This review focuses on the effects of thyroid hormones in vascular and renal systems. Special emphasis is given to the mechanisms by which thyroid hormones affect the regulation of body fluids, vascular resistance and, ultimately, blood pressure. Vascular function is markedly affected by thyroid hormones that produce changes in vascular reactivity and endothelial function in hyper- and hypothyroidism. The hypothyroid state is accompanied by a marked decrease in sensitivity to vasoconstrictors, especially to sympathetic agonists, alteration that may play a role in the reduced blood pressure of hypothyroid rats, as well as in the preventive effects of hypothyroidism on experimental hypertension. Moreover, in hypothyroid rats, the endothelium-dependent and nitric oxide donors vasodilation is reduced. Conversely, the vessels from hyperthyroid rats showed an increased endothelium-dependent responsiveness that may be secondary to the shear-stress induced by the hyperdynamic circulation, and that may contribute to the reduced vascular resistance characteristic of this disease. Thyroid hormones also have important effects in the kidney, affecting renal growth, renal haemodynamics, and salt and water metabolism. In hyperthyroidism, there is a resetting of the pressure-natriuresis relationship related to hyperactivity of the reninangiotensin system, which contributes to the arterial hypertension associated with this endocrine disease. Moreover, thyroid hormones affect the development and/or maintenance of various forms of arterial hypertension. This review also describes recent advances in our understanding of thyroid hormone action on nitric oxide and oxidative stress in the regulation of cardiovascular and renal function and in the long-term control of blood pressure.

Hyperthyroidism is associated with low exercise tolerance despite high cardiac output and sometimes with the development of heart failure. L-type calcium channels may play a role in the mechanism, but this has not been fully understood. We examined the effects of thyroid hormone on gene expression and function of L-type calcium channels in rat ventricles by the ribonuclease protection assay and whole-cell patch-clamp technique, respectively. The effects of bisoprolol, beta-blocking agent, on the regulation of calcium channel by thyroid hormone was also studied. In hyperthyroid animals, the mRNA of the calcium channel alpha1c subunit was reduced on day 4, compared with that in euthyroid animals, and remained low on day 8. Bisoprolol did not affect the thyroid hormone mediated decrease in alpha1c subunit mRNA. While L-type calcium current was greater in hyperthyroid than euthyroid myocytes on day 4, it was smaller on day 8. In addition, the isoproterenol-induced increase in calcium current in euthyroid rats was attenuated in hyperthyroid rats. Acetylcholine decreased calcium current in hyperthyroid myocytes, but not in euthyroid myocytes. In conclusion, L-type calcium current was increased by thyroid hormone in rat ventricular myocytes by the activation of the adenylate cyclase cascade, despite a decreased calcium channel gene expression. These genomic and non-genomic modifications may play an important role in the association of high cardiac output with low exercise tolerance, and in the development of heart failure in hyperthyroidism.

The heart is a major target organ for thyroid hormone action, and marked changes occur in cardiac function in patients with hypo- or hyperthyroidism. T(3)-induced changes in cardiac function can result from direct or indirect T(3) effects. Direct effects result from T(3) action in the heart itself and are mediated by nuclear or extranuclear mechanisms. Extranuclear T(3) effects, which occur independent of nuclear T(3) receptor binding and increases in protein synthesis, influence primarily the transport of amino acids, sugars, and calcium across the cell membrane. Nuclear T(3) effects are mediated by the binding of T(3) to specific nuclear receptor proteins, which results in increased transcription of T(3)-responsive cardiac genes. The T(3) receptor is a member of the ligand-activated transcription factor family and is encoded by cellular erythroblastosis A (c-erb A) genes. T(3) also leads to an increase in the speed of diastolic relaxation, which is caused by the more efficient pumping of the calcium ATPase of the sarcoplasmic reticulum. This T(3) effect results from T(3)-induced increases in the level of the mRNA coding for the sarcoplasmic reticulum calcium ATPase protein, leading to an increased number of calcium ATPase pump units in the sarcoplasmic reticulum.

Increased or reduced action of thyroid hormone on certain molecular pathways in the heart and vasculature causes relevant cardiovascular derangements. It is well established that overt hyperthyroidism induces a hyperdynamic cardiovascular state (high cardiac output with low systemic vascular resistance), which is associated with a faster heart rate, enhanced left ventricular (LV) systolic and diastolic function, and increased prevalence of supraventricular tachyarrhythmias - namely, atrial fibrillation - whereas overt hypothyroidism is characterized by the opposite changes. However, whether changes in cardiac performance associated with overt thyroid dysfunction are due mainly to alterations of myocardial contractility or to loading conditions remains unclear. Extensive evidence indicates that the cardiovascular system responds to the minimal but persistent changes in circulating thyroid hormone levels, which are typical of individuals with subclinical thyroid dysfunction. Subclinical hyperthyroidism is associated with increased heart rate, atrial arrhythmias, increased LV mass, impaired ventricular relaxation, reduced exercise performance, and increased risk of cardiovascular mortality. Subclinical hypothyroidism is associated with impaired LV diastolic function and subtle systolic dysfunction and an enhanced risk for atherosclerosis and myocardial infarction. Because all cardiovascular abnormalities are reversed by restoration of euthyroidism ("subclinical hypothyroidism") or blunted by beta-blockade and L-thyroxine (L-T4) dose tailoring ("subclinical hyperthyroidism"), timely treatment is advisable in an attempt to avoid adverse cardiovascular effects. Interestingly, some data indicate that patients with acute and chronic cardiovascular disorders and those undergoing cardiac surgery may have altered peripheral thyroid hormone metabolism that, in turn, may contribute to altered cardiac function. Preliminary clinical investigations suggest that administration of thyroid hormone or its analogue 3,5-diiodothyropropionic acid greatly benefits these patients, highlighting the potential role of thyroid hormone treatment in patients with acute and chronic cardiovascular disease.

Thyroid hormone has well-recognized effects on the cardiovascular system and blood pressure regulation. Blood pressure is altered across the entire spectrum of thyroid disease. The effects of hyperthyroidism include increased cardiac output, contractility, tachycardia, widened pulse pressure, decreased systemic vascular resistance, and increased basal metabolic rate. The manifestations of hypothyroidism are in marked contrast to those of hyperthyroidism and include decreased cardiac output, narrow pulse pressure, increased systemic vascular resistance, and decreased metabolic rate. Although thyroid hormone affects almost all tissues of the body and mediates changes in homeostasis, adaptations of the cardiovascular system can result in changes in blood pressure to accommodate the new demands on the system. In this paper, we review the direct and indirect thyroid hormone-mediated effects on blood pressure.

A 27-year-old woman with toxicity of pregnancy and congestive heart failure underwent an emergency cesarean section. In spite of antihypertensive drugs, blood pressure and heart rate were high preoperatively. She coughed many times and SpO2 was 88%. Circulatory state became stable without antihypertensive drugs under combined spinal-epidural anesthesia and continuous intravenous infusion of propofol intraoperatively. After surgery, blood pressure and heart rate became elevated again and congestive heart failure became worse. She was diagnosed as hyperthyroidism by postoperative laboratory examination. If we had discovered her hyperthyroidism, her symptoms of congestive heart failure would not have become worse. We should be more careful about hyperthyroidism in pregnancy because it is not rare.

BACKGROUND: Exercise-induced dyspnea is a frequent feature in patients with hyperthyroidism. HYPOTHESIS: Data from clinical studies to elucidate the origin of this symptom are lacking. In the current study, we examined the hemodynamic and oxygenation responses to exercise and beta-adrenergic blockade in patients with hyperthyroidism and their relationship with dyspnea. METHODS: Hemodynamic studies were performed under resting conditions and after isotonic exercise in 15 patients with hyperthyroidism and 11 control subjects. Exercise was applied using a bicycle ergometer, with progressive loads. In the hyperthyroid group, measurements were repeated at rest and during supine exercise after administering 15 mg of intravenous metoprolol. RESULTS: End-diastolic pulmonary artery pressure and cardiac index were higher in the hyperthyroid group than in controls (18.6 +/- 5.3 vs. 11.2 +/- 4.9 mmHg; p = 0.02, and 6.0 +/- 1.7 vs. 2.8 +/- 0.5 l/min/m2; p = 0.0001, respectively). After exercise, there was an increase in end-diastolic pulmonary artery pressure in the hyperthyroid group (18.6 +/- 5.3 to 25.5 +/- 9.9 mmHg; p = 0.02), revealing impaired cardiocirculatory reserve. Pulmonary arteriolar resistance increased significantly in parallel with end-diastolic pulmonary artery pressure after drug administration, suggesting an inadequate cardiovascular response after beta blockade in patients with hyperthyroidism. CONCLUSION: We observed that functional left ventricular reserve is impaired in patients with hyperthyroidism, suggesting an explanation for the frequent symptom of dyspnea and impaired exercise tolerance. Moreover, we also suggest that beta-adrenergic blockade may adversely affect cardiovascular function in patients with hyperthyroidism.

OBJECTIVE: The study's objective was to examine factors associated with persistent or recurrent congestive heart failure after mitral valve replacement. METHODS: Patients who underwent mitral valve replacement with contemporary prostheses (N = 708) were followed with annual clinical assessment and echocardiography. Cox proportional hazard models were developed to evaluate the impact of demographic, comorbid, and valve-related variables on the occurrence of congestive heart failure after mitral valve replacement, defined as the composite outcome of New York Heart Association class III or IV symptoms or death caused by congestive heart failure postoperatively. Factors associated with all-cause mortality were also examined. Models were bootstrapped 1000 times. RESULTS: The total follow-up was 3376 patient-years (mean 4.8 +/- 3.7 years, range 60 days to 17.1 years). Freedom from New York Heart Association III or IV symptoms or death caused by congestive heart failure was 96.1%+/- 0.8%, 82.7%+/- 1.7%, 66.4%+/- 3.0%, and 38.8%+/- 6.9% at 1, 5, 10, and 15 years, respectively. Preoperative New York Heart Association class, left ventricular grade, atrial fibrillation, coronary artery disease, smoking, persistent tricuspid regurgitation, and redo status predicted congestive heart failure postoperatively (all P <.05). Patients who underwent mitral valve replacement for pure mitral stenosis had less congestive heart failure events after surgery than those with regurgitation or mixed disease. Prosthesis size and elevated transprosthesis gradients were not predictive of freedom from congestive heart failure after mitral valve replacement. Atrial fibrillation, persistent tricuspid regurgitation, and surgical referral for mitral valve replacement at an advanced functional stage were also risk factors for all-cause mortality. CONCLUSIONS: This study identifies the incidence of and risk factors for congestive heart failure and death late after mitral valve replacement. Although prosthesis size has no effect, other potentially modifiable factors such as atrial fibrillation, persistent tricuspid regurgitation, and late surgical referral have a negative impact on freedom from congestive heart failure and overall survival after mitral valve replacement.

Heart failure is one of the most prevalent diseases in industrialized countries. Although the prognosis of patients with heart failure is still poor, in recent decades new therapies have been investigated in order to improve quality of life and survival. However, up to 30% of the patients with advanced heart failure present disturbances in intraventricular conduction, and this produces asynchrony of ventricular contractility, leading to further deterioration in heart function. Cardiac resynchronization therapy can improve the synchrony of ventricular contractility. Numerous studies have demonstrated the benefits of biventricular stimulation therapy for improving hemodynamic parameters, quality of life, 6-minute walking test performance and functional class in patients with heart failure, ventricular systolic dysfunction and disturbances in intraventricular conduction. Some studies have demonstrated longer survival times in patients treated with cardiac resynchronization plus a defibrillator. Nonetheless, many questions about the benefits of heart resynchronization therapy, site of stimulation and best type of device (pacemaker or defibrillator) remain unresolved.

BACKGROUND: Neurohormones and cytokines have been associated with poor prognosis in patients with congestive heart failure. However, direct comparisons between them are rare and the best predictor for worsening of heart failure remains to be elucidated. The aim of the study was to identify independent predictors for worsening of heart failure. METHODS: We studied 100 patients with congestive heart failure (LVEF <or=25%). Serum levels of interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, aminoterminal atrial natriuretic peptide (N-ANP), B-type natriuretic peptide (BNP), aminoterminal B-type natriuretic peptide (N-BNP), norepinephrine (NE) and big endothelin (big ET) were measured at entry into the study. Univariate and stepwise multivariate regression analyses were performed to compare variables and clinical parameters. The end-point was defined as worsening of heart failure. RESULTS: During follow-up (mean 378 days), 30 patients reached the defined end-point. Univariate risk factors of worsening of heart failure were IL-6 (p = 0.0001), log BNP (p = 0.0001), log N-ANP (p = 0.0259), big ET (p = 0.0032), log N-BNP (p = 0.0495), NE (p = 0.0013) and LVEF (p = 0.0498). Multivariate regression analysis identified IL-6 as the strongest independent predictive value for worsening of heart failure (p = 0.0001), followed by log BNP (p = 0.0002). Mean IL-6 levels were 1.76 +/- 1.73 in stable patients and 4.62 +/- 7.98 pg/ml in patients who developed worsening of heart failure. Using a cut-off value of 1.66 pg/ml for IL-6 Kaplan-Meier freedom from worsening, heart failure was significantly higher in patients below this cut-off point compared with those above (p = 0.0002). CONCLUSIONS: IL-6 and BNP independently predict worsening of heart failure. A single measurement could help to identify patients at high risk for worsening of heart failure and these individuals should be monitored more closely.

PURPOSE OF REVIEW Recent findings on the relationship between congestive heart failure and renal failure are summarized in this review. RECENT FINDINGS Congestive heart failure is found in about one-quarter of cases of chronic kidney disease. The most common cause of congestive heart failure is ischemic heart disease. The prevalence of congestive heart failure increases greatly as the patient's renal function deteriorates, and, at end-stage renal disease, can reach 65-70%. There is mounting evidence that chronic kidney disease itself is a major contributor to severe cardiac damage and, conversely, that congestive heart failure is a major cause of progressive chronic kidney disease. Uncontrolled congestive heart failure is often associated with a rapid fall in renal function and adequate control of congestive heart failure can prevent this. The opposite is also true: treatment of chronic kidney disease can prevent congestive heart failure. There is new evidence showing the cardioprotective effect of carvedilol in patients on dialysis, and of simvastatin and eplerenone in patients with congestive heart failure. Use of non-steroidal anti-inflammatory drugs doubles the rate of hospitalization in patients with congestive heart failure. Anemia has been found in one-third to half the cases of congestive heart failure, and may be caused not only by chronic kidney disease but by the congestive heart failure itself. The anemia is associated with worsening cardiac and renal status and often with signs of malnutrition. Control of the anemia and aggressive use of the recommended medication for congestive heart failure may improve the cardiac function, patient function and exercise capacity, stabilize the renal function, reduce hospitalization and improve quality of life. Congestive heart failure, chronic kidney disease and anemia therefore appear to act together in a vicious circle in which each condition causes or exacerbates the other. Both congestive heart failure and anemia are often undertreated. Cooperation between nephrologists and other physicians in the treatment of patients with anemic congestive heart failure may improve the quality of care and the subsequent prognosis for both congestive heart failure and chronic kidney disease. SUMMARY Adequate and early detection and aggressive treatment of congestive heart failure and chronic kidney disease and the associated anemia may markedly slow the progression of both diseases.

BACKGROUND: Previous validation studies of congestive heart failure (CHF) signs and symptoms were performed in acute settings. Few data have supported the validity of CHF clinical findings during the chronic stages of the disease. This study was designed to evaluate the reliability and prognostic value of traditional signs and symptoms in stable CHF outpatients. METHODS: Sixty CHF outpatients who underwent 102 simultaneous clinical and echocardiographic evaluations were prospectively examined. A clinical congestion score was built summing all grades of CHF signs and symptoms. Hemodynamic parameters were estimated according to previously validated echocardiography-based protocols. Major cardiac events were evaluated after 180 days. RESULTS: Most CHF patients were male (67%), middle-aged (56+/-15 years) and in Specific Activity Scale functional classes I to II (70%). Isolated clinical findings demonstrated limited sensitivity and specificity to identify hemodynamic parameters. Absence of all signs of congestion, however, had a predictive value of 95% for a left atrial pressure less than 20 mmHg. Patients with no CHF signs or symptoms (score of 0) had significantly lower right (P<0.001) and left (P=0.03) atrial pressures compared with those with higher scores (scores of at least 5). In multivariate analysis, a congestion score of at least 3 (RR 4.8, 95% CI 1.3 to 17.4, P=0.02) and beta-blockers use (P=0.02) remained associated with future cardiac events. CONCLUSIONS: Although CHF signs and symptoms did not accurately identify hemodynamic parameters, combined data from history and physical examination provided meaningful information to guide clinical decisions and for prognostication.

OBJECTIVE: To determine whether the short-term systemic and renal hemodynamic response to dopamine is influenced by clinical severity of congestive heart failure. DESIGN: Effects of increasing doses of dopamine were assessed in patients consecutively admitted for acutely decompensated congestive heart failure. SETTING: Intensive care unit. PATIENTS: We enrolled 16 congestive heart failure patients stratified by clinical severity (New York Heart Association [NYHA] class III, n = 8; NYHA class IV, n = 8) and two additional NYHA class III patients as controls. INTERVENTIONS: Measurements were carried out throughout five 20-min experimental periods: baseline, dopamine infusion at 2, 4, and 6 microg x kg(-1) x min(-1), and recovery. Controls received a similar amount of saline. MEASUREMENTS AND MAIN RESULTS: Systemic and renal hemodynamics were determined respectively by right cardiac catheterization and radioisotopes (iodine 131-labeled hippuran and iodine 125-labeled iothalamate clearance). The peak increase in heart rate and cardiac index occurred at a dopamine dose of 4-6 microg x kg(-1) x min(-1). The dose-response relation was similar in NYHA classes III and IV. Improvement in effective renal plasma flow and glomerular filtration rate, peaking at 4 microg x kg(-1) x min(-1), was more rapid and marked in NYHA class III than class IV patients, in whom the renal fraction of cardiac output failed to increase. The systemic and renal effects of dopamine were independent of age. No change occurred in controls. CONCLUSIONS: The dose of dopamine producing an optimal improvement of systemic and renal hemodynamics in congestive heart failure is higher than usually reported. A greater clinical severity of congestive heart failure impairs the renal effects of dopamine, probably through a selective loss in renal vasodilating capacity.

BACKGROUND Cardiac resynchronization therapy (CRT) represents a new therapeutic modality of proven efficacy for selected patients with heart failure and ventricular asynchrony. The aim of this study was to assess the effects of CRT on clinical variables and cardiac remodeling in patients with moderate-to-severe congestive heart failure and inter/intraventricular conduction delays. METHODS Thirty-seven patients (32 males, 5 females, mean age 73 +/- 7 years), in NYHA functional class III-IV, with left ventricular ejection fraction (LVEF)< or = 35%, QRS > or = 150 ms, and left ventricular end-diastolic diameter (LVEDD)> or = 55 mm, underwent CRT by biventricular pacing (InSync, InSync III, InSync ICD; Medtronic Inc.). Fourteen (37.8%) had a previous pacemaker, and 11 (29.7%) were in permanent atrial fibrillation. The QRS width, NYHA functional class, LVEDD, left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic volume (LVEDV), left ventricular endsystolic volume (LVESV), and LVEF were retrospectively evaluated in the period before CRT. For the purposes of the present study, the pre-CRT period was divided in two: T(-2)(from 6 to 3 years) and T(-1)(from 3 years to CRT). Moreover, these parameters were measured at the time of CRT (T0) and prospectively in the post-CRT follow-up (Tp). RESULTS Before CRT, a progressive worsening of the parameters was observed. The QRS duration steadily increased from T(-2) to T(-1) and T0 (both p = 0.000). The NYHA functional class increased from T(-2) to T(-1) and T0 (both p = 0.000). LVEDD and LVESD also increased and were higher at T(-1)(p = 0.001 and p = 0.000, respectively) and at T0 (both p = 0.000) compared to T(-2). Similar results were observed for LVEDV and LVESV. Finally, LVEF was higher at T(-2) than T(-1) and T0 (both p = 0.000). After CRT, there was a reduction in the QRS duration and an improvement in the NYHA functional class compared to T0 (both p = 0.000). LVEDD and LVESD were also reduced (p = 0.005 and p = 0.016, respectively), LVEDV and LVESV decreased (both p = 0.000), and LVEF increased (p = 0.000) with respect to T0. A highly significant correlation was found between LVEDD and LVESD both in the pre- and post-CRT time intervals, with a non-significant difference between the two linear regression lines. Similar results were obtained for the correlations between LVEDV and LVESV. CONCLUSIONS Congestive heart failure is associated with a progressive widening of the QRS complex and a worsening of the clinical status and results in anatomic remodeling with deterioration of the left ventricular function. CRT induces opposite changes in QRS duration, clinical status, and left ventricular remodelling.