Mechanisms of heart failure with well preserved ejection fraction in dogs following limited coronary microembolization

OBJECTIVE: It has been suggested that in some settings, heart failure (HF) may occur with normal ejection fraction (EF) as a consequence of undetected systolic dysfunction. However, others have argued that this can only occur in the presence of diastolic dysfunction. We therefore sought to determine the contribution of diastolic dysfunction in an animal model of HF with normal EF. METHODS AND RESULTS: Limited myocardial injury was induced in 21 dogs chronically instrumented to measure hemodynamics and LV properties by daily coronary microembolization ( approximately 115 microm beads) until LV end diastolic pressure (LVEDP) was > or =16 mm Hg. Nine dogs developed HF within 16+/-6 days (LVEDP 12+/-2 vs. 21+/-2 mm Hg, p<0.001) with no significant change in dP/dt(max) (2999+/-97 vs. 2846+/-189 mm Hg/s), mean arterial pressure (103+/-4 vs. 100+/-4 mm Hg), EF (57+/-5% vs. 53+/-4%) or E(es) (end-systolic elastance, 3.1+/-0.9 vs. 2.9+/-0.8 mm Hg/ml) but with an approximately 10 ml increase in V(o) (14+/-12 vs. 25+/-16 ml; p<0.01). The EDPVR and time constant of relaxation (tau, 25+/-3 vs. 28+/-3 ms) did not change significantly. These animals were hemodynamically stable out to 3 1/2 months. Neurohormonal activation occurred (elevations of NE, AngII, BNP) and there was intravascular volume expansion by approximately 16% (p<0.05). CONCLUSIONS: A small amount of myocardial injury can lead to neurohormonal activation with intravascular volume expansion and elevation of LVEDP in the absence of reductions in dP/dt(max) or EF and without diastolic dysfunction. Thus, HF with preserved EF does not a priori equate with diastolic heart failure.     

Effects of indapamide, a thiazide-like diuretic, on structure of cerebral arterioles in hypertensive rats

We examined the effects of indapamide, a thiazide-like diuretic, on cerebral arterioles in spontaneously hypertensive rats (SHR). The structure and mechanics of cerebral arterioles were examined in untreated Wistar Kyoto rats (WKY) and SHR that were untreated or treated for 3 months with a low (1 mg/kg per day) or a high (10 mg/kg per day) dose of indapamide. We measured pressure, diameter, and cross-sectional area of the vessel wall (CSA) in maximally-dilated (EDTA) cerebral arterioles. Treatment of SHR with the high dose of indapamide normalized cerebral arteriolar mean pressure (62+/-4 [mean+/-SEM] versus 59+/-3 mm Hg in WKY and 88+/-6 mm Hg in untreated SHR; P<0.05), pulse pressure (13+/-1 versus 10+/-1 mm Hg in WKY and 20+/-1 mm Hg in untreated SHR; P<0.05), and CSA (1080+/-91 versus 1100+/-48 microm2 in WKY and 1439+/-40 microm2 in untreated SHR; P<0.05). In contrast, treatment of SHR with the low dose of indapamide did not normalize arteriolar mean (72+/-3) and pulse pressure (20+/-1 mm Hg), but did normalize CSA (1091+/-52 microm2). Treatment with either dose of indapamide failed to increase external diameter in cerebral arterioles of SHR (89+/-4 and 92+/-4 microm, respectively, versus 103+/-6 microm in WKY and 87+/-4 microm in untreated SHR). Finally, treatment with indapamide attenuated the rightward shift of the stress-strain curve in SHR, suggesting that treatment with indapamide attenuated increases in distensibility of cerebral arterioles in SHR. These findings suggest that, whereas thiazide-like diuretics may not attenuate eutrophic inward remodeling of cerebral arterioles in SHR, they may attenuate hypertrophic inward remodeling via a mechanism unrelated to their pressor effects.     

Right ventricular preload recruitable stroke work, end-systolic pressure-volume, and dP/dtmax-end-diastolic volume relations compared as indexes of right ventricular contractile performance in conscious dogs.

Three indexes developed originally to assess left ventricular contractile performance were applied instead to the right ventricle (RV) in 11 conscious dogs: the relation between stroke work and end-diastolic volume (EDV), termed the preload recruitable stroke work (PRSW) relation; the end-systolic pressure-volume (ESPV) relation; and the maximum dP/dt (dP/dtmax)-EDV relation. The reproducibility, inotropic sensitivity, chronotropic sensitivity, and afterload sensitivity of these RV relations were compared. RV volume was determined with an ellipsoidal shell subtraction model from orthogonal dimensions measured by sonomicrometry. RV transmural pressure was measured with micromanometers. After autonomic blockade, preload was varied by repeated, transient vena caval occlusions before and during partial occlusion of the main pulmonary artery, after release of the pulmonary arterial occlusion, after calcium infusion, and over a range of heart rates induced by atrial pacing. The slope and volume-axis intercept of the PRSW relation were more reproducible (SD/mean, 7.8 +/- 3.3% and 6.2 +/- 4.1%, respectively) than the slope and volume-axis intercept of the ESPV relation (10.1 +/- 6.7% and 23.0 +/- 31.3%, both p less than 0.05) or the slope and volume-axis intercept of the dP/dtmax-EDV relation (43.4 +/- 70.4% and 153.8 +/- 184.6%, both p less than 0.05). The slope of the PRSW relation increased 32 +/- 17% (p less than 0.05) after calcium infusion, but the volume-axis intercept did not change significantly. In contrast, the slopes of the ESPV and dP/dtmax-EDV relations did not change significantly after calcium infusion, but the volume-axis intercepts decreased significantly (both p less than 0.05). Despite a 71 +/- 26% increase in mean RV ejection pressure during partial occlusion of the main pulmonary artery, the slopes and volume-axis intercepts of both the PRSW and dP/dtmax-EDV relations did not change significantly, but the slope of the ESPV relation increased 45 +/- 22% (p less than 0.05) without significant change in the volume-axis intercept. None of the relations demonstrated significant chronotropic sensitivity. The PRSW relation is the preferred index of RV contractile performance because 1) it is the most reproducible, 2) its slope alone sensitively detects changes in contractile state, and 3) unlike the ESPV relation, it is relatively insensitive to afterload.     

Calcimimetic NPS R-568 induces hypotensive effect in spontaneously hypertensive rats

BACKGROUND: The discovery of calcium receptors and calcimimetics created the possibility of "pharmacologic parathyroidectomy" (phPTX), which decreased secretion of parathormone (PTH). Parathyroid glands of spontaneously hypertensive rats (SHR) and of patients with primary hyperparathyroidism and hypertension secrete parathyroid hypertensive factor (PHF). Parathyroidectomy decreases blood pressure in these rats and in patients. The present study determined whether phPTX induced by calcimimetics decreases mean arterial blood pressure (MAP) in hypertensive rats. METHODS: Hypertensive SHR and normotensive Wistar Kyoto (WKY) rats were used. Clearance experiments were performed and the effect of 1 mg/kg body weight (given intravenously) synthesized NPS R-568 (NPS) on MAP in the presence or absence of thyroparathyroidectomy (TPTX) was monitored. RESULTS: The success phPTX and TPTX were proven by a significant decrease in plasma Ca(2+) concentration and a decrease in urinary fractional phosphate excretion (FE Pi). The administration of NPS significantly decreased blood pressure in SHR versus SHR/control: Delta(0-50 min of experiment) MAP -16.5 +/- 2.5 mm Hg v -3.2 +/- 1.5 mm Hg (P < .002). The TPTX decreased blood pressure in SHR versus SHR/control and was not different versus SHR/TPTX/NPS (DeltaMAP: -10.2 +/- 1.6 mm Hg v -3.2 +/- 1.5 mm Hg (P < .01) and v -8.3 +/- 2.2 mm Hg (P = not significant). In normotensive WKY rats application of NPS did not reach significance in DeltaMAP: -6.7 +/- 1.8 mm Hg v -2.6 +/- 2.8 mm Hg (P = not significant) in WKY/control. The TPTX lowered blood pressure in WKY versus WKY/control and remained unchanged versus WKY/TPTX/NPS (DeltaMAP: -11.3 +/- 1.7 mm Hg v -2.6 +/- 2.8 mm Hg (P < .04) and v -11.4 +/- 2.6 mm Hg (P = not significant). CONCLUSIONS: We conclude that phPTX with NPS R-568 is responsible for a decrease of MAP in SHR.     

Activation of the Na(+)-H+ exchanger modulates angiotensin II-stimulated Na(+)-dependent Mg2+ transport in vascular smooth muscle cells in genetic hypertension.

This study investigated the role of the Na(+)-H+ exchanger (NHE) on angiotensin II (Ang II)-induced activation of Na(+)-dependent Mg2+ transport in vascular smooth muscle cells (VSMCs) from Wistar-Kyoto rats (WKY; n=20) and spontaneously hypertensive rats (SHR; n=20). Intracellular free concentrations of Mg2+ ([Mg2+]i) and Na+ ([Na+]i) and intracellular pH (pHi) were measured with the specific fluorescent probes mag-fura 2-AM, SBFI-AM, and BCECF-AM, respectively. Na+ dependency of Mg2+ transport was assessed in Na(+)-free buffer, and the role of the NHE was determined with the highly selective NHE blocker 5-(N-methyl-N-isobutyl) amiloride (MIA). Basal [Mg2+]i was lower in SHR than WKY (0.59+/-0.01 versus 0.71+/-0.01 mmol/L, P<0.05). Basal pHi and [Na+]i were not different between the 2 groups. Ang II dose dependently increased [Na+]i and pHi and decreased [Mg2+]i. Responses were significantly greater (P<0.05) in SHR versus WKY ([Na+]i E(max)=37.5+/-1.1 versus 33.7+/-1.9 mmol/L; pHi E(max)=7.35+/-0.04 versus 7.20+/-0.01; [Mg2+]i E(min)=0. 28+/-0.09 versus 0.53+/-0.02 mmol/L, SHR versus WKY). In Na(+)-free buffer, Ang II-elicited [Mg2+]i responses were inhibited. MIA (1 micromol/L) inhibited Ang II-stimulated responses in WKY and normalized responses in SHR ([Mg2+]i E(min)=0.49+/-0.02). Ang II-stimulated activation of NHE was significantly increased (P<0.05) in SHR (0.07+/-0.002 DeltapH(i)/s) compared with WKY (0.05+/-0.004 DeltapH(i)/s). These data demonstrate that in VSMCs [Mg2+]i regulation is Na+ dependent, that activation of NHE modulates Na(+)-Mg2+ transport, and that increased activity of NHE may play a role in altered Na(+)-dependent regulation of [Mg2+]i in SHR.     

Effects of perfusion pressure on energy and work of isolated rat hearts

A chemomechanical study of hypertrophied hearts of 6-month-old spontaneously hypertensive rats (SHR) and that of age-matched Wistar-Kyoto (WKY) rats was carried out, analyzing the response of the heart to steady-state changes in coronary perfusion pressure. The ratio of heart (dry)-to-body (wet) weight of WKY rats was 0.37 +/- 0.02 (10(-3] and for SHR was 0.58 +/- 0.03 (10(-3] (p less than 0.01). In the apex-ejecting, isolated, pyruvate-perfused working hearts of WKY rats and SHR, coronary flow was constant when coronary perfusion pressure was set between 140 and 190 cm H2O (range of autoregulation). Coronary flow was perfusion pressure dependent when the coronary perfusion pressure was set below 110 cm H2O for both WKY rats and SHR. Cardiac output, developed pressure, rate of pressure development (dP/dt), and oxygen consumption were constant in the range of autoregulation but decreased in the direction of coronary flow when coronary flow was reduced by a drop in perfusion pressure. Similarly, the phosphorylation potential, phosphocreatine, adenosine triphosphate, and cyclic adenosine monophosphate were constant in the range of autoregulation but decreased directionally with coronary perfusion pressure below 110 cm H2O for both SHR and WKY rats. There was a significantly lower phosphorylation potential in SHR as compared with WKY rats when coronary perfusion pressure was reduced to 80 cm H2O. In the region of autoregulation, coronary flow and oxygen consumption were significantly less in SHR, although developed pressure was significantly greater at both high and low workloads.(ABSTRACT TRUNCATED AT 250 WORDS)     

beta(2)-adrenergic receptor overexpression exacerbates development of heart failure after aortic stenosis

BACKGROUND: Beta-adrenergic signaling is downregulated in the failing heart, and the significance of such change remains unclear. METHODS AND RESULTS: To address the role of beta-adrenergic dysfunction in heart failure (HF), aortic stenosis (AS) was induced in wild-type (WT) and transgenic (TG) mice with cardiac targeted overexpression of beta(2)-adrenergic receptors (ARs), and animals were studied 9 weeks later. The extents of increase in systolic arterial pressure (P<0.01 versus controls), left ventricular (LV) hypertrophy (TG, 94+/-6 to 175+/-7 mg; WT, 110+/-6 to 168+/-10 mg; both P<0.01), and expression of ANP mRNA were similar between TG and WT mice with AS. TG mice had higher incidences of premature death and critical illness due to heart failure (75% versus 23%), pleural effusion (81% versus 45%), and left atrial thrombosis (81% versus 36%, all P<0.05). A more extensive focal fibrosis was found in the hypertrophied LV of TG mice (P<0.05). These findings indicate a more severe LV dysfunction in TG mice. In sham-operated mice, LV dP/dt(max) and heart rate were markedly higher in TG than WT mice (both P<0.01). dP/dt(max) was lower in both AS groups than in sham-operated controls, and this tended to be more pronounced in TG than WT mice (-32+/-5% versus -16+/-6%, P=0.059), although dP/dt(max) remained higher in TG than WT groups (P<0.05). CONCLUSIONS: Elevated cardiac beta-adrenergic activity by beta(2)-AR overexpression leads to functional deterioration after pressure overload.     

Baroreflex function in lifetime-captopril-treated spontaneously hypertensive rats

The effects of lifetime oral captopril treatment on baroreflex control of heart rate and lumbar sympathetic nerve activity were measured in 19-21-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The sensitivity of baroreflex control of heart rate and lumbar sympathetic nerve activity were determined by the slopes of the relation between the change in mean arterial pressure (MAP) (mm Hg) versus the change in pulse interval (msec/beat) and the change in MAP versus the percent change in nerve activity, respectively. Untreated SHR had significantly higher MAP than WKY (157 +/- 3 vs. 115 +/- 3 mm Hg, p less than 0.001) and exhibited a decreased baroreflex control of heart rate. Lifetime treatment with captopril prevented the development of hypertension in SHR (MAP = 110 +/- 5 mm Hg) and increased the sensitivity of baroreflex function. The gains of the baroreflex control of heart rate for captopril-treated SHR and control SHR when MAP was raised or lowered by phenylephrine or nitroprusside were 2.38 +/- 0.49 vs. 1.10 +/- 0.33 msec/mm Hg (p less than 0.05) and 0.74 +/- 0.20 vs. 0.54 +/- 0.09 (NS) msec/mm Hg, respectively. The sensitivity of the baroreflex control of lumbar sympathetic nerve activity was greater in captopril-treated SHR than in control SHR when MAP was increased or decreased (-1.03 +/- 0.26 vs. -0.38 +/- 0.11, p less than 0.05; -0.84 +/- 0.2 vs. -0.04 +/- 0.58 (NS) mm Hg-1, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional and global biventricular function during dipyridamole stress testing

This study assesses the relation between regional ventricular performance (using 2-dimensional echocardiography) and global systolic and diastolic indexes of biventricular myocardial function (using hemodynamic monitoring) during dipyridamole stress testing. Simultaneous 2-dimensional echocardiographic and biventricular hemodynamic monitoring during dipyridamole infusion (0.56 mg/kg over 4 minutes) was performed in 19 patients. All patients had a normal resting function. Eleven of the 19 patients had a positive echocardiography test (new wall motion dyssynergy with dipyridamole) and they formed group 1. Eight patients had a negative echocardiography test (group 2). During baseline conditions, no significant differences were found in the 2 groups: rate pressure product (107 +/- 16 vs 108 +/- 13 mm Hg x beats/min x 1/100), positive left ventricular (LV) dP/dt (1,950 +/- 473 vs 2,262 +/- 430 mm Hg/s), negative LV dP/dt (-2,069 +/- 620 vs -2,205 +/- 245), LV end-diastolic pressure (8.2 +/- 4.4 vs 9.6 +/- 4.0 mm Hg), right ventricular positive dP/dt (368 +/- 133 vs 400 +/- 190 mm Hg/s) and negative dP/dt (-281 +/- 89 vs -383 +/- 147). At peak dipyridamole, the 2 groups were different for LV end-diastolic pressure (20 +/- 10 vs 8 +/- 5 mm Hg, p less than 0.01), LV positive dP/dt (2,100 +/- 688 vs 3,013 +/- 851 mm Hg/s, p less than 0.01) and negative dP/dt (-1,868 +/- 518 vs -2,564 +/- 272, p less than 0.01). At peak ischemia, LV positive dP/dt increased slightly, but not significantly, while negative dP/dt decreased significantly (p less than 0.01) in comparison with resting values.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interaction of angiotensin II type 1 and D5 dopamine receptors in renal proximal tubule cells

Angiotensin II type 1 (AT1) receptor and D1 and D3 dopamine receptors directly interact in renal proximal tubule (RPT) cells from normotensive Wistar-Kyoto rats (WKY). There is indirect evidence for a D5 and AT1 receptor interaction in WKY and spontaneously hypertensive rats (SHR). Therefore, we sought direct evidence of an interaction between AT1 and D5 receptors in RPT cells. D5 and AT1 receptors colocalized in WKY cells. Angiotensin II decreased D5 receptors in WKY cells in a time- and concentration-dependent manner (EC50=2.7x10(-9) M; t(1/2)=4.9 hours), effects that were blocked by an AT1 receptor antagonist (losartan). In SHR, angiotensin II (10(-8) M/24 hours) also decreased D5 receptors (0.96+/-0.08 versus 0.72+/-0.08; n=12) and to the same degree as in WKY cells (1.44+/-0.07 versus 0.92+/-0.08). However, basal D5 receptors were decreased in SHR RPT cells (SHR 0.96+/-0.08; WKY 1.44+/-0.07; n=12 per strain; P<0.05) and renal brush border membranes of SHR compared with WKY (SHR 0.54+/-0.16 versus WKY 1.46+/-0.10; n=5 per strain; P<0.05). Angiotensin II decreased AT1 receptor expression in WKY (1.00+/-0.04 versus 0.72+/-0.08; n=8; P<0.05) but increased it in SHR (0.96+/-0.04 versus 1.32+/-0.08; n=8; P<0.05). AT(1) and D5 receptors also interacted in vivo; renal D5 receptor protein was higher in mice lacking the AT1A receptor (AT1A-/-; 1.61+/-0.31; n=6) than in wild-type littermates used as controls (AT1A+/+; 0.81+/-0.08; n=6; P<0.05), and renal cortical AT1 receptor protein was higher in D5 receptor null mice than in wild-type littermates (1.18+/-0.08 versus 0.84+/-0.07; n=4; P<0.05). We conclude that D5 and AT1 receptors interact with each other. Altered interactions between AT1 and dopamine receptors may play a role in the pathogenesis of hypertension.     

Reduced intracellular pH in lymphocytes from the spontaneously hypertensive rat

This study was designed to determine the cytoplasmic pH (pHi) profile of lymphocytes from a rat model of genetic hypertension that is well suited for study before and after the development of spontaneous hypertension. For this purpose, pHi was measured in thymic lymphocytes obtained from spontaneously hypertensive rats (SHR) and from age-matched Wistar-Kyoto (WKY) control rats using 2',7'-bis carboxyethyl-5,6-carboxyfluorescein (BCECF), a pH-sensitive fluorescence probe. At the age of 16-20 weeks, pHi of lymphocytes suspended in a HCO3-free HEPES-buffered solution, was markedly lower in the SHR than in the WKY rats (7.07 +/- 0.02, n = 16 and 7.22 +/- 0.01, n = 15, respectively, p less than 0.001), whereas systolic blood pressure was higher in SHR than in WKY rats (175 +/- 5.0 and 105 +/- 3.0 mm Hg, respectively, p less than 0.001). In rats less than 5 weeks of age, pHi was also lower in SHR than in WKY rat lymphocytes (7.12 +/- 0.04, n = 11 and 7.23 +/- 0.04, n = 11, respectively, p less than 0.05), although at this age systolic blood pressure was not different between the two groups (87 +/- 4.0 and 85 +/- 3.0 mm Hg, respectively). In lymphocytes suspended in a more physiological HCO3/CO2-buffered solution, pHi was again lower in the adult SHR than in the WKY rat (7.18 +/- 0.02, n = 16 and 7.31 +/- 0.02, n = 16, respectively, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhanced myogenic responsiveness of renal interlobular arteries in spontaneously hypertensive rats.

We recently demonstrated that the interlobular artery (ILA) constricts in response to elevating renal arterial pressure (RAP), suggesting that the ILA contributes to renal autoregulation. In the present study, we examined the segmental myogenic responsiveness of the ILA in kidneys from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). The tapered nature of the ILA allowed us to characterize the regional responsiveness, using the basal diameter to define segments as either proximal (greater than 60 microns), intermediate (40-60 microns), or distal (less than 40 microns). At 80 mm Hg, segmental diameters were similar in WKY and SHR arteries (proximal, 76.0 +/- 3.1 versus 71.6 +/- 3.5 microns; intermediate, 48.2 +/- 1.4 versus 48.1 +/- 1.7 microns; distal, 30.7 +/- 0.9 versus 27.9 +/- 1.3 microns for WKY and SHR, respectively). In both strains, intermediate and distal segments exhibited graded reductions in diameter as RAP was elevated, whereas proximal segments did not. Pressure-induced decrements in the diameters of distal ILA segments were similar in WKY (-24 +/- 2%) and SHR (-20 +/- 2%; p greater than 0.1). The intermediate ILA of SHR exhibited an augmented myogenic responsiveness, constricting at lower RAP levels and exhibiting greater maximal decrements in diameter at 180 mm Hg (i.e., -19 +/- 2% and -12 +/- 2% for SHR and WKY, respectively; p less than 0.05). Nifedipine (1.0 microM) reduced pressure-induced vasoconstriction of intermediate and distal ILA segments by 56 +/- 11% and 79 +/- 7%, respectively, in WKY.(ABSTRACT TRUNCATED AT 250 WORDS)     

Training-induced pressure fall in spontaneously hypertensive rats is associated with reduced angiotensinogen mRNA expression within the nucleus tractus solitarii

Knowing that exercise training reduces arterial pressure in hypertensive individuals and that pressure fall is accompanied by blockade of brain renin-angiotensin system, we sought to investigate whether training (T) affects central renin-angiotensin system. Spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto controls (WKY) were submitted to training or kept sedentary (S) for 3 months. After functional recordings, brain was removed and processed for autoradiography (brain stem sequential slices hybridized with (35)S-oligodeoxynucleotide probes for angiotensinogen [Aogen] and angiotensin II type 1 [AT(1A)] receptors). Resting arterial pressure and heart rate were higher in SHR(S) (177+/-2 mm Hg, 357+/-12 bpm versus 121+/-1 mm Hg, 320+/-9 bpm in WKY(S); P<0.05). Training was equally effective to enhance treadmill performance and to cause resting bradycardia (-10%) in both groups. Training-induced blood pressure fall (-6.3%) was observed only in SHR(T). In SHR(S) (versus WKY(S)) AT(1A) and Aogen mRNA expression were significantly increased within the NTS and area postrema (average of +67% and +41% for AT(1A) and Aogen, respectively; P<0.05) but unchanged in the gracilis nucleus. Training did not change AT(1A) expression but reduced NTS and area postrema Aogen mRNA densities specifically in SHR(T) (P<0.05 versus SHR(S), with values within the range of WKY groups). In SHRs, NTS Aogen mRNA expression was correlated with resting pressure (y=5.95x +41; r=0.55; P<0.05), with no significant correlation in the WKY group. Concurrent training-induced reductions of both Aogen mRNA expression in brain stem cardiovascular-controlling areas and mean arterial pressure only in SHRs suggest that training is as efficient as the renin-angiotensin blockers to reduce brain renin-angiotensin system overactivity and to decrease arterial pressure.     

Predictors of systolic augmentation from left ventricular preexcitation in patients with dilated cardiomyopathy and intraventricular conduction delay

BACKGROUND: VDD pacing can enhance systolic function in patients with dilated cardiomyopathy and discoordinate contraction; however, identification of patients likely to benefit is unclear. We tested predictors of systolic responsiveness on the basis of global parameters as well as directly assessed mechanical dyssynchrony. METHODS AND RESULTS: Twenty-two DCM patients with conduction delay were studied by cardiac catheterization with a dual-sensor micromanometer to measure LV and aortic pressures during sinus rhythm and LV free-wall pacing. Pacing enhanced isovolumetric (dP/dt(max)) and ejection-phase (pulse pressure, PP) systolic function by 35+/-21% and 16.4+/-11%, respectively, and these changes correlated directly (r=0.7, P=0.001). %DeltadP/dt(max) was weakly predicted by baseline QRS (r=0.6, P<0.02), more strongly by baseline dP/dt(max) (r=0.7, P=0.001), and best by bidiscriminate analysis combining baseline dP/dt(max) < or =700 mm Hg/s and QRS > or =155 ms to predict %DeltadP/dt(max) > or =25% and %DeltaPP > or =10% (P<0.0005, chi(2)), with no false-positives. Benefit could not be predicted by %DeltaQRS. To test whether basal mechanical dyssynchrony predicted responsiveness to LV pacing, circumferential strains were determined at approximately 80 sites throughout the LV by tagged MRI in 8 DCM patients and 7 additional control subjects. Strain variance at time of maximal shortening indexed dyssynchrony, averaging 28.0+/-7.1% in normal subjects versus 201.4+/-84.3% in DCM patients (P=0.001). Mechanical dyssynchrony also correlated directly with %DeltadP/dt(max) (r=0.85, P=0.008). Conclusions-These results show that although mechanical dyssynchrony is a key predictor for pacing efficacy in DCM patients with conduction delay, combining information about QRS and basal dP/dt(max) provides an excellent tool to identify maximal responders.     

Potentiation of the baroreceptor-heart rate reflex by sympathectomy in conscious rats

In both animals and humans, stimuli leading to sympathetic activation are accompanied by an impairment of the baroreceptor-heart rate reflex. To determine whether sympathetic activity normally interferes with this reflex function we examined in conscious Wistar-Kyoto (WKY) rats the effect of chemical sympathectomy by 6-hydroxydopamine on the bradycardic response to baroreceptor stimulation induced by raising blood pressure via intravenous phenylephrine boluses; control rats received vehicle. Spontaneously hypertensive rats were also studied because in these animals there is both a baroreceptor reflex impairment and a sympathetic overactivity. Baroreceptor reflex sensitivity, calculated as the ratio of the peak increase in pulse interval to the peak increase in mean arterial pressure, was 75% greater in sympathectomized WKY rats than in control WKY rats (1.28 +/- 0.15 versus 0.73 +/- 0.10 msec/mm Hg, mean +/- SEM; p less than 0.01). The sympathectomy-induced increase in sensitivity was even larger in spontaneously hypertensive rats (SHR) (1.26 +/- 0.12 versus 0.44 +/- 0.06 msec/mm Hg in sympathectomized SHR versus control SHR, +186%; p less than 0.01) so that the impaired baroreceptor reflex sensitivity observed in control SHR as compared with control WKY rats (-40%, p less than 0.01) was no longer detectable in the sympathectomized groups. To establish whether the sympathectomy-induced potentiation of the reflex was due to an increase in cardiac responsiveness to vagal stimuli, we subjected separate groups of anesthetized, vagotomized SHR and WKY rats to graded electrical stimulation of the right efferent vagus. The bradycardic effects of vagal stimulation, however, were similar in sympathectomized and control animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma adrenomedullin relation with Doppler-derived dP/dt in patients with congestive heart failure

BACKGROUND: Increased circulating adrenomedullin (AM) concentration has been reported in congestive heart failure (HF) and considered as a possible marker of cardiac dysfunction. HYPOTHESIS: The study was undertaken to assess the relationship between circulating AM concentration and left ventricular (LV) functional state, estimated by echo-Doppler techniques in patients with mild to moderate HF and different degrees of LV dysfunction. METHODS: Plasma AM, B-type natriuretic peptide (BNP), and N-terminal (NT) proBNP levels were measured in 55 patients with HF (New York Heart Association [NYHA] I n = 8, II n = 26, III n = 21) and in 20 controls; dP/dt was calculated by the Doppler tracing of the mitral regurgitation jet. RESULTS: The study was completed in 51 patients. Adrenomedullin levels were higher than in controls (19.2 +/- 1.4 vs. 13.3 +/- 0.7, p < 0.005) and elevated in proportion to NYHA functional class. B-type natriuretic peptide and NT-proBNP were 344 +/- 67 vs. 12 +/- 2 pg/ml and 2196 +/- 623 vs. 52 +/- 4 pg/ml, respectively (p < 0.0001); dP/dt was better related to AM (r = 0.582, p < 0.001) than to the other peptides. Adrenomedullin was significantly (p < 0.001) different between patients grouped according to the dP/dt cut-off predictive of event-free survival. CONCLUSIONS: The combination of depressed contractility and increased AM may provide a clue for further characterization of the severity of LV dysfunction in HF, independent of baseline LV ejection fraction.     

Noninvasive estimation of the instantaneous first derivative of left ventricular pressure using continuous-wave Doppler echocardiography

BACKGROUND. The complete continuous-wave Doppler mitral regurgitant velocity curve should allow reconstruction of the ventriculoatrial (VA) pressure gradient from mitral valve closure to opening, including left ventricular (LV) isovolumic contraction, ejection, and isovolumic relaxation. Assuming that the left atrial pressure fluctuation is relatively minor in comparison with the corresponding LV pressure changes during systole, the first derivative of the Doppler-derived VA pressure gradient curve (Doppler dP/dt) might be used to estimate the LV dP/dt curve, previously measurable only at catheterization (catheter dP/dt). METHODS AND RESULTS. This hypothesis was examined in an in vivo mitral regurgitant model during 30 hemodynamic stages in eight dogs. Contractility and relaxation were altered by inotropic stimulation and hypothermia. The Doppler mitral regurgitant velocity spectrum was recorded along with simultaneously acquired micromanometer LV and left atrial pressures. The regurgitant velocity profiles were digitized and converted to VA pressure gradient curves using the simplified Bernoulli equation. The instantaneous dP/dt of the VA pressure gradient curve was then derived. The instantaneous Doppler-derived VA pressure gradients, instantaneous Doppler dP/dt, dP/dtmax, and -dP/dtmax were compared with corresponding catheter measurements. This method of estimating dP/dtmax from the instantaneous dP/dt curve was also compared with a previously proposed Doppler method of estimating dP/dtmax using the Doppler-derived mean rate of LV pressure rise over the time period between velocities of 1 and 3 m/sec on the ascending slope of the Doppler velocity spectrum. Both instantaneous Doppler-derived VA pressure gradients (r = 0.95, p less than 0.0001) and Doppler dP/dt (r = 0.92, p less than 0.0001) correlated well with corresponding measurements by catheter during systolic contraction and isovolumic relaxation (pooled data). The Doppler dP/dtmax (1,266 +/- 701 mm Hg/sec) also correlated well (r = 0.94) with the catheter dP/dtmax (1,200 +/- 573 mm Hg/sec). There was no difference between the two methods for measurement of dP/dtmax (p = NS). Although Doppler -dP/dtmax was slightly lower than the catheter measurement (961 +/- 511 versus 1,057 +/- 540 mm Hg/sec, p less than 0.01), the correlation between measurements by Doppler and catheter was excellent (r = 0.93, p less than 0.0001). The alternative method of mean isovolumic pressure rise (896 +/- 465 mm Hg/sec) underestimated the catheter dP/dtmax (1,200 +/- 573 mm Hg/sec) significantly (on average, 25%; p less than 0.001). CONCLUSIONS. The present study demonstrated an accurate and reliable noninvasive Doppler method for estimating instantaneous LV dP/dt, dP/dtmax, and -dP/dtmax.     

Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure

OBJECTIVES: We studied the acute effects of cardiac resynchronization therapy (CRT) on functional mitral regurgitation in heart failure (HF) patients with left bundle branch block (LBBB). BACKGROUND: Both an decrease [corrected] in left ventricular (LV) closing force and mitral valve tethering have been implicated as mechanisms for functional mitral regurgitation (FMR) in dilated hearts. We hypothesized that an increase in LV closing force achieved by CRT could act to reduce FMR. METHODS: Twenty-four HF patients with LBBB and FMR were studied after implantation of a biventricular CRT system. Acute changes in FMR severity between intrinsic conduction (OFF) and CRT were quantified according to the proximal isovelocity surface area method by measuring the effective regurgitant orifice area (EROA). Results were compared with the changes in estimated maximal rate of left ventricular systolic pressure rise (LV+dP/dt(max)) and transmitral pressure gradients (TMP), both measured by Doppler echocardiography. RESULTS: Cardiac resynchronization therapy was associated with a significant reduction in FMR severity. Effective regurgitant orifice area decreased from 25 +/- 19 mm(2) (OFF) to 13 +/- 8 mm(2) (CRT). The change in EROA was directly related to the increase in LV+dP/dt(max) (r = -0.83, p < 0.0001). Compared with OFF, TMP increased more rapidly during CRT, and a higher maximal TMP was observed (OFF 73 +/- 24 mm Hg vs. CRT 85 +/- 26 mm Hg, p < 0.01). CONCLUSIONS: Functional mitral regurgitation is reduced by CRT in patients with HF and LBBB. This effect is directly related to the increased closing force (LV+dP/dt(max)). The results support the hypothesis that an increase in TMP, mediated by a rise in LV+dP/dt(max) due to more coordinated LV contraction, may facilitate effective mitral valve closure.     

Vascular remodeling and improvement of coronary reserve after hydralazine treatment in spontaneously hypertensive rats

The purpose of these studies was to evaluate cardiovascular structural and functional changes in a model of hypertension-induced myocardial hypertrophy in which vasodilator therapy decreased blood pressure to normal levels. Thus, we determined the separate contributions of hypertension and hypertrophy on myocardial and coronary vascular function and structure. Twelve-month-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) with and without 12 weeks of vasodilator antihypertensive treatment (hydralazine) were studied using an isolated perfused rat heart model. Hydralazine treatment normalized blood pressure in SHR but did not cause regression of cardiac hypertrophy (heart weight to body weight ratio of SHR + hydralazine 4.33 +/- 0.098 vs. SHR 4.66 +/- 0.091; WKY 3.21 +/- 0.092 and WKY + hydralazine 3.38 +/- 0.152; mean +/- SEM). Coronary flow reserve, elicited by adenosine vasodilation in the perfused heart, was decreased in SHR (29%) compared with WKY (105%) and WKY + hydralazine (100%) and was significantly improved in SHR + hydralazine (75%). Morphometric evaluation of perfusion-fixed coronary arteries and arterioles (30-400 microns diameter) demonstrated a significant increase in the slope of the regression line comparing the square root of medial area versus outer diameter in SHR (0.444) compared with WKY (0.335) and WKY + hydralazine (0.336, p less than 0.05). Blood vessels from SHR + hydralazine were not different from control (0.338). Cardiac oxygen consumption was decreased in SHR (10.9 +/- 0.74 mumols oxygen/min/g/60 mm Hg left ventricular pressure) compared with WKY (22.4 +/- 1.47) and WKY + hydralazine (23.4 +/- 1.90; p less than 0.01), while SHR + hydralazine was intermediate (16.0 +/- 1.60). These studies suggest that significant alterations in myocardial and coronary vascular structure and function occur in hypertension-induced cardiac hypertrophy. The coronary vasculature is responsive to blood pressure, independent of cardiac hypertrophy, although moderate coronary deficits do remain after chronic antihypertensive therapy.