. Furthermore, Relax % was not significantly different between the NORM and the THYR, NORM-RITO, and THYR-RITO groups, 64.5%(3.7) vs 67.3%(6.7), 73.5% (4.3) and 81.8 %(4.7), P>0.05. CONCLUSIONS: PE induced vasoconstriction in isolated rat aortic rings was reduced after both ritodrine and thyroxine treatment. However, co-administration of thyroid hormone and ritodrine did not result in a synergistic reduction of PE induced vasoconstriction. Thus, thyroxine may modulate the alpha1-adrenergic vascular responsiveness by enhancing beta2-adrenergic stimulation.

Ischemic preconditioning fails to confer additional protection against ischemia-reperfusion injury in the hypothyroid rat heart.

There is accumulating evidence showing that ischemic preconditioning (PC) may lose its cardioprotective effect in the diseased states. The present study investigated whether PC can be effective in hypothyroidism, a clinical condition which is common and often accompanies cardiac diseases such as heart failure and myocardial infarction. Hypothyroidism was induced in rats by 3-week administration of 6n-propyl-2-thiouracil in water (0.05 %). Normal and hypothyroid hearts (HYPO) were perfused in Langendorff mode and subjected to 20 min of zero-flow global ischemia and 45 min of reperfusion. A preconditioning protocol (PC) was also applied prior to ischemia. HYPO hearts had significantly improved post-ischemic recovery of left ventricular developed pressure, end-diastolic pressure and reduced lactate dehydrogenase release. Furthermore, phospho-JNK and p38 MAPK levels after ischemia and reperfusion were 4.0 and 3.0 fold lower in HYPO as compared to normal hearts (P<0.05). A different response to PC was observed in normal than in HYPO hearts. PC improved the post-ischemic recovery of function and reduced the extent of injury in normal hearts but had no additional effect on the hypothyroid hearts. This response, in the preconditioned normal hearts, resulted in 2.5 and 1.8 fold smaller expression of the phospho-JNK and phospho-p38 MAPK levels at the end of reperfusion, as compared to non-PC hearts (P<0.05), while in HYPO hearts, no additional reduction in the phosphorylation of these kinases was observed after PC. Hypothyroid hearts appear to be tolerant to ischemia-reperfusion injury. This response may be, at least in part, due to the down-regulation of ischemia-reperfusion induced activation of JNKs and p38 MAPK kinases. PC is not associated with further reduction in the activation of these kinases in the hypothyroid hearts and fails to confer added protection in those hearts.

"Cardiovascular magnetic resonance imaging reveals myocardial inflammation and coronary artery ectasia during the acute phase of Kawasaki disease".

In a patient with Kawasaki disease, during the acute phase, cardiovascular magnetic resonance has been successfully used for simultaneous evaluation of coronary arteries, myocardial function and the presence of myocardial inflammation. This comprehensive protocol revealed clinically relevant information that was missed by routinely used diagnostic approach.

Thyroid hormone receptor alpha 1: a switch to cardiac cell "metamorphosis"?

Thyroid hormone receptor alpha1 (TRalpha1) is predominantly expressed in the myocardium but its biological function under physiological or pathological conditions remains largely unknown. The present study investigated possible interactions between alpha1 adrenergic and thyroid hormone signaling at the level of TRalpha1, potential underlying mechanisms and physiological consequences, as well as the role of TRalpha1 in cell differentiation. This may be of physiological relevance since both thyroid hormone and adrenergic signalling are implicated in the pathophysiology of cardiac remodelling. Neonatal cardiomyocytes obtained from newborn rats (2-3 days) were exposed to phenylephrine (PE, an alpha1 adrenergic agonist) for 5 days, in the absence or excess of T3 in the culture medium. PE, in the absence of T3, resulted in 5.0 fold increase in TRalpha1 expression in nucleus and 2.0 fold decrease in TRalpha1 expression in cytosol, P<0.05. As a result, a fetal pattern of myosin isoform expression with marked expression of beta-MHC was observed in PE treated vs the untreated cells, P<0.05. PD98059 (an ERK signalling inhibitor) abrogated this response. In the presence of T3 in the culture medium, TRalpha1 expression was increased 1.6 fold in nucleus and 2.0 fold in cytosol in PE-T3 vs PE treated cells, P<0.05, and the fetal pattern of myosin isoform expression was prevented. Parallel studies with H9c2 myoblasts showed that reduction of T3 binding to TRalpha1 receptor delayed cardiac myoblasts differentiation without affecting proliferation. In conclusion, in neonatal cardiomyocytes, nuclear TRalpha1 is overexpressed after prolonged activation of the alpha1- adrenergic signalling by PE. This response seems to be an ERK kinase dependent process. Over-expression of TRalpha1 may lead to fetal cardiac phenotype in the absence of thyroid hormone availability. Furthermore, TRalpha1 seems to be critical in cardiac myoblast differentiation.

Intermittent acute aortic valve regurgitation: a case report of a prosthetic valve dysfunction.

Complications of any mechanical prosthesis include thrombus or pannus formation. In our case report we demonstrate that prosthetic aortic valve regurgitation due to pannus formation may be intermittent and non-cyclic in pattern and therefore not obvious at the time of original clinical examination. Under these conditions and as transesophageal echocardiography cannot be repeated promptly, transthoracic 2-D and Doppler echocardiography should be available at any time when symptoms occur and present the method of choice for acute patient evaluation. Thrombolysis seems to be the first treatment of choice in case of thrombus formation and re-do surgery in case of pannus formation.

[Prognostic value of ventricular longitudinal systolic velocities and maximal oxygen consumption in patients with dilated cardiomyopathy].

OBJECTIVE: To compare the prognostic value of regional longitudinal ventricular systolic velocities with that of maximal oxygen consumption (VO(2max)) in patients with dilated cardiomyopathy (DCM). METHODS: VO(2max) derived from cardiopulmonary exercise tests and regional longitudinal ventricular systolic velocities obtained from tissue Doppler imaging were compared in 18 DCM patients with cardiac events (death, cardiac transplantation, hospitalization, group A) and 24 patients without cardiac events (group B). Peak velocities during isovolumic contraction (is) and ejection (ez) were interrogated at the mitral or tricuspid annulus (site 1), at the mid parts of the walls (site 3, at the level of papillary muscle), and at the midpoints (site 2) between sites 1 and 3 of interventricular septum (S), lateral wall of LV (L) and of RV (R) in apical 4 chambers view. RESULTS: R1is, R2is, R2ez, R3is, S1is, S1ez, S2ez, L1is, L1ez and L2ez of group A were significantly lower than those in group B (all P < 0.05). Independent of VO(2max), high sensitivity and specificity were shown for R3ez, S1ez, L1ez, L1is, L2is and L3is in predicting cardiac events of DCM patients. CONCLUSION: LV and RV systolic velocities could independently predict cardiac events in DCM patients.

Pharmacological inhibition of TRalpha1 receptor potentiates the thyroxine effect on body weight reduction in rats: potential therapeutic implications in controlling body weight.

It has been previously reported that thyroid hormone receptor alpha1 (TRalpha1) is involved in the regulation of food intake and heart rhythm. Herein, we show that pharmacological inhibition of TRalpha1 by dronedarone, an amiodarone like compound (shown to antagonize thyroid hormone binding to TRalpha1), prevented the thyroid hormone induced increase in food intake and heart rate acceleration in rats. This resulted in a marked reduction in body weight. It is likely that thyroid analogs may prove potential therapeutic agents for controlling body weight.

No incremental clinical information of NT Pro BNP at peak exercise over resting levels in patients with impaired left ventricular function.

There is an increasing tension to use NT Pro BNP blood levels at peak exercise testing. Their possible superiority over resting levels in congestive heart failure or factors associated with their increase have not been adequately studied. We studied 65 patients, 51 males and 14 females with impaired left ventricular function. Mean left ventricular ejection fraction (LVEF) was 35+/-9%. Our findings suggest that in patients with heart failure NT Pro BNP plasma levels at peak exercise do not provide incremental clinical information over resting levels. Baseline NT Pro BNP alone can provide sufficient clinical information.

Long-term oral bosentan treatment in patients with pulmonary arterial hypertension related to congenital heart disease: a 2-year study.

OBJECTIVE: To evaluate the long-term clinical and exercise effect of chronic oral administration of the non-selective endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD). DESIGN: Extension of a preceding prospective non-randomised open clinical study on bosentan treatment in PAH related to CHD. SETTING: A tertiary referral centre for cardiology. PATIENTS: 19 of the original 21 patients of mean (standard deviation (SD)) age 22 (3) years (13 with Eisenmenger syndrome) in World Health Organization (WHO) class II-IV and having a mean (SD) oxygen saturation of 87 (2) %. INTERVENTION: Patients received bosentan treatment for 2.4 (0.1) years and underwent clinical and exercise evaluation at baseline, 16 weeks and 2 years of treatment, with haemodynamic assessment at baseline and 16 weeks. RESULTS: All patients remained stable with sustained subjective clinical and WHO class improvement (p<0.01) at 16 weeks and 2 years of treatment without significant side effects or changes in oxygen saturation. After the initial 16-week improvement (p<0.05) in peak oxygen consumption and exercise duration at treadmill test, and walking distance and Borg dyspnoea index at 6-min walk test, all exercise parameters appeared to return to their baseline values at 2 years of follow-up. CONCLUSIONS: Long-term bosentan treatment in patients with PAH related to CHD is safe and induces clinical stability and improvement, but the objective exercise values appear to slowly return to baseline. Larger studies on long-term endothelin receptor antagonism including quality of life assessment are needed to evaluate the therapeutic role of bosentan in this population.

Spatial QRS-T angle: association with diabetes and left ventricular performance.

The spatial QRS-T angle obtained by vectorcardiography is a combined measurement of the electrical activity of the heart and predicts cardiovascular morbidity and mortality. Disturbances in repolarization and depolarization are common in diabetes. No data, however, exist on the effect of diabetes on QRS-T angle. In this study we examined differences in QRS-T angle between type 2 diabetic and non-diabetic subjects; in addition, the potential relationship between QRS-T angle and left ventricular performance as well as glycaemic control were also examined. A total of 74 subjects with type 2 diabetes and 74 non-diabetic individuals, matched for age and sex with the diabetic subjects were examined. All subjects were free of clinically apparent macrovascular complications. Spatial vectorcardiogaphic descriptors of ventricular depolarization and repolarization were reconstructed from the 12-electrocardiographic leads using a computer-based electrocardiogram. Left ventricular mass and performance were measured using M-mode and Doppler echocardiography. QRS-T angle values were higher (by almost 2-fold) in the diabetic in comparison with the non-diabetic subjects (P < 0.001). After multivariate adjustment, QRS-T angle was independently associated with age (P = 0.01), HbA(1c) (P = 0.003), and low-density lipoprotein cholesterol levels (P = 0.04) in the non-diabetic, and with HbA(1c) (P = 0.03) as well as Tei index (P = 0.003) in the diabetic subjects. The spatial QRS-T angle is high in subjects with type 2 diabetes and is associated with glycaemic control and left ventricular performance. The prognostic importance of the higher spQRS-T angle values in subjects with diabetes remains to be evaluated in prospective studies.

Cardiac repair--fact or fancy?

Patients with ischemic cardiomyopathy have a poor prognosis despite all pharmacological, interventional and surgical treatment modalities currently applied. Heart transplantation remains the ideal treatment for this group of patients but the scarcity of donors hinders its widespread application. The autologous transplantation of stem cells (SCs) for cardiac repair is emerging as a new therapy for patients with myocardial dysfunction early after an acute infarction or ischemic cardiomyopathy. The rationale of this novel method is the enhancement of the repair mechanisms achieved by tissue-specific and circulating stem/progenitor cells. SCs assist naturally occurring myocardial repair by contributing to increased myocardial perfusion and contractile performance especially in the setting of acute myocardial infarction (AMI), but also in patients with chronic ischemic heart failure and advanced, diffuse coronary artery disease. The exact mechanism of their action has not been fully elucidated. Few studies continue to suggest a formation of few new contractile tissue. The majority if investigators believe that these cells do not persist long in the myocardium but that they secrete vascular growth and other cardioprotective factors.

Differential pulse pressure response to various antihypertensive drug families.

Pulse pressure (PP) is emerging as a major pressure predictor of cardiac disease. The study comprised 10 185 untreated patients with essential hypertension. A total of 5395 men and 4790 women 56+/-13 years old, with uncomplicated essential hypertension, after a 15-day washout period and after 6 months of antihypertensive monotherapy were included. All patients included in the final cohort were responders and had normalized their blood pressure. PP was decreased least with diuretics (-5 mm Hg) and most with angiotensin II receptor blockers (ARBs) and calcium antagonists (-15 mm Hg), followed by angiotensin-converting enzyme inhibitors (ACEI) (-12 mm Hg) alpha- and beta-blockers (-10 and -9 mm Hg), differentiating among antihypertensive classes (P<0.001). The magnitude of PP fall was related to the degree of left ventricular (LV) mass reduction (P<0.001), seen best with ARBs (r=0.42) and least with ACEIs (r=0.18). Of the antihypertensive medications used in everyday practice, PP decrease may be achieved best with ARBs and calcium antagonists, whereas diuretics confer poor response. PP was decreased least with diuretics (-5 mm Hg) and most with ARBs and calcium channel blockers (-15 mm Hg), followed by ACEI (-12 mm Hg) alpha- and beta-blockers (-10 and -9 mm Hg), differentiating among antihypertensive classes (P<0.001). Of the antihypertensive medications used in everyday practice, PP decrease may be achieved best with ARBs and calcium antagonists.

Iloprost for prevention of contrast-mediated nephropathy in high-risk patients undergoing a coronary procedure. Results of a randomized pilot study.

OBJECTIVE: The prevention of contrast-mediated nephropathy (CMN), which accounts for considerable morbidity and mortality, remains a vexing problem. Contrast induced renal vasoconstriction is believed to play a pivotal role in the CMN mechanism. The aim of this pilot study was to examine the safety and efficacy of two doses of the prostacyclin analogue iloprost in preventing CMN in high-risk patients undergoing a coronary procedure. METHODS: Forty-five patients undergoing coronary angiography and/or intervention who had a serum creatinine concentration >or=1.4 mg/dL were randomized to receive iloprost at 1 or 2 ng/kg/min or placebo, beginning 30-90 minutes before and terminating 4 hours after the procedure. CMN was defined by an absolute increase of serum creatinine >or=0.5 mg/dL or a relative increase of >or=25% measured 2 to 5 days after the procedure. Study drug infusion was discontinued in 2 patients in the low-dose iloprost group due to flush/nausea and in 5 patients in the high-dose group due to severe hypotension. RESULTS: The mean creatinine concentration change in the placebo group (0.02 mg/dL) was unfavorable compared to that in the low-dose iloprost group (-0.11 mg/dL; p=0.08) and high-dose iloprost group (-0.23 mg/dL; p=0.048). The difference between the absolute changes in creatinine clearance was favorable compared to placebo for both the low (mean difference 6.1 mL/min, 95%CI -0.5 to 12.8 mL/min, p=0.07) and the high-dose iloprost group (11.8 mL/min, 95%CI 4.7 to 18.8 mL/min, p=0.002). Three cases of CMN were recorded; all in the placebo group (p=0.032). CONCLUSIONS: The results of this pilot study suggest that prophylactic administration of iloprost may effectively prevent CMN, but higher dosages are connected with substantial tolerability issues.

Decreased vascular reactivity to alpha1 adrenergic stimulation in the presence of hypothyroid state: a part of an adaptive response?

AIM: A hypothyroid state frequently accompanies cardiac illnesses but its physiological significance for the cardiovascular hemodynamics remains largely unknown. Therefore, the present study investigated possible physiological consequences on vascular function in an experimental model of low thyroid hormone state. METHODS: Hypothyroidism was induced in rats by the administration of 6-n-propyl-2-thiouracil in drinking water (final concentration of 0.05%) for 3 weeks, HYPO rats, and untreated rats served as controls (Control). Isolated aortic rings with or without endothelium (E+, E-) were contracted with KCl (10 to 60 mM) and phenylephrine (PE) (10(-10) to 10(-5) M). Maximal tension (Tmax) in g and EC(50) in response to PE and KCl were measured. RESULTS: Tmax was significantly lower while EC(50) was significantly higher in response to PE in HYPO(E+) than in Control(E+). Upon endothelium removal, Tmax was not significantly different between the groups but EC(50) was still significantly higher in HYPO(E-) than in Control(E-). EC(50) in response to KCl was significantly higher in HYPO with or without endothelium and no difference was found in Tmax. CONCLUSIONS: Hypothyroid aortic rings respond less to a1 adrenergic stimulation probably due to the endothelium modulatory effect as well as to intrinsic smooth muscle defect. This seems to be of important clinical relevance.