Paul Milliez

Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat.

OBJECTIVESnThe purpose of this study was to determine the pathogenic factors and molecular mechanisms involved in fibrosis of the atria.nnnBACKGROUNDnFibrosis is an important component of the pathophysiology of atrial fibrillation, especially when the arrhythmia is associated with heart failure (HF) or atrial dilation.nnnMETHODSnWe used a rat model of myocardial infarction (MI) complicated by various degrees of left ventricular dysfunction and atrial dilation to study fibrosis and matrix metalloproteinase (MMP) activity in the left atrial (LA) myocardium by means of histologic, Western blot, zymographic, and immunohistologic techniques.nnnRESULTSnThree months after surgical ligature of the left coronary artery, 27 rats had a large MI, 12 were in mild HF, and 15 in severe HF. Both groups had LA enlargement at the echocardiography. Massons trichrome and picrosirius staining of tissue sections revealed marked fibrosis at the periphery of trabeculae and also surrounding myolytic myocytes, in both mild and severe HF. In mild HF, the activity and expression of the matrilysin MMP-7 were increased (122%), whereas in severe HF, both MMP-7 (211%) and the gelatinase MMP-2 (187%) were up-regulated. There were no changes in the expression or activity of MMP inhibitors, TIMP-1, -2, and -4. Immunostaining of cryosections showed that MMP-2 was present in the interstitial spaces, whereas MMP-7 accumulated in myolytic myocytes.nnnCONCLUSIONSnHemodynamic overload of the atria is an important pathogenic factor of fibrosis; MMP-7 appears to be involved in the early stage of this tissue remodeling process.

Role of Myocardial Neuronal Nitric Oxide Synthase–Derived Nitric Oxide in β-Adrenergic Hyporesponsiveness After Myocardial Infarction–Induced Heart Failure in Rat

Background—An emerging concept is that a neuronal isoform of nitric oxide synthase (NOS1) may regulate myocardial contractility. However, a role for NOS1-derived nitric oxide (NO) in heart failure (HF) has not been defined. Methods and Results—Using a model of myocardial infarction-induced HF, we demonstrated that cardiac NOS1 expression and activity increased in HF rats (P<0.05 and P<0.001 versus shams, respectively). This was associated with translocation of NOS1 from the ryanodine receptor to the sarcolemma through interactions with caveolin-3 in HF hearts. With ex vivo and in vivo pressure-volume analysis, cardiac NOS1-derived NO was found to be negatively inotropic in shams but not HF hearts. Ventricular elastance (Ees) was significantly reduced in HF rats (P<0.05), and &tgr;, the time constant of left ventricular relaxation, was prolonged (both P<0.05). Acute NOS1 inhibition significantly increased Ees by 33±3% and &tgr; by 17±2% (P<0.05) in shams, although these effects were significantly attenuated in HF hearts. &bgr;-Adrenergic stimulation induced a marked increase in systolic performance in sham hearts, with the responses being significantly blunted in HF hearts. Ees increased by 163±42% (P<0.01) in sham hearts and 56±9% in HF hearts, and LV +dP/dt increased by 97±9% (P<0.01) in shams and 37±7% (P<0.05) in the HF group. Interestingly, preferential NOS1 inhibition enhanced the blunted responses of LV +dP/dt and Ees to &bgr;-adrenergic stimulation in HF rats but had no effect in shams. Conclusions—These results provide the first evidence that increased NOS1-derived NO production may play a role in the autocrine regulation of myocardial contractility in HF.

Hemodynamic study of 85 patients with borderline hypertension

Hemodynamic changes in supine and upright position (50 ° head-up tilt) and during exercise were studied in 40 normal subjects and 85 patients with borderline hypertension. The latter were classified in 2 groups, according to the level of cardiac index. In group I, with patients in the supine position, cardiac index, stroke index, heart rate and plasma volume were normal, but total peripheral resistance was increased (P < 0.01). During upright tilt, orthostatic decrease of mean arterial pressure (P < 0.05) was observed, and the increase in total peripheral resistance was not greater than in normal subjects. The hemodynamic response to exercise was similar to that of normal subjects. In patients in group II, cardiac index, stroke index and heart rate were increased (P < 0.001), but plasma volume was decreased (P < 0.01) and total peripheral resistance was below normal (P < 0.001). With patients in the upright position, diastolic orthostatic hypertension was observed (P < 0.001) and total peripheral resistance was greater than normal (P < 0.01) despite an abnormal fall of cardiac index (P < 0.05). The hemodynamic response to exercise indicated that total peripheral resistance did not decrease as in normal subjects and in patients of group I (P < 0.001). This study provides evidence that (1) total peripheral resistance is abnormal in patients with borderline hypertension, but only during upright tilt and exercise in patients with high cardiac index, and (2) 2 main disorders seem to be important in the early stage of hypertension: abnormality of blood volume (or blood volume distribution, or both) and impaired neurogenic activity.

Isoproterenol Sensitivity and Total Body Clearance of Propranolol in Hypertensive Patients

The isoproterenol sensitivity (dose-response curve) and the total body clearance of propranolol were measured in 80 men including 15 normal subjects and 65 essential hypertensive patients (20 borderline and 45 permanent hypertensives). The critical dose of isoproterenol was found to be directly correlated to weight (P less than 0.01), age (P less than 0.001), and basal diastolic arterial pressure (P less than 0.001). A partial correlation coefficient study showed that the diastolic arterial pressure was of greater influence than weight and age. The total body clearance of propranolol was inversely related to the basal diastolic arterial pressure (P less than 0.0001) in hypertensive patients. The study provides evidence that the level of basal diastolic arterial pressure could influence the beta-receptor responsiveness and the beta-adrenergic blockade in hypertensive patients.

Vascular reactivity to norepinephrine and hemodynamic parameters in borderline hypertension

Pressor response to norepinephrine, cardiopulmonary blood volume, and hemodynamic parameters were studied in 41 borderline hypertensive patients in comparison with 42 permanent essential hypertensive patients and 28 normal subjects. Borderline hypertensive subjects had high cardiac index (p less than 0.0001), normal total peripheral resistance, and low total blood volume (p less than 0.005). The ratio between cardiopulmonary blood volume (CPBV) and total blood volume (TBV) was significantly higher in comparison with normal subjects (p less than 0.01) and permanent hypertensive subjects subjects (p less than 0.0001). The pressor dose of norepinephrine was elevated (p less than 0.0001) and was directly correlated with the basal values of the cardiac output (p less than 0.005), the cardiopulmonary blood volume (p less than 0.001), and the CPBV/TBV ratio (p less than 0.01). None of these results was observed in permanent hypertensive subjects: the only significant result was a negative correlation between the pressor dose of norepinephrine and the basal diastolic arterial pressure (p less than 0.0001). This study provides evidence that the cardiac output elevation in borderline hypertensive subjects was related to increased venous return and enhanced sympathetic venous tone.

The long QT interval is not only inherited but is also linked to cardiac hypertrophy

This review focuses on the molecular determinants of the duration of the QT interval as measured on by electrocardiography in normal subjects and during cardiac hypertrophy and failure. (a) In control conditions, on a single cell, the shape and duration of the action potential is the result of a balance between different ion currents which in turn were determined by the number of functional channels. On multicellular preparations the QT duration also represents the repolarization time; nevertheless it is modified by the transmural gradients. On body-surface electrocardiography the duration of the QT interval depends also of an additional factor: the spatial three-dimensional projection of the electrical waves vectors, which makes any determination of the epicardial dispersion by measuring QT interval dispersion questionable. (b) The enhanced action potential duration is well documented in cardiac hypertrophy and heart failure and is usually caused by a reduction in outward current densities in most of the species except mice. Among these currents ItO is the most frequently altered, especially in humans. Such an altered current density is caused by a diminished expression of the genes encoding either the ion channel subunits or regulatory proteins, such as KChIP2. In addition, hypertrophy modifies or even reverses the transmural gradient. In human and rats hypertensive cardiopathy is associated with a prolongation of the QT interval duration. The reduction in ItO is likely to be adaptive; it participates in the slowing of the cardiac cycle and reflects the fetal genetic reprogramming. Recent data also suggest that a reduction in the transient outward K+ current density triggers protein synthesis through an activation of the calcineurin pathways. Thus a prolongation of the QT interval is not only inherited or drug-induced; it is also an essential component of the adaptive process in chronic mechanical overload. It is fundamentally incorrect to measure QT dispersion on a surface electrocardiography, but the mean QT interval may provide information concerning the progression of the disease, just as, and with the same restrictions, in the case of the quantification of Vmax.

Control of cardiac output in essential hypertension

Cardiac and renal hemodynamics and cardiopulmonary and total blood volume were determined in 202 men, 101 with normotension and 101 of the same age with chronic essential hypertension, normal renal function and balanced sodium intake and urinary output. Cardiac output was identical in the two groups, whereas blood pressure and total peripheral resistance were significantly different. The two groups exhibited strong differences in the correlation study: (1) Correlations of blood pressure with, respectively, heart rate, cardiopulmonary blood volume and total blood volume were significant in the normotensive group but not in the hypertensive group. (2) Correlations of cardiac output with, respectively, heart rate, cardiopulmonary blood volume and total blood volume were significant in both groups. (3) Correlations of renal blood flow with, respectively, cardiac output, blood pressure and total blood volume were significant in the hypertensive group but not in the normotensive group. This study provides evidence that: (1) the volume and neural control of blood pressure are disrupted in hypertension whereas control of cardiac output is maintained; and (2) adaptive mechanisms involving renal function are necessary to the maintenance of normal cardiac output in patients with essential hypertension.

Urinary Aldosterone-to-active-renin Ratio: A Useful Tool for Predicting Resolution of Hypertension After Adrenalectomy in Patients With Aldosterone-producing Adenomas

BACKGROUNDnThe purpose of this study was to determine the preoperative clinical and biological factors that predict the clinical outcomes after surgery, in subjects with aldosterone-producing adenomas (APAs).nnnMETHODSnFifty-eight patients (mean age 52 +/- 11 years) with APA were followed up for 43 +/- 13 months after they had undergone unilateral adrenalectomy. The subjects were classified as cured (n = 23) if the blood pressure (BP) was <140/90 mm Hg without postoperative medication, normalized (n = 20) if BP was <140/90 mm Hg with antihypertensive therapy, and uncontrolled (n = 15) if a BP of < or =140/90 mm Hg was not achieved despite intensive therapy.nnnRESULTSnThe cured patients had a significantly lower mean preoperative age, cardiac mass, and serum creatinine (P < 0.001) than the other subjects. The main independent predictors of surgical curability were: age (P < 0.01), low serum potassium (P < 0.0001), and the urinary aldosterone-to-active-renin (UAAR) ratio (P < 0.008). Among the hormonal parameters, the UAAR ratio provided the best area under the receiver operating-characteristics curve (0.802 (confidence interval (CI) 95%: 0.676-0.944)). For a cutoff value of 15, the positive and negative predictive values of the UAAR ratio were 85 and 92%, respectively. In the study population as a whole, surgical treatment restored the age-systolic BP (SBP) relationship (P < 0.006), which was insignificant before surgery.nnnCONCLUSIONSnAlthough all the subjects showed lowering of BP after surgery, and the age-BP relationship was restored, the long-term cure rate of APA subjects was 40%. The UAAR ratio, by comparison with other classical hormonal features of primary aldosteronism, was the best independent predictor of the cure of hypertension after adrenalectomy.

Altered blood volume regulation in sustained essential hypertension: A hemodynamic study

Cardiac and renal hemodynamics and total blood volume were determined in 28 normal subjects and 60 patients with untreated essential well-established hypertension. Endogenous creatinine clearance was within normal ranges and sodium intake was 110 mEq/day. A significant negative volume-resistance relationship was observed both in normal subjects (P less than 0.005) and hypertensive patients (P less than 0.001). In comparison with the normal curve, the hypertensive curve has two characteristics: 1) the curve was reset on the right-hand side and, 2) the slope was significantly shallower, indicating a reduced ability to decrease the volume per unit rise in resistance. By using the normal curve as a reference system, a quantitative evaluation of the blood volume disturbance was proposed. In hypertensives, the value of the total peripheral resistance could correspond to two different values of the total blood volume: the real value and the theoretical value extrapolated from the normal curve. The difference between the two values was called relative variation in blood volume and was used as a mathematical model. In hypertensives, the real blood volume was significantly reduced (P less than 0.001) while a significant relative increase in total blood volume was observed (P less than 0.001). This relative increase was directly correlated with the diastolic arterial pressure (r=0.064; P less than 0.00001) and was inversely related to the renal blood flow (r=-0.54; P less than 0.0001) and the creatinine clearance. Such correlations were not observed with the real blood volume. In agreement with Guytons theory, this study highly suggests that sustained hypertension is related to an increase in blood volume relative to the capacity of the circulatory system and that a renal defect is necessary for the blood pressure elevation mechanism.

Effects of aldosterone on coronary function

Our understanding of the effects of aldosterone and its mechanisms has increased substantially in recent years, probably because of the importance of the mineralocorticoid receptor (MR) antagonists in several major cardiovascular diseases. Recent clinical studies have confirmed the benefits of MR antagonists in patients with heart failure, left ventricular dysfunction after myocardial infarction, hypertension or diabetic nephropathy. However, it would be a gross oversimplification to conclude that the role of aldosterone is unequivocally negative. Aldosterone is synthesized in the adrenal glands and binds to specific MRs in target epithelial cells. The steroid-receptor complex penetrates the cell nucleus where it modulates gene expression and activates specific aldosterone-induced proteins that control sodium reabsorption. Recent studies have shown that aldosterone also impacts a wide range of non-epithelial tissues such as the heart and blood vessels. Remarkably, aldosterone can also be synthesized in extra-adrenal tissues and it may act in a rapid non-genomic manner.We note the existence of glucocorticoids that exhibit plasma concentrations much higher than those of aldosterone and that are structurally very similar to aldosterone. It is thus possible that glucocorticoids may bind to the aldosterone receptor in some cell types. Diverse experimental models and several strains of transgenic mice have allowed us to better understand the effects of aldosterone on the heart. Specifically, it seems that a slight increase in cardiac aldosterone concentrations induces a decreased coronary reserve in mice by decreasing the BKCa potassium channels associated with coronary smooth muscle cells. Taken together, these experiments indicate that vascular cells are the primary targets of aldosterone in the cardiovascular system. The hormone directly affects NO and EDHF-mediated coronary relaxation. Both mechanisms may contribute to the deleterious cardiovascular effects of MR stimulation.