Limited Impact of ß-Adrenergic Receptor Activation on Left Ventricular Diastolic Function in Rat Models of Hypertensive Heart Disease.

BACKGROUND: Hypertension is a major cause of left ventricular (LV) diastolic dysfunction. Although ß-adrenergic receptor (ß-AR) blockers are often used to manage hypertension, the impact of ß-AR activation on LV lusitropic effects and hence filling pressures in the hypertensive heart with LV diastolic dysfunction is uncertain. METHODS: Using tissue Doppler imaging and Speckle tracking software, we assessed LV function in isoflurane anesthetised spontaneously hypertensive (SHR) and Dahl salt-sensitive (DSS) rats before and after ß-AR activation [isoproterenol (ISO) administration]. RESULTS: As compared to normotensive Wistar Kyoto control rats, or DSS rats not receiving NaCl in the drinking water, SHR and DSS rats receiving NaCl in the drinking water had a reduced myocardial relaxation as indexed by lateral wall e' (early diastolic tissue velocity at the level of the mitral annulus) and an increased LV filling pressure as indexed by E/e'. However, LV ejection fraction and deformation and motion were preserved in both SHR and DSS rats. The administration of ISO resulted in a marked increase in ejection fraction and decrease in LV filling volumes in all groups, and an increase in e' in SHR, but not DSS rats. However, after ISO administration, although E/e' decreased in DSS rats in association with a reduced filling volume, E/e' in SHR remained unchanged and SHR retained greater values than Wistar Kyoto control. CONCLUSIONS: The hypertensive heart is characterized by reductions in myocardial relaxation and increases in filling pressures, but ß-AR activation may fail to improve myocardial relaxation and when this occurs, it does not reduce LV filling pressures.

Role of atrial natriuretic peptide in the dissociation between flow relations with ventricular mass and function in a community with volume-dependent hypertension.

Background: Whether differential effects of volume load on left ventricular mass (LVM) and function occur in sustained volume-dependent primary hypertension, and the impact of atrial natriuretic peptide (ANP) on these effects, is unknown. Methods: From aortic pressure, velocity and diameter measurements and echocardiography, we determined in an African community (n = 772), the impact of systemic flow-induced increases in central pulse pressure (PPc) and circulating ANP (ELISA) on LVM and indexes of function. Results: Stroke volume (SV), but not aortic flow (Q), was associated with LVM and mean wall thickness (MWT) beyond stroke work and confounders (p < 0.0001). Adjustments for SV markedly decreased the relationships between PPc and LVMI or MWT. However, neither SV, nor Q were independently associated with either myocardial s', e', or E/e' (p > 0.14) and adjustments for neither SV nor Q modified relationships between PPc and s', e' or E/e' (p < 0.005 to <0.0001). SV was nevertheless strongly and independently associated with ANP (p < 0.0001) and ANP was similarly strikingly associated with s' (p < 0.0001) and e' (p < 0.0005), but not E/e', independent of confounders and several determinants of afterload. Importantly, ANP concentrations were inversely rather than positively associated with LV diastolic dysfunction (DD) (p < 0.005) and lower rather than higher ANP concentrations contributed markedly to the ability to detect DD in those with, but not without LV hypertrophy. Conclusion: In populations with sustained volume-dependent hypertension, flow (SV)-related increases in PP have a major impact on LV structure, but not on function, an effect attributed to parallel striking beneficial actions of ANP on myocardial function.

Attenuated Relationships Between Indexes of Volume Overload and Atrial Natriuretic Peptide in Uncontrolled, Sustained Volume-Dependent Primary Hypertension.

BACKGROUND: Whether systolic blood pressure (SBP) control in sustained volume-dependent primary hypertension is associated with blunted ANP (atrial natriuretic peptide) relationships with indexes of volume load is unknown. METHODS: Systemic hemodynamics (central pressure, echocardiographic aortic velocity and diameter measurements in the outflow tract), circulating ANP concentrations (ELISA assays) and glomerular and tubular function (24-hour urine collections [n=519]) were determined in a community of African ancestry (n=772). RESULTS: As compared with those with a controlled SBP, those with an uncontrolled SBP (n=198) showed lower ANP concentrations (P<0.005) despite higher stroke volume and cardiac output (P<0.0001) and renal differences consistent with enhanced fluid retention. In those with a controlled SBP, fractional Na+ excretion (FeNa+; P<0.0005) and creatinine clearance (glomerular filtration rate; P<0.005) were inversely associated with ANP concentrations independent of confounders. Moreover, in those with a controlled SBP, stroke volume and cardiac output (P<0.0001) were independently and positively associated with ANP concentrations. In addition, in those with a controlled SBP, ANP concentrations were independently and inversely associated with systemic vascular resistance (SVR; P<0.0001) and aortic characteristic impedance (Zc; P<0.005). By contrast, in those with uncontrolled SBP, no relationships between either stroke volume (P>0.25), cardiac output (P>0.29), FeNa+ (P>0.77), or glomerular filtration rate (P>0.47) and ANP concentrations were noted. Furthermore, in those with an uncontrolled SBP, no relationships between ANP concentrations and SVR or Zc were observed (P>0.34). CONCLUSIONS: In a population where primary hypertension is strongly volume-dependent, those with an uncontrolled SBP have an attenuated relationship between ANP and both renal and hemodynamic indexes of volume overload and the vascular effects of ANP.

Increased Backward Wave Pressures Rather than Flow Explain Age-Dependent Heart Rate Effects on Central, But not Peripheral Arterial Pressure.

Through both backward (Pb) and forward (Pf) wave effects, a lower heart rate (HR) associates with increased central (PPc), beyond brachial pulse pressure (PP). However, the relative contribution to Pf of aortic flow (Q) versus re-reflection of Pb, has not been determined. Using central pressure, aortic velocity and diameter measurements in the outflow tract (echocardiography), we constructed central pressure waveforms that account for the relative contribution of Q versus re-reflection to Pf. We thus evaluated the mechanisms of HR-PPc relations in a community sample (n=824) and the impact of age thereon. Inverse HR-PPc (P<0.0001), but not HR-brachial PP (P=0.064) relations were noted. The slope of HR-PPc relation was increased in older adults (P<0.005). HR was inversely associated with ventricular filling time, ejection duration, stroke volume, and peak Pf (P<0.001 to P<0.0001). However, an increased Q and hence pressures generated by the product of aortic characteristic impedance and Q did not account for Pf effects. Age-dependent HR-PPc and Pf relations were both accounted for by enhanced Pb (P<0.0001) with an increased Pf mediated by increments in wave re-reflection (P<0.0001). The lack of impact of ejection duration on PPc was explained by an increased time to peak Pb (P<0.0001). In conclusion, increases in PPc and Pf at a decreased HR are accounted for by an enhanced Pb rather than by a prolonged ejection or filling duration and hence flow (Q). These effects at a young-to-middle age are of little clinical significance, but at an older age, are of clinical importance.

Contribution of Increases in Late Systolic Ejection Volume to the Impact of Heart Rate on Central Arterial Pulse Pressure in a Community Sample.

BACKGROUND: A lower heart rate (HR) increases left ventricular (LV) ejection volume. Whether this contributes to the adverse effects of HR on central pulse pressure (PPc) through reservoir volume effects is uncertain. METHODS: Using noninvasive central pressure, aortic velocity, and diameter measurements in the outflow tract (echocardiography), we assessed the role of LV ejection volume as a determinant of HR relations with PPc in 824 community participants. RESULTS: A lower HR was independently associated with both stroke volume (SV) (P < 0.001) and a shift in ejection volume from early (until the first systolic shoulder) to late (from first systolic shoulder to peak PP) systole (P < 0.05 to P < 0.005). Adjustments for LV end diastolic volume markedly diminished HR relations with SV and indexes of the shift in ejection volume to late systole. A lower HR was also independently associated with increases in forward traveling pressure waves (Pf) and PPc (P < 0.0001). However, adjustments for neither SV, nor indexes of a shift in ejection volume to late systole modified HR-Pf or PPc relations. This was despite relationships between indexes of a shift in ejection volume to late systole and both Pf and PPc (P < 0.0001). In contrast, adjustments for the increases in re-reflected and backward traveling wave pressures with a lower HR, eliminated HR-Pf and PPc relations. CONCLUSIONS: In contrast to current thought, a lower HR is not associated with increases in PPc through an impact of increases in late systolic ejection volume on aortic reservoir volume, but rather through increases in backward wave pressures.

Proximal aortic stiffness modifies the relationship between heart rate and backward wave and hence central arterial pulse pressure.

Aims: A lower heart rate (HR) increases central blood pressure through enhanced backward wave pressures (Pb). We aimed to determine whether these relationships are modified by increases in aortic stiffness. Methods: Using non-invasive central pressure, aortic velocity and diameter measurements in the outflow tract (echocardiography), we assessed the impact of aortic stiffness on relationships between HR and arterial wave morphology in 603 community participants < 60 years of age, 221 ≥ 60 years, and in 287 participants with arterial events [stroke and critical limb ischemia (CLI)]. Results: As compared to community participants < 60 years, those ≥ 60 years or with events had increased multivariate adjusted proximal aortic characteristic impedance (Zc) and carotid femoral pulse wave velocity (PWV) (p < 0.05 to < 0.0001). Community participants ≥ 60 years and those with events also had a greater slope of the inverse relationship between HR and Pb (p < 0.001 for comparison). While in community participants < 60 years, no interaction between indexes of aortic stiffness and HR occurred, in those ≥ 60 years (p < 0.02) and in those with arterial events (p = 0.001), beyond aortic root diameter, an interaction between Zc and HR, but not between PWV and HR independently associated with Pb. This translated into stepwise increases in the slope of HR-Pb relationships at incremental tertiles of Zc. Although HR was inversely associated with the systemic reflection coefficient in community participants ≥ 60 years (p < 0.0001), adjustments for the reflection coefficient failed to modify HR-Pb relations. Conclusion: Beyond the impact on systemic wave reflection, increases in proximal aortic stiffness enhance the adverse effects of HR on Pb and hence central BP.

Hemodynamic and Functional Correlates of Concentric vs. Eccentric LVH in a Community-Based Sample With Prevalent Volume-Dependent Hypertension.

BACKGROUND: Whether in volume-dependent primary hypertension, concentric left ventricular (LV) remodeling beyond hypertrophy (LVH) represents the impact of a pressure rather than a volume overload, is unclear. METHODS: Using central arterial pressure, and aortic velocity and diameter measurements in the outflow tract (echocardiography), we determined the factors that associate with concentric LVH or remodeling in a community of African ancestry (n = 709) with prevalent volume-dependent primary hypertension. RESULTS: Both left ventricular mass index (LVMI) and relative wall thickness (RWT) were positively and independently associated with end diastolic volume (EDV), stroke volume (SV), and peak aortic flow (Q) (P < 0.05 to <0.0001). However, neither LVMI nor RWT were positively and independently associated with systemic vascular resistance (SVR), or aortic characteristic impedance (Zc) or inversely associated with total arterial compliance (TAC). Consequently, both concentric (P < 0.0001) and eccentric (P < 0.0001) LVH were associated with similar increases in EDV, SV, and either office brachial, central arterial, or 24-hour blood pressures (BP), but neither increases in SVR or Zc nor decreases in TAC. LV RWT, but not LVMI was nevertheless independently and inversely associated with myocardial systolic function (midwall shortening and s') (P < 0.05 to <0.005) and decreases in LV systolic function were noted in concentric (P < 0.05), but not eccentric LVH. CONCLUSIONS: In volume-dependent primary hypertension, concentric LVH is determined as much by volume-dependent increases in systemic flow and an enhanced BP as eccentric LVH. Concentric remodeling nevertheless reflects decreases in systolic function beyond LVH.

Impact of stroke work on the ability of left ventricular mass to account for pressure effects on function in a community with prevalent systemic flow-dependent hypertension.

AIMS: To determine whether the confounding influence of stroke work on left ventricular mass (LVM) limits the ability of LVM to detect hypertensive LV dysfunction in systemic flow-dependent hypertension. METHODS: In a community with prevalent systemic flow-dependent hypertension (n = 709), arterial haemodynamics, LVM and LV function were determined using central arterial pressure, aortic velocity and diameter measurements in the outflow tract, and echocardiography with tissue Doppler imaging. RESULTS: In multivariate models, stroke work showed markedly stronger relations with LVM index (LVMI) than blood pressure load [central arterial SBP (SBPc), backward wave pressure (Pb), 24-h SBP] (P < 0.0001 for comparisons). In contrast, although SBPc, Pb, and 24-h SBP were inversely associated with myocardial tissue shortening (s') and lengthening (e') velocity, stroke work was not. With adjustments for stroke work, positive relationships between SBPc, Pb, or 24-h SBP and LVMI were eliminated (P = 0.20 to P = 0.89), but strong relations between BP and s', e' or E/e' (P = 0.009 to P < 0.0001) remained. In mediation analysis, stroke work fully accounted for BP effects on LVMI, but explained none of the effects of BP on LV function. Hence LVMI accounted for little of the impact of BP load on LV function. Although LVMI beyond stroke work (inappropriate LVM) improved on relations between LVMI and s', it failed to improve on relations with e' or E/e' and contributed little beyond LVMI to the impact of BP on LV function. CONCLUSION: In systemic flow-dependent hypertension, the impact of stroke work markedly limits the ability of LVM to account for adverse effects of hypertension on LV function.

Triple emergencies: Hyperosmolar hyperglycemic state, venous thromboembolism, and huge free-floating right heart thrombus successfully managed with anticoagulation.

A 57-year-old man, with type 2 diabetes mellitus, was admitted with a hyperosmolar hyperglycemic state, who developed in-hospital venous thromboembolism with huge free-floating right heart thrombus, and there is no available optimal treatment option for the huge free-floating right heart thrombus, except anticoagulation with warfarin and low molecular weight heparin with successful outcome.

Hemodynamic Determinants of Age Versus Left Ventricular Diastolic Function Relations Across the Full Adult Age Range.

The relative contribution of loading conditions at different ages across the full adult lifespan to decreases in left ventricular (LV) diastolic function is unclear. Using central arterial pressure and aortic velocity and diameter measurements in the outflow tract, we determined the contribution of systemic vascular resistance, compression wave pressures (characteristic impedance [Zc]×aortic flow [Q], [PQ×Zc]) and backward wave pressures (Pb) to LV diastolic function (echocardiography) in a community sample across the full adult lifespan (n=605). Starting from early adulthood, stepwise age-related increases in LV filling pressures (E/e') and decreases in myocardial relaxation (e') were noted (P<0.0001). Before 50 years of age, before when PQ×Zc positively correlates with age, Pb, but not systemic vascular resistance was independently associated with LV mass index (P<0.002), E/e' (P<0.002), and e' (P<0.05). Moreover, in those over 50 years of age, when PQ×Zc positively correlates with age, again Pb, but neither PQxZc nor systemic vascular resistance was independently associated with LV mass index (P<0.01), E/e' (P<0.001), and e' (P<0.001). The contribution of Pb to age-related decreases in LV diastolic function was as strong in those younger as compared with older than 50 years of age and poorly indexed by brachial BP. In conclusion, a striking age-related deterioration in LV diastolic function begins at an early adult age and Pb is the dominant hemodynamic factor that accounts for this relationship. Age-related increases in Pb in young adults contribute as much to functional abnormalities ultimately responsible for LV diastolic dysfunction in hypertension as at an older age, effects poorly indexed by brachial BP.

Insulin resistance influences the impact of hypertension on left ventricular diastolic dysfunction in a community sample.

BACKGROUND: Although obesity-associated metabolic abnormalities (insulin resistance-IR) may not play as marked a role in determining left ventricular (LV) diastolic dysfunction (DD) as hypertension, the impact of combinations of these risk factors on DD is unknown. HYPOTHESIS: We hypothesized that IR influences the impact of hypertension on DD. METHODS: In 704 randomly selected participants from a community sample with a high prevalence of hypertension (50.6%) and obesity (46.5%), we determined adiposity indices, IR from the homeostasis model (HOMA-IR) and LV diastolic function using standard echocardiographic techniques. RESULTS: HOMA-IR was independently associated with lateral wall e' and E/e' (P < 0.05 to P < 0.005) as well as a diagnosis of DD (P < 0.02). Importantly, however, an enhanced relationship between HOMA-IR and E/e' in hypertensives (n = 356, partial r = 0.15, P < 0.005) as compared to normotensives (n = 348, partial r = 0.02 P = 0.75) was noted. Consequently, as compared to normotensives, with adjustments for confounders, hypertension was independently associated with DD only in those with the highest tertile of HOMA-IR (odds ratio = 2.65, 95% confidence interval = 1.29-5.42, P < 0.01), while in those with the lowest tertile of HOMA-IR, hypertension failed to show a higher prevalence of DD (P = 0.22). CONCLUSIONS: Insulin resistance enhances the impact of hypertension on LV DD. Thus, DD is more likely to occur with the combination of hypertension and IR.

Limited contribution of left ventricular mass and remodelling to the impact of blood pressure on diastolic function in a community sample.

AIMS: Although the development of left ventricular (LV) dysfunction in hypertension has traditionally been viewed as a transition process from a phase of structural LV remodelling to dysfunction, the extent to which LV mass (LVM) and remodelling account for blood pressure (BP)-associated alterations in LV diastolic function is uncertain. In product of coefficient mediation analysis, we aimed to determine the extent to which LVM index (LVMI) or relative wall thickness (RWT) account for relations between BP and LV diastolic function. METHODS: In 709 randomly selected participants from a community sample with a high prevalence of hypertension (49.6%), we determined BP and LVMI, RWT and several indices of diastolic function from transmitral blood flow and myocardial tissue Doppler (E/A, e'/a', e' and E/e') and left atrial volume using standard echocardiographic techniques. RESULTS: With adjustments for confounders, LVMI (P < 0.001-0.0001) and RWT (P < 0.05-0.001) were independently associated with E/A, e'/a', e' and E/e'. However, in product of coefficient mediation analysis, LVM and RWT failed to account for most BP-associated changes in diastolic function. Indeed, whilst a one SD increase in DBP or SBP (13 and 22 mmHg, respectively) translated into a 0.07, 0.13 and 0.53 decrease in E/A, e'/a', e' and a 0.73 increase in E/e', respectively, in mediation analysis LVMI accounted for only 0.0005, 0.0017, 0.05 and 0.08 of the impact of a one SD effect of LVMI on E/A, e'/a', e' and E/e', respectively. Similar contributions of RWT as for LVMI to BP-associated LV diastolic functional changes were noted and the contribution of LVMI or RWT to BP-related alterations in diastolic function was similar in those participants not receiving antihypertensive therapy. CONCLUSION: Although structural LV remodelling is independently associated with changes in LV diastolic function, LVMI and RWT account for only a minor proportion of the impact of BP on diastolic function. Thus, most BP-associated decreases in LV diastolic function are likely to be a transition process independent of LV hypertrophy or concentric remodelling.

Limited contribution of insulin resistance and metabolic parameters to obesity-associated increases in ambulatory blood pressure in a black African community.

Although accounting for a striking proportion of obesity effects on blood pressure (BP) in other populations, the extent to which obesity-associated increases in BP are explained by insulin resistance and metabolic changes in populations of African ancestry is uncertain. We determined the contribution of insulin resistance and associated metabolic abnormalities to variations in office or ambulatory BP in a black African community with prevalent obesity and hypertension. In 1225 randomly selected participants of black South African ancestry (age>16years, 43.1% obese, 47.4% abdominal obesity), we assessed adiposity indexes, the homeostasis model of insulin resistance (HOMA-IR) and associated metabolic abnormalities and office or ambulatory (n â€‹= â€‹798) BP. In separate models, waist circumference (p â€‹< â€‹0.0005-<0.0001) and HOMA-IR (p â€‹< â€‹0.51-0.005), were independently associated with office, 24 â€‹h, day or night systolic (SBP) or diastolic (DBP) BP. However, whilst a one standard deviation increase in waist circumference translated into a 1.47-3.08 â€‹mm Hg increased in office, 24-h SBP or DBP, in mediation analysis HOMA-IR accounted for only 0.12-0.30 â€‹mm Hg of the impact of a one standard deviation effect of waist circumference on office, and 24-h SBP and 0.003-0.17 â€‹mm Hg of the impact of a one standard deviation effect of waist circumference on office and 24-h DBP. In conclusion, in a black African community, insulin resistance accounts for a negligible proportion of the impact of obesity on office or ambulatory BP.