Evidence for a Prehypertensive Water Dysregulation Affecting the Development of Hypertension: Results of Very Early Treatment of Vasopressin V1 and V2 Antagonism in Spontaneously Hypertensive Rats.

In addition to long-term regulation of blood pressure (BP), in the kidney resides the initial trigger for hypertension development due to an altered capacity to excrete sodium and water. Betaine is one of the major organic osmolytes, and its betaine/gamma-aminobutyric acid transporter (BGT-1) expression in the renal medulla relates to interstitial tonicity and urinary osmolality and volume. This study investigated altered water and sodium balance as well as changes in antidiuretic hormone (ADH) activity in female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats from their 3-5 weeks of age (prehypertensive phase) to SHR's 28-30 weeks of age (established hypertension-organ damage). Young prehypertensive SHRs showed a reduced daily urine output, an elevated urine osmolarity, and higher immunostaining of tubule BGT-1, alpha-1-Na-K ATPase in the outer medulla vs. age-matched WKY. ADH circulating levels were not different between young prehypertensive SHR and WKY, but the urine aquaporin2 (AQP2)/creatinine ratio and labeling of AQP2 in the collecting duct were increased. At 28-30 weeks, hypertensive SHR with moderate renal failure did not show any difference in urinary osmolarity, urine AQP2/creatinine ratio, tubule BGT-1, and alpha-1-Na-K ATPase as compared with WKY. These results suggest an increased sensitivity to ADH in prehypertensive female SHR. On this basis, a second series of experiments were set to study the role of ADH V1 and V2 receptors in the development of hypertension, and a group of female prehypertensive SHRs were treated from the 25th to 49th day of age with either V1 (OPC21268) or V2 (OPC 41061) receptor antagonists to evaluate the BP time course. OPC 41061-treated SHRs had a delayed development of hypertension for 5 weeks without effect in OPC 21268-treated SHRs. In prehypertensive female SHR, an increased renal ADH sensitivity is crucial for the development of hypertension by favoring a positive water balance. Early treatment with selective V2 antagonism delays future hypertension development in young SHRs.

Assessment of mitoxantrone-induced cardiotoxicity in patients with multiple sclerosis: a tissue Doppler echocardiographic analysis.

AIM: Tissue Doppler echocardiography was investigated for its applicability in detecting subtle myocardial involvement in multiple sclerosis patients receiving a low dose of mitoxantrone. METHODS AND RESULTS: Twenty Caucasian patients with multiple sclerosis (mean age 43.9+/-9.3 years, 12 males and 8 females) treated with mitoxantrone (mean cumulative dose 35.4+/-21.6 mg/m(2)), were compared to 20 healthy subjects (mean age 45.4+/-15.3 years, 11 males and 9 females) matched for age and gender. All subjects underwent conventional and Tissue Doppler echocardiography. Patients with heart failure, life-threatening arrhythmias, and other prominent manifestations of heart disease were excluded. No differences were observed in blood pressure, heart rate, and conventional systolic and diastolic echocardiographic parameters. At Tissue Doppler echocardiography, patients with multiple sclerosis showed differences of the systolic mechanic expressed by a significant lower S-wave peak velocity at the lateral site of mitral annulus (11.4+/-2.5 cm/sec vs. 15.0+/-4.1 cm/sec, P < 0.02). Such S-wave peak velocity significantly correlated with a cumulative dose of mitoxantrone (r =-0.37, P < 0.05). CONCLUSION: Tissue Doppler echocardiography suggests an early involvement of the systolic myocardial function at the low dose of mitoxantrone. Therefore, Tissue Doppler echocardiography may be used as a noninvasive method for monitoring subclinical cardiotoxicity in multiple sclerosis patients receiving mitoxantrone.

Myocardial involvement during the early course of type 2 diabetes mellitus: usefulness of myocardial performance index.

To evaluate whether myocardial performance index detects a subclinical impairment of left ventricular systolic and diastolic function in patients with early stage of type 2 diabetes, without coronary artery disease, with or without hypertension. Furthermore, to evaluate whether some echocardiographic parameters relate to the metabolic control. Fourty-five consecutive male patients (mean age 52.5 years) with type 2 diabetes mellitus of recent onset (23 hypertensives and 22 normotensives) and 22 age matched healthy controls males were analysed. All participants had normal exercise ECG. All subjects underwent standard and Doppler echocardiography for the assessment of the isovolumic Doppler time interval and Doppler-derived myocardial performance index. In all diabetic patients a glycated haemoglobin test was also performed. No differences were observed in blood pressure, heart rate, and conventional echocardiographic parameters comparing the 2 subgroups of diabetic patients and the controls. Myocardial performance index was significantly higher in diabetic patients independently of the hypertension occurrence, compared to the controls (0.49 and 0.49 diabetic normotensives and hypertensives respectively vs. 0.39, p < 0.01). Myocardial performance index correlated to glycated haemoglobin significantly (r = 0.37, p < 0.01) in both diabetic subgroups. Thus, an early involvement of left ventricular performance was shown by myocardial performance index in patients with type 2 diabetes of recent onset without coronary artery disease, independently of the hypertension presence. These abnormalities can provide a feasible approach to detect a pre-clinical diabetic cardiomyopathy and could be useful for an indirect assessment of the metabolic control.

Impact of myocardial geometry on left ventricular performance in healthy black and white young adults.

Racial differences in left ventricular (LV) structure are suggested by clinical and experimental studies. This study evaluates if racial differences in LV performance exist comparing black to white young males, by tissue Doppler echocardiography and myocardial performance index (MPI). We examined 40 healthy males, 20 blacks (mean age 27.6 +/- 4.4 years) and 20 whites (mean age 26.5 +/- 6.7 years). All subjects underwent conventional echocardiography, tissue Doppler echocardiography, and MPI assessment. No differences were found in LV diameters, volumes, mass, and hemodynamic measurements. Septal and posterior wall thicknesses were significantly increased in black subjects as well as the relative wall thickness. Systolic and diastolic functions estimated by conventional parameters were superimposable in the two groups. In black subjects, a significant increase of septal S-wave, peak velocity, and time-velocity integral were found. MPI was significantly higher in black compared to white subjects (0.46 +/- 0.05 vs 0.40 +/- 0.06, P < 0.002). A significant correlation between MPI and relative wall thickness (r = 0.54) was demonstrated. Besides, MPI correlated with S(pv) (r = 0.55) and S(tvi) (r = 0.38) at the septal site. In conclusion our data show a higher MPI in black subjects that seems to be geometry-dependent. Correlations between MPI and tissue Doppler echocardiography systolic indexes were found. Our findings suggest that racial differences in LV performance exist, especially, in the systolic function, even in the absence of other conventional echocardiographic changes.

Characterization of myocardial hypertrophy in prehypertensive spontaneously hypertensive rats: interaction between adrenergic and nitrosative pathways.

OBJECTIVE AND METHODS: Left ventricular hypertrophy in human and experimental hypertension is not always associated with pressure overload but seems to precede an increase in blood pressure. In this study, performed in male 5-week-old prehypertensive spontaneously hypertensive rats (SHR; n = 65) and age-matched Wistar-Kyoto rats (n = 56), the relationship between myocardial structure and activation of the adrenergic and nitric oxide systems was evaluated. RESULTS: Body weight, blood pressure and heart rate were similar in both groups. A higher left ventricle/body weight ratio was found in SHR, as a result of greater mononuclear (+47%) and binuclear (+43%) myocyte volumes, without changes in interstitial collagen. Both adrenergic and nitric oxide pathways were activated in SHR, as expressed by higher myocardial norepinephrine content, tyrosine hydroxylase activity, myocardial nitric oxide synthase 3 expression and protein nitration, indicating greater peroxynitrite (ONOO) generation from nitric oxide and superoxide. No difference was measured in nitric oxide synthase 1 expression, whereas nitric oxide synthase 2 was undetectable. A positive correlation between myocardial tyrosine hydroxylase activity and protein nitration was observed in SHR (r = 0.328; P < 0.01). Early treatment with a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl, from the third to the fifth week of age, reduced ONOO generation, protein nitration and sympathetic activation in SHR without changes in myocardial structure. CONCLUSION: In prehypertensive SHR, left ventricular hypertrophy is associated with adrenergic and nitrosative imbalance. Early superoxide dismutase mimetic treatment in SHR effectively reduces higher myocardial ONOO generation, sympathetic activation, and heart rate without affecting the development of myocardial hypertrophy.

Apical hypertrophic cardiomyopathy and atrial septal defect: part of a multi-organ syndrome?

AIM: We describe a case of non-obstructive apical hypertrophic cardiomyopathy with atrial septal defect, in a 48-year-old caucasian female patient with chronic renal failure, hypothyroidism and primary amenorrhea, referred to our hospital for syncope, palpitation and shortness of breath. METHODS AND RESULTS: Electrocardiogram, transthoracic echocardiogram and cardiac magnetic resonance showed classical features of apical hypertrophic cardiomyopathy. Apical hypertrophic cardiomyopathy is morphologically characterized by apical ventricular hypertrophy, and is reported to be a relatively benign prognosis compared with the other type of hypertrophic cardiomyopathy. CONCLUSION: Apical hypertrophic cardiomyopathy is very rare in the West, is occasionally encountered in Japanese persons, but there have been only a few reports of its coexistence with atrial septal defect. Our present report is the first case of apical hypertrophic cardiomyopathy with atrial septal defect associated with renal failure, hypothyroidism and primary amenorrhea that could represent a multi-organ syndrome. This hypothesis was supported by the finding of the same characteristics in a sister of the patient.

Evaluation of the myocardial performance index for early detection of mitoxantrone-induced cardiotoxicity in patients with multiple sclerosis.

AIMS: Multiple sclerosis is the most common cause of neurological disability in young adults. Mitoxantrone is a synthetic anthracenedione, recently approved for the treatment of worsening multiple sclerosis, which is known to induce cardiotoxicity. This study was designed to evaluate the early alterations in left ventricular function in patients with multiple sclerosis receiving mitoxantrone, by the use of the myocardial performance index, a new parameter of global (systolic and diastolic) ventricular function. METHODS AND RESULTS: The study included 29 Caucasian patients with multiple sclerosis (mean age 41.8+/-9.3 years, 12 males and 17 females) treated with mitoxantrone (mean cumulative dose 30.8+/-18.2 mg/m(2)) who were compared with 28 healthy subjects (mean age 37.8+/-11.8 years, 13 males and 15 females). Both groups underwent a complete two-dimensional and Doppler echocardiography including assessment of the mitral inflow and left ventricular outflow patterns for estimation of the Doppler-derived myocardial performance index. This parameter is defined as the sum of isovolumic contraction time and isovolumic relaxation time, divided by ventricular ejection time. No differences were observed in blood pressure, heart rate, left ventricular diameters, mass and ejection fraction in multiple sclerosis patients compared to the controls. The mitral flow pattern showed a significant decrease of E wave calculated as peak velocity (E(pv)) (63.3+/-13.4 vs. 77.2+/-17.2, P<0.002) and time velocity integral (E(tvi)) (8.8+/-1.9 vs. 10.3+/-2.4, P<0.02), with a significant decrease of E(pv)/A(pv) ratio and a non-significant decrease of E(tvi)/A(tvi) ratio in the patients. In addition, E-wave deceleration time was significantly increased in multiple sclerosis patients compared to controls (178.2+/-30.2 vs. 137.9+/-14.7, P<0.0001). The mean value of myocardial performance index was 0.55+/-0.1 in patients compared to 0.37+/-0.06 in the controls (P<0.0001). A significant correlation between the given cumulative dose of mitoxantrone and myocardial performance index (r=0.67, P<0.001) and E-wave deceleration time (r=0.45, P<0.001) respectively were demonstrated. CONCLUSION: The myocardial performance index represents a parameter of combined systolic and diastolic myocardial performance strongly correlated with the given cumulative dose of mitoxantrone. The myocardial performance index may be an adjunctive parameter to conventional echocardiography for detecting sub-clinical cardiotoxicity of mitoxantrone in the clinical management of the multiple sclerosis patients.

Circadian blood pressure and heart rate changes in patients in a persistent vegetative state after traumatic brain injury.

Alteration of autonomic nervous system regulation is known to be present in the persistent vegetative state after traumatic brain injury, termed the dysautonomic syndrome. This study assessed the circadian blood pressure and heart rate pattern and variability in the persistent vegetative state through noninvasive 24-hour ambulatory blood pressure monitoring. The study was performed in 20 subjects: 10 patients (six men and four women; mean age, 29.5+/-9.9 years; range, 19-39 years) in a vegetative state (mean, 27.3+/-5.6 days after trauma) and 10 healthy subjects as controls (six men and four women; mean age, 28+/-5.7 years; range, 29-37 years). The patients showed a blood pressure nondipper pattern; 24-hour, daytime, and nighttime values of blood pressure and heart rate were significantly higher in patients than in controls. The day-night difference in heart rate and blood pressure was also significantly lower in patients. Finally, SD and variation coefficients were significantly lower in patients. The results show changes in the variability and circadian blood pressure and heart rate patterns in persistent vegetative state patients with dysautonomic syndrome, as an expression of the sympathetic-parasympathetic activity imbalance in the control of vasomotor tone.

Early proinflammatory activation of renal tubular cells by normal and pathologic IgG.

BACKGROUND/AIMS: To verify whether human IgG induces proinflammatory activation of human proximal tubular epithelial cells (PTEC) independent of the metabolic overload of protein reabsorption. METHODS: Cultured PTEC were incubated with normal IgG, IgG from systemic lupus erythematosus (SLE) patients, albumin or transferrin. IL-6 secretion and extracellular regulated kinase (ERK) activation (dual-phosphorylated ERK) were measured by ELISA and by Western blotting of PTEC extracts, respectively; renal biopsy specimens from patients with IgG and non-IgG proteinuria were analyzed by immunohistochemistry and in situ hybridization to detect ERK-P and IL-6. RESULTS: Normal and SLE IgG, but not albumin or transferrin, induced an early significant increase in IL-6 secretion by PTECs. Also ERK activation was found after 1-hour incubation of PTEC with IgG, but not with control medium and albumin-treated PTEC. Activated ERK and IL-6 were found to colocalize in tubular cells in the kidney specimens of patients with IgG proteinuria only. CONCLUSION: IgG-dependent early activation of ERK and increased IL-6 secretion in PTEC suggest that IgG filtered during nonselective proteinuria may play a specific role in tubulointerstitial disease. Such a role could be particularly relevant in diseases associated with abnormal IgG pool compositions, such as SLE. Preliminary results on human renal biopsy specimens suggest that our in vitro observations may also be relevant in vivo.

Effects of the reduction of preload on left and right ventricular myocardial velocities analyzed by Doppler tissue echocardiography in healthy subjects.

AIMS: Previous studies using Doppler Tissue Echocardiography (DTE) have suggested that the early-diastolic myocardial velocity behaves as a relatively load-independent index of left ventricular relaxation in patients with cardiac diseases; it is not ascertained if this holds true also in normal human hearts. METHODS AND RESULTS: We assessed the influence of a progressive reduction of preload, obtained by Lower Body Negative Pressure (LBNP), on the diastolic and systolic myocardial waves compared to the inflow patterns estimated in left and right ventricles in nine healthy subjects. LBNP caused a significant decrease in end-diastolic volume, stroke volume and systolic arterial pressure, whilst heart rate increased only at maximum preload reduction; meridional end-systolic stress did not change significantly. The early (E') and late (A') myocardial velocities, at mitral and tricuspid annulus, decreased similarly during lower body suction, so that E'/A' ratio did not change. However, due to reduced early (E) but unchanged late (A) diastolic velocities, the E/A ratio of inflow patterns decreased. Systolic (S') myocardial velocities also decreased during LBNP. LBNP induced greater changes of myocardial diastolic and systolic velocities in the right than in the left ventricle. CONCLUSION: In this study, myocardial E', A' and S' velocities, in both the left and the right ventricle, were significantly affected by preload in healthy subjects. Our results support the usefulness of the E'/A' ratio as a relatively load-independent index of diastolic function.

Prognostic value of dobutamine stress echocardiography in patients with diabetes.

OBJECTIVE: The aim of this study was to assess the incremental value of dobutamine stress echocardiography (DSE) for the risk stratification of diabetic patients who are unable to perform an adequate exercise stress test. Exercise capacity is frequently impaired in patients with diabetes. The role of pharmacologic stress echocardiography in the risk stratification of diabetic patients has not been well defined. RESEARCH DESIGN AND METHODS: We studied 396 diabetic patients (mean age 61 +/- 11 years, 252 men [64%]) with limited exercise capacity who underwent DSE for evaluation of known or suspected coronary artery disease (CAD). End points were hard cardiac events (cardiac death and nonfatal myocardial infarction) and all causes of mortality. RESULTS: During a median follow-up of 3 years, 97 patients (24%) died (55 cardiac deaths), and 27 patients had nonfatal myocardial infarction. In an incremental multivariate analysis model, clinical predictors of hard cardiac events were history of congestive heart failure, previous myocardial infarction, hypercholesterolemia, and ejection fraction at rest. The percentage of ischemic segments was incremental to the clinical model in the prediction of hard cardiac events (chi(2) = 37 vs. 18, P < 0.05). Clinical predictors of all causes of mortality were history of congestive heart failure, age, hypercholesterolemia, and ejection fraction at rest. Wall motion score index at peak stress was incremental to the clinical model in the prediction of mortality (chi(2) = 52 vs. 43, P < 0.05). CONCLUSIONS: DSE provides incremental data for the prediction of mortality and hard cardiac events in patients with diabetes who are unable to perform an adequate exercise stress test.

Sympathetic activation in adipose tissue and skeletal muscle of hypertensive rats.

The activation of the sympathetic nervous system is a common feature of arterial hypertension and other cardiovascular diseases. This activation might be dependent on an altered baroreflex control of vascular resistance of which the inhibitory response on sympathetic activity appears impaired. The aim of the study was to monitor during the natural course of arterial hypertension in spontaneously hypertensive (SHR) and age-matched Wistar Kyoto (WKY) rats (5, 16, 30, and 54 weeks of age) the peripheral sympathetic activity expressed as interstitial norepinephrine (NE) release and as tyrosine hydroxylase (TH) activity, the rate-limiting enzyme of NE synthesis, in the differently baroreflex-controlled subcutaneous adipose tissues and skeletal muscles. Blood pressure and plasma NE in SHR were similar to WKY at 5 weeks of age but increased at all other ages. Body weight was similar in both 5-week-old rats but reduced in SHR at all other ages. The interstitial NE levels were greater in both SHR tissues at all ages as compared with WKY. In adipose tissue of SHR, TH activity was higher at all ages as compared with WKY, whereas TH activity in skeletal muscle was higher only after the development of hypertension. These data show that in both SHR tissues, an increase of interstitial NE release is always present during its lifespan. This suggests that increased sympathetic activation in the SHR model is not specific to baroreflex-controlled tissues such as skeletal muscle but involves also subcutaneous adipose tissue, the sympathetic efferents of which are independent from baroreflexes.