Lawrence M. Resnick

Influence of age, risk factors, and cardiovascular and renal disease on arterial stiffness: Clinical applications

Age is the main clinical determinant of large artery stiffness. Central arteries stiffen progressively with age, whereas peripheral muscular arteries change little with age. A number of clinical studies have analyzed the effects of age on aortic stiffness. Increase of central artery stiffness with age is responsible for earlier wave reflections and changes in pressure wave contours. The stiffening of aorta and other central arteries is a potential risk factor for increased cardiovascular morbidity and mortality. Arterial stiffening with aging is accompanied by an elevation in systolic blood pressure (BP) and pulse pressure (PP). Although arterial stiffening with age is a common situation, it has now been confirmed that older subjects with increased arterial stiffness and elevated PP have higher cardiovascular morbidity and mortality. Increase in aortic stiffness with age occurs gradually and continuously, similarly for men and women. Cross-sectional studies have shown that aortic and carotid stiffness (evaluated by the pulse wave velocity) increase with age by approximately 10% to 15% during a period of 10 years. Women always have 5% to 10% lower stiffness than men of the same age. Although large artery stiffness increases with age independently of the presence of cardiovascular risk factors or other associated conditions, the extent of this increase may depend on several environmental or genetic factors. Hypertension may increase arterial stiffness, especially in older subjects. Among other cardiovascular risk factors, diabetes type 1 and 2 accelerates arterial stiffness, whereas the role of dyslipidemia and tobacco smoking is unclear. Arterial stiffness is also present in several cardiovascular and renal diseases. Patients with heart failure, end stage renal disease, and those with atherosclerotic lesions often develop central artery stiffness. Decreased carotid distensibility, increased arterial thickness, and presence of calcifications and plaques often coexist in the same subject. However, relationships between these three alterations of the arterial wall remain to be explored.

Cellular ions in hypertension, diabetes, and obesity : a nuclear magnetic resonance spectroscopic study

To investigate the cellular basis linking hypertension, non-insulin-dependent diabetes melllrus (NIDDM), and obesity, we used 31P and 19F nuclear magnetic resonance spectroscopy to measure intracellular pH (pHJ, free magnesium (M&), and cytosolic free calcium (Ca1) in erythrocytes of obese and NIDDM subjects with and without hypertension. Compared with nonnotensive, nondiabetic controls (Ca1 25.2 ±1.4 nM; Mg1232 ±8 μM), Cat was elevated in both nonnotensive (36.8±2.7 nM, sig=0.005) and hypertensive (43.4±2.9 nM, sig=0.001) NIDDM subjects, and Mg1 was concomitantly suppressed (nonnotensive: 206±ll μM, sig=0.05; hypertensive: 196±8 μM, sig=0.001). Similar but less striking changes were noted in obese subjects. Values of pH, were significantly lower (sig=0.05) in all hypertensive groups compared with their nonnotensive controls. Continuous relations were observed for all subjects between Ca1, and diastolic blood pressure (r=0.649,/7<0.001) and body mass index (r=0-565, p<0.001), between Mg, and diastolic blood pressure (r=-0.563, p<0.001) and fasting blood glucose (r=-0.580, p<0.001), and in diabetics, between pH1 and diastolic blood pressure (r= -0.680, p<0.001). Thus, the constellation of elevated Ca1, and suppressed Mg1 and pH1 levels is characteristic of the hypertensive state. These abnormalities of cellular ion handling in whole or in part common to hypertension, diabetes, and obesity may contribute to the pathophysiology of these syndromes and may help to explain their frequent clinical coexistence.

Intracellular and extracellular magnesium depletion in Type 2 (non-insulin-dependent) diabetes mellitus

SummaryTo investigate alterations of magnesium metabolism in Type 2 (non-insulin-dependent) diabetes mellitus, we utilized a new magnesium-specific selective ion electrode apparatus to measure serum ionized magnesium (Mg-io) in fasting subjects with and without Type 2 diabetes, and compared these values to levels of serum total magnesium, and of intracellular free magnesium (Mgi) analysed by 31P-NMR spectroscopy. Both Mg-io (0.630±0.008 vs 0.552± 0.008 mmol/l, p<0.001) and Mgi (223.3±8.3 vs 184± 13.7 mmol/l,p<0.001), but not serum total magnesium, were significantly reduced in Type 2 diabetes compared with nondiabetic control subjects. Furthermore, a close relationship was observed between serum Mg-io and Mgi (r=0.728, p<0.001). We suggest that magnesium deficiency, both extracellular and intracellular, is a characteristic of chronic stable mild Type 2 diabetes, and as such, may predispose to the excess cardiovascular morbidity of the diabetic state. Furthermore, by more adequately reflecting cellular magnesium metabolism than total serum magnesium levels, Mg-io measurements may provide a more readily available tool than has heretofore been available to analyse magnesium metabolism in a variety of diseases.

Cellular Calcium and Magnesium Metabolism in the Pathophysiology and Treatment of Hypertension and Related Metabolic Disorders

We have investigated the cellular basis for the clinical and epidemiologic linkage of hypertension, left ventricular hypertrophy (LVH), obesity, and non-insulin-dependent diabetes mellitus (NIDDM) and have studied cytosolic free calcium and free magnesium levels in these syndromes. Specifically, intracellular free calcium is elevated and free magnesium is deficient in hypertension, and both are related (directly and inversely, respectively) to the ambient level of blood pressure, to LV mass index (and thus to the degree of cardiac hypertrophy), and to the hyperinsulinemia and insulin resistance of essential hypertension. Dynamically, the ability of dietary salt loading to elevate blood pressure corresponds to its ability to elevate cytosolic free calcium and reciprocally to suppress free magnesium levels. Conversely, the ability of calcium channel blockade to reverse salt-induced hypertension is related to its ability to prevent these transmembrane ionic effects. Higher steady-state free calcium or lower free magnesium, or both, are also observed in clinical states linked to hypertension, such as obesity and NIDDM. Oral glucose loading in normal subjects itself elevates free calcium and suppresses free magnesium levels, as does hyperglycemia in vitro. These data suggest an ionic hypothesis of cardiovascular and metabolic disease, in which a generalized defect in cell ion handling is present in all tissues, resulting in higher steady-state free calcium and lower free magnesium levels. In pancreatic beta cells, this would produce hyperinsulinemia; in fat and skeletal muscle, cause peripheral insulin resistance; and in renal tissue, increase proximal sodium resorption and increase urinary calcium excretion--all features of essential hypertension. In vascular smooth muscle, high cytosolic free calcium would increase smooth muscle tone and cause vasoconstriction, and in heart muscle, independent of blood pressure, would increase contractility and predispose to LVH. Therefore, what may appear clinically to be the separate syndromes of hypertension, obesity, and NIDDM may pathophysiologically be different manifestations of the same underlying cellular defect, thus explaining their frequent clinical coexistence. Therapeutically, reversal of this excess free calcium accumulation and/or free magnesium deficit with ion-specific agents, such as calcium channel blocking drugs, may thus ameliorate not only the elevated blood pressure of hypertension but also the concurrent excess morbidity and mortality of the concurrent cardiac, vascular, and metabolic aspects of the hypertensive state.

Calcium metabolism and parathyroid function in primary aldosteronism

Calcium and magnesium metabolism was investigated in 10 hypertensive subjects with primary aldosteronism (seven adenomatous, three idiopathic). Serum levels of total calcium (9.03 +/- 0.2 mg/dl) and ionized calcium (2.06 +/- 0.06 meq/liter) were in the low-normal range, except for two patients who had levels of serum ionized calcium clearly above normal. Furthermore, both serum total (n = 6, p less than 0.01) and ionized calcium levels (n = 3) rose postoperatively in the patients who had an aldosterone-producing tumor removed. Dramatic elevations of parathyroid hormone levels (mean, 645 +/- 109 pgeq/liter; normal, less than 150 to 375 pgeq/liter) were seen in the majority of patients, including those two with frank ionized calcium elevations. Magnesium levels were within normal limits (2.07 +/- 0.07 meq/liter). These results indicate that parathyroid hypersecretion is a common feature of primary aldosteronism and also suggest a physiologic relationship between the activity of the renin-aldosterone system and parathyroid physiology. Sodium-volume expansion and negative calcium balance induced by aldosterone excess may predispose to hyperparathyroidism.

Pulse waveform analysis of arterial compliance: relation to other techniques, age, and metabolic variables

To assess the physiologic and clinical relevance of newer noninvasive measures of vascular compliance, computerized arterial pulse waveform analysis (CAPWA) of the radial pulse was used to calculate two components of compliance, C1 (capacitive) and C2 (oscillatory or reflective), in 87 normotensive (N1BP, n = 20), untreated hypertensive (HiBP, n = 21), and treated hypertensive (HiBP-Rx, n = 46) subjects. These values were compared with two other indices of compliance, the ratio of stroke volume to pulse pressure (SV/PP) and magnetic resonance imaging (MRI)-based aortic distensibility; and were also correlated with demographic and biochemical values. The HiBP subjects displayed lower C1 (1.34 +/- 0.09 v. 1.70 +/- 0.11 mL/mm Hg, significance [sig] = .05) and C2 (0.031 +/- 0.003 v 0.073 +/- 0.02 mL/mm Hg, sig = .005) than N1BP subjects. This was not true for C1 (1.64 +/- 0.08 mL/mm Hg) and C2 (0.052 +/- 0.005 mL/mm Hg) values in HiBP-Rx subjects. The C1 (r = 0.917, P < .0001) and C2 (r = 0.677, P < .0001) were both closely related to SV/PP, whereas C1 (r = 0.748, P = .002), but not C2, was significantly related to MRI-determined aortic distensibility. Among other factors measured, age exerted a strong negative influence on both C1 (r = -0.696, P < .0001) and C2 (r = -0.611, P < .0001) compliance components. Positive correlations were observed between C1 (r = 0.863, P = .006), aortic distensibility (r = 0.597, P = .19) and 24-h urinary sodium excretion, and between C1- and MR spectroscopy-determined in situ skeletal muscle intracellular free magnesium (r = 0.827, P = .006), whereas C2 was inversely related to MRI-determined abdominal visceral fat area (r = -0.512, P = .042) and fasting blood glucose (r = -0.846, P = .001). Altogether, the close correspondence between CAPWA, other compliance techniques, and known cardiovascular risk factors suggests the clinical relevance of CAPWA in the assessment of altered vascular function in hypertension.

Vascular Effects of Progesterone: Role of Cellular Calcium Regulation

Vascular actions of progesterone have been reported, independently of estrogen, affecting both blood pressure and other aspects of the cardiovascular system. To study possible mechanisms underlying these effects, we examined the effects of P in vivo in intact rats and in vitro in isolated artery and vascular smooth muscle cell preparations. In anesthetized Sprague-Dawley rats , bolus intravenous injections of P (100 &mgr;g/kg) significantly decreased pressor responses to norepinephrine (0.3 &mgr;g/kg). In vitro, progesterone (10−8 to 10−5 mmol/L) produced a significant, dose-dependent relaxation of isolated helical strips, both of rat tail artery precontracted with KCl (60 mmol/L) or arginine vasopressin (3 nmol/L), and of rat aorta precontracted with KCl (60 mmol/L) or norepinephrine (0.1 &mgr;mol/L). In isolated vascular smooth muscle cells, progesterone (5×10−7 mol/L) reversibly inhibited KCl (30 mmol/L) -induced elevation of cytosolic-free calcium by 64.1±5.5% (P <0.05), and in whole-cell patch-clamp experiments, progesterone (5×10−6 mol/L) reversibly and significantly blunted L-type calcium channel inward current, decreasing peak inward current to 65.7±4.3% of the control value (P <0.05). Our results provide evidence that progesterone is a vasoactive hormone, inhibiting agonist-induced vasoconstriction. The data further suggest that progesterone effects on vascular tissue may, at least in part, be mediated by modulation of the L-type calcium channel current activity and, consequently, of cytosolic-free calcium content.

Hypertension and abnormal glucose homeostasis: Possible role of divalent ion metabolism

Recent epidemiologic and clinical evidence emphasizes the association of hypertension, peripheral insulin resistance, hyperinsulinemia, and/or frank diabetes mellitus. The underlying basis for this clinical association remains unknown, and much attention has been focused on a possible role for hyperinsulinemia in these processes. However, evidence also suggests direct hypotensive effects of insulin. It is therefore unclear to what extent hyperinsulinemia contributes to, rather than merely reflects, these multiple metabolic abnormalities. Recent research links both hypertension and diabetes to common defects in calcium and magnesium metabolism, at least in part described by increased cytosolic free calcium, suppressed intracellular free magnesium, and their associated intracellular and hormonal alterations. Thus, hypertension, peripheral insulin resistance, and hyperinsulinemia may be different clinical manifestations of a common underlying cellular defect in divalent ion metabolism.

Uniformity and diversity of calcium metabolism in hypertension. A conceptual framework.

Calcium metabolism plays an important role in blood pressure homeostasis, although it remains unclear to what extent calcium contributes to or, alternatively, protects against clinical hypertension. To resolve this confusion, hypertensive subgroups were first defined by plasma renin activity, dietary salt sensitivity, sensitivity to calcium channel blockade, and calcium metabolic indices. Using these classification schemes, different patterns of calcium metabolism emerged, each predictive of divergent clinical responses. Patients with low plasma renin activity, low serum ionized calcium levels, and dietary salt sensitivity, such as black and elderly hypertensive patients, may preferentially benefit from calcium supplementation. It is postulated that calcium-regulating hormones and the renin-angiotensin-aldosterone system coordinately monitor dietary mineral intake, and transduce these environmental signals at the cellular level by altering cellular calcium uptake and disposition. Analysis of these hormonal systems is useful diagnostically in defining those patients who would most benefit from non-pharmacologic dietary forms of treatment.

Cellular ionic effects of insulin in normal human erythrocytes: a nuclear magnetic resonance study

SummaryElevated erythrocyte cytosolic free calcium, and suppressed free magnesium and pH values are associated with the hyperinsulinaemia and insulin resistance of hypertension, obesity, and Type 2 (non-insulin-dependent) diabetes mellitus. To determine the role of insulin in this process, we utilized 19F- and 31P-nuclear magnetic resonance spectroscopy to study the cellular ionic effects of insulin in vitro on normal human erythrocytes. Insulin elevated cytosolic free calcium levels in a dose- and time-dependent manner. The effect began at 10 μU/ml, peaked at 200 μU/ml, and continued at both the 500 μU/ml and 1000 μU/ml doses. At 200 μU/ml, free calcium levels rose from 24.6±2.5 nmol/l to a peak value at 120 min of 66.4±11 nmol/l (p<0.05 vs basal), levels remaining elevated throughout the incubation (45.7±5.6 nmol/l at 60 min, and 47.9±9.1 nmol/l at 180 min, p<0.05 vs basal, respectively). Similarly, insulin also increased intracellular free magnesium at all time points (basal: 177± 11 μmol/l; 60 min: 209±19 μmol/l; 120 min: 206±22 μmol/l; and 180 min: 202±12 μmol/l; p<0.05 vs basal at all times). No insulin-induced changes in pH were observed. We conclude (i) that insulin in physiological concentrations may participate in regulating divalent cations in the mature human erythrocyte, (ii) that insulin per se cannot account for the previously described cellular ionic lesions of hypertension and diabetes, and (iii) that future clinical studies of cell ion metabolism should be conducted in the fasting state, be controlled for ambient circulating insulin levels, or both.