Cardiac symptoms related to paroxysmal atrial fibrillation varied with menstrual cycle in a premenopausal woman.

Atrial fibrillation, an arrhythmia observed more frequently in men than women, is induced by both sympathetic and parasympathetic autonomic nerve activations. The menstrual cycle in premenopausal women has been reported to modulate the autonomic nervous system: parasympathetic activity is dominant in the follicular phase and sympathetic activity is dominant in the luteal phase. However, the relationship between atrial fibrillation and the menstrual cycle has not yet been reported, because this arrhythmia is very rarely detected in premenopausal women. We experienced a 38 year-old woman with paroxysmal atrial fibrillation. Her menstrual cycle was 30.4 ± 0.5 days and the menstrual period was 3.9 ± 0.2 days for 22 cycles. Although she had taken flecainide 200 mg/day, bepridil 200 mg/day, and propranolol 20 mg/day, she sometimes experienced mild palpitations. QTc intervals measured at her visits to our clinic were 440 ± 3 msec in the follicular phase and 425 ± 2 msec in the luteal phase (P = 0.01). These changes in QTc intervals during the menstrual cycle are compatible with earlier reports. During the 22 menstrual cycles, she felt palpitations on 3.2 ± 0.7 days in the menstrual period, 6.4 ± 0.3 days in the follicular phase, and 4.1 ± 0.4 days in the luteal phase (P = 0.01). Afterward, the medication was changed from daily to periodic administration for one week beginning a couple of days before the expected menstrual time, and she did not feel symptomatic variation in her menstrual cycle. These data suggest that her symptoms related to atrial fibrillation might have been dependent on parasympathetic activity.

Primary aldosteronism with right-dominant heart failure.

A 48 year-old obese male with hypertension was admitted to our department because of severe right-dominant heart failure. His heart rhythm was 2:1 atrial flutter and the left ventricle was diffusely hypertrophic and hypokinetic. Primary aldosteronism was diagnosed based on severe hypokalemia (2.6 mEq/L) and a low renin-high aldosterone state with hypertension despite the use of an angiotensin-II receptor blocker, but its etiology could not be clarified with computed tomography, adrenal scintigraphy, and adrenal vein sampling. Ascites and edema rapidly worsened. Ascites aspiration was performed daily, until serum potassium was normalized by a full dose of an aldosterone receptor blocker (spironolactone 100 mg/day). A diuretic (furosemide) was then added. Rate control of atrial flutter was obtained with a beta-adrenergic blocker, and anticoagulation therapy was started. His heart failure was successfully controlled. Coronary arteries were normal on coronary arteriograms, and an endomyocardial biopsy sample obtained from the left ventricle did not show any specific pathological findings. Blood pressure was well controlled with the full dose of the aldosterone receptor blocker, but he died one year later due to intracerebral hemorrhage. As his heart failure was right dominant, we believe that its etiology may have been hyperaldosteronism-induced cardiomyopathy, and not advanced hypertensive heart disease.

A case of iron overload cardiomyopathy: beneficial effects of iron chelating agent and calcium channel blocker on left ventricular dysfunction.

We experienced an 81 year-old man with heart failure and macrocytic anemia. His serum ferritin level was extremely high (> 3,000 ng/mL). Echocardiography showed a normal left ventricular (LV) ejection fraction (EF), although the total ejection isovolume index (TEI index) was markedly elevated (0.60). In a cardiac catheterization study, cardiac index, pulmonary arterial wedge pressure, LV wall motion, and coronary arteries were shown to be normal. However, atrial pacing demonstrated a negative force-frequency relationship (a decrease in arterial blood pressure with higher pacing rates). Pathological study showed hemosiderin accumulation in his liver, but not in his myocardial tissue. As earlier studies have reported that iron may play an important role in oxidative cell damage and that this ion can enter cardiomyocytes through L-type Ca(2+) channels, we started an iron chelating agent (deferoxamine) and a calcium channel blocker (verapamil) in this case. Eighteen months later, his serum ferritin levels fell significantly without any changes in anemia. The TEI index was normalized (0.21) and the atrial pacing provoked a less negative force-frequency relationship. Thus, this combination treatment may be effective in iron overload cardiomyopathy at its early stage, when LV diastolic dysfunction is dominant and LV systolic dysfunction is only latent.

Postpartum complete atrioventricular block due to cardiac sarcoidosis: steroid therapy without permanent pacemaker.

A 32 year-old woman with bilateral hilar lymphadenopathy suffered from syncopal attacks after her first delivery. Electrocardiograms showed complete atrioventricular block (AVB) and myocardial scintigrams demonstrated a decreased uptake in the anteroseptal area. She was diagnosed as having postpartal cardiac acceleration of sarcoidosis. Because she rejected permanent pacemaker implantation, we started steroid therapy under temporary pacing. Fortunately, the treatment was very effective. Even after tapering-off of the steroid, the AVB has never reappeared. Permanent pacemaker implantation with subsequent steroid therapy is generally recommended for complete AVB due to cardiac sarcoidosis. However, steroid therapy alone can be considered for some selected cases.

Upregulated neurohumoral factors are associated with left ventricular remodeling and poor prognosis in rats with monocrotaline-induced pulmonary arterial hypertension.

BACKGROUND: Left ventricular remodeling might be involved in the pathophysiology of right ventricular hypertrophy/failure due to pulmonary arterial hypertension (PAH), while the left ventricle is considered not under pressure/volume overload. METHODS AND RESULTS: Rats with monocrotaline-induced PAH were used in the present study to examine whether upregulated neurohumoral factors may induce left ventricular (LV) remodeling and(/or) contribute to prognosis. Morphological analysis revealed a significant increase in the weight of the free walls of both ventricles and the interventricular septum, indicating biventricular hypertrophy, although systemic blood pressure was not elevated. RNase protection assay demonstrated the activation of a fetal gene program in the cardiac muscle of the left and right ventricular free walls. Similar activation of the fetal gene program was observed in the LV of rats continuously infused with angiotensin (AT) II, although this was not the case for rats infused with isoproterenol. Measured plasma levels of ATII, noradrenaline, and brain natriuretic peptide (BNP) were all significantly elevated in the PAH rats. Furthermore, the plasma BNP level positively correlated with the ratio of heart weight to body weight and the plasma level of ATII. Not right but LV hypertrophy was significantly reduced by treatment with an AT II type 1 receptor blocker, valsartan, whereas the effect of an adrenergic alpha1 and beta1,2 blocker, carvedilol, was borderline. Survival rate in the PAH rats was significantly improved when they were treated with valsartan or carvedilol. CONCLUSIONS: Upregulated neurohumoral factors seem to play an important role in LV remodeling without mechanical overload, and are associated with impairment of prognosis in rats with PAH.

Iron overload augments angiotensin II-induced cardiac fibrosis and promotes neointima formation.

BACKGROUND: Abnormal iron deposition may cause oxidant-induced damage in various organs. We have previously reported that continuous administration of angiotensin II to rats results in an overt iron deposition in the renal tubular epithelial cells, which may have a role in angiotensin II-induced renal damage. In the present study, we investigated the role of iron in the development of cardiac injury induced by angiotensin II. METHODS AND RESULTS: Angiotensin II was continuously infused to rats at a dose of 0.7 mg/kg per day for 7 consecutive days. No iron deposits were observed in the hearts of untreated rats, whereas iron deposition was seen in the cells in the subepicardial and granulation regions after angiotensin II infusion. Concomitant administration of deferoxamine, an iron chelator, significantly reduced the extent of cardiac fibrosis, which suggests that iron deposition aggravates the cardiac fibrosis induced by angiotensin II. Iron overload caused by the administration of iron-dextran resulted in an augmentation of cardiac fibrosis and the generation of neointimal cells in the coronary artery in angiotensin II-infused rats. By contrast, neointima was not formed in the cardiac vessels in norepinephrine-infused rats with iron overload. CONCLUSIONS: Cardiac iron deposition may be involved in the development of cardiac fibrosis induced by angiotensin II. In addition, iron overload may enhance the formation of neointima under conditions of increased circulating angiotensin II but not catecholamines.

A rapid PCR method of genotyping LDL receptor mutations in WHHL rabbits.

WHHL rabbits are a valuable model for the study of human familial hypercholesterolemia and atherosclerosis. To use this animal model, it is often necessary to confirm LDL receptor status in WHHL rabbits. Here, we described a simple and rapid PCR method to detect LDL mutations in WHHL rabbits.

In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage.

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses the expression of multiple aging-associated phenotypes. This gene is predominantly expressed in the kidney. Recent studies have shown that expression of renal klotho gene is regulated in animal models of metabolic diseases and in humans with chronic renal failure. However, little is known about the mechanisms and the physiological relevance of the regulation of the expression of the klotho gene in the kidney in some diseased conditions. In the present study, we first investigated the role of angiotensin II in the regulation of renal klotho gene expression. Long-term infusion of angiotensin II downregulated renal klotho gene expression at both the mRNA and protein levels. This angiotensin II-induced renal klotho downregulation was an angiotensin type 1 receptor-dependent but pressor-independent event. Adenovirus harboring mouse klotho gene (ad-klotho, 3.3x10(10) plaque forming units) was also intravenously administered immediately before starting angiotensin II infusion in some rats. This resulted in a robust induction of Klotho protein in the liver at day 4, which was still detectable 14 days after the gene transfer. Ad-klotho gene transfer, but not ad-lacZ gene transfer, caused an improvement of creatinine clearance, decrease in urinary protein excretion, and amelioration of histologically demonstrated tubulointerstitial damage induced by angiotensin II administration. Our data suggest that downregulation of the renal klotho gene may have an aggravative role in the development of renal damage induced by angiotensin II, and that induction of the klotho gene may have therapeutic possibilities in treating angiotensin II-induced end organ damage.

Angiotensin II and catecholamines increase plasma levels of 8-epi-prostaglandin F(2alpha) with different pressor dependencies in rats.

We investigated the extent of oxidative stress evoked in the hypertensive rat by measuring plasma levels of 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)), a marker of in vivo oxidative stress. Administration of angiotensin (Ang) II and norepinephrine at doses of 0.7 and 2.8 mg. kg(-1). d(-1), respectively, resulted in similar significant elevations in plasma levels of 8-epi-PGF(2alpha). A 7-day infusion of Ang II at a nonpressor dose, but not norepinephrine at a nonpressor dose, also increased plasma levels of 8-epi-PGF(2alpha). The norepinephrine-induced increase in 8-epi-PGF(2alpha) levels could be completely normalized by 3 different classes of antihypertensive drugs: prazosin, an alpha-adrenergic receptor blocker; hydralazine, a nonspecific vasodilator; and losartan, a specific angiotensin type 1 (AT(1)) receptor antagonist. This finding suggests that the norepinephrine-induced increase is a pressor-dependent event. In contrast, among these antihypertensive drugs, only losartan was effective in inhibiting the Ang II-induced increase in plasma 8-epi-PGF(2alpha), suggesting that Ang II increases plasma levels of 8-epi-PGF(2alpha) in both a pressor-independent and an AT(1) receptor-dependent manner. In summary, continuous infusion of both Ang II and norepinephrine potently increases plasma levels of 8-epi-PGF(2alpha) and thus in vivo oxidative stress. Ang II and norepinephrine seem to induce this increase in 8-epi-PGF(2alpha) via mechanisms with different pressor dependencies.

Abnormal iron deposition in renal cells in the rat with chronic angiotensin II administration.

Acute experimental iron loading causes iron to accumulate in the renal tissue. The accumulation of iron may play a role in enhancing oxidant-induced tubular injury by producing increased amounts of reactive oxygen species. From findings in cells from heme oxygenase-1 (HO-1)-deficient mice, HO-1 is postulated to prevent abnormal intracellular iron accumulation. Recently, it has been reported that HO-1 is induced in the renal tubular epithelial cells, in which iron is deposited after iron loading, and that this HO-1 induction may be involved in ameliorating iron-induced renal toxicity. We previously showed that chronic administration of angiotensin II to rats induces HO-1 expression in the tubular epithelial cells. These observations led us to investigate whether there is a link between iron deposition and HO-1 induction in renal tubular cells in rats undergoing angiotensin II infusion. In the present study, rats were given angiotensin II for continuously 7 days. Prussian blue staining revealed the distinct deposits of iron in the proximal tubular epithelial cells after angiotensin II administration. Electron microscopy demonstrated that iron particles were present in the lysosomes of these cells. Histologic and immunohistochemical analyses showed that stainable iron and immunoreactive ferritin and HO-1 were colocalized in the tubular epithelial cells. Treatment of angiotensin II-infused rats with an iron chelator, deferoxamine, blocked the abnormal iron deposition in kidneys and also the induced expression of HO-1 and ferritin expression. Furthermore, deferoxamine treatment suppressed the angiotensin II-induced increase in the urinary excretion of protein and N-acetyl-beta-D-glucosaminidase, a marker of tubular injury; however, deferoxamine did not affect the angiotensin II-induced decrease in glomerular filtration rate. These results suggest that angiotensin II causes renal injury, in part, by inducing the deposition of iron in the kidney.