Anand Prasad

Effect of Aging and Physical Activity on Left Ventricular Compliance

Background—Left ventricular compliance appears to decrease with aging, which may contribute to the high incidence of heart failure in the elderly. However, whether this change is an inevitable consequence of senescence or rather secondary to reduced physical activity is unknown. Methods and Results—Twelve healthy sedentary seniors (69.8±3 years old; 6 women, 6 men) and 12 Masters athletes (67.8±3 years old; 6 women, 6 men) underwent pulmonary artery catheterization to define Starling and left ventricular pressure-volume curves. Data were compared with those obtained in 14 young but sedentary control subjects (28.9±5 years old; 7 women, 7 men). Pulmonary capillary wedge pressures and left ventricular end-diastolic volumes by use of echocardiography were measured at baseline, during decreased cardiac filling by use of lower-body negative pressure (−15 and −30 mm Hg), and after saline infusion (15 and 30 mL/kg). Stroke volume for any given filling pressure was greater in Masters athletes compared with the age-matched sedentary subjects, whereas contractility, as assessed by preload recruitable stroke work, was similar. There was substantially decreased left ventricular compliance in healthy but sedentary seniors compared with the young control subjects, which resulted in higher cardiac pressures for a given filling volume and higher myocardial wall stress for a given strain. The pressure-volume curve for the Masters athletes was indistinguishable from that of the young, sedentary control subjects. Conclusions—A sedentary lifestyle during healthy aging is associated with decreased left ventricular compliance, leading to diminished diastolic performance. Prolonged, sustained endurance training preserves ventricular compliance with aging and may help to prevent heart failure in the elderly.

Abnormal haemodynamic response to exercise in heart failure with preserved ejection fraction

Peak oxygen uptake (VO2) is diminished in patients with heart failure with preserved ejection fraction (HFpEF) suggesting impaired cardiac reserve. To test this hypothesis, we assessed the haemodynamic response to exercise in HFpEF patients.

Echocardiographic Indices Do Not Reliably Track Changes in Left-Sided Filling Pressure in Healthy Subjects or Patients with Heart Failure with Preserved Ejection Fraction

Background— In select patient populations, Doppler echocardiographic indices may be used to estimate left-sided filling pressures. It is not known, however, whether changes in these indices track changes in left-sided filling pressures within individual healthy subjects or patients with heart failure with preserved ejection fraction (HFpEF). This knowledge is important because it would support, or refute, the serial use of these indices to estimate changes in filling pressures associated with the titration of medical therapy in patients with heart failure. Methods and Results— Forty-seven volunteers were enrolled: 11 highly screened elderly outpatients with a clear diagnosis of HFpEF, 24 healthy elderly subjects, and 12 healthy young subjects. Each patient underwent right heart catheterization with simultaneous transthoracic echo. Pulmonary capillary wedge pressure (PCWP) and key echo indices (E/e′ and E/Vp) were measured at two baselines and during 4 preload altering maneuvers: lower body negative pressure −15 mm Hg; lower body negative pressure −30 mm Hg; rapid saline infusion of 10 to 15 mL/kg; and rapid saline infusion of 20 to 30 mL/kg. A random coefficient mixed model regression of PCWP versus E/e′ and PCWP versus E/Vp was performed for (1) a composite of all data points and (2) a composite of all data points within each of the 3 groups. Linear regression analysis was performed for individual subjects. With this protocol, PCWP was manipulated from 0.8 to 28.8 mm Hg. For E/e′, the composite random effects mixed model regression was PCWP=0.58×E/e′+7.02 (P<0.001), confirming the weak but significant relationship between these 2 variables. Individual subject linear regression slopes (range, −6.76 to 11.03) and r 2 (0.00 to 0.94) were highly variable and often very different than those derived for the composite and group regressions. For E/Vp, the composite random coefficient mixed model regression was PCWP=1.95×E/Vp+7.48 (P=0.005); once again, individual subject linear regression slopes (range, −16.42 to 25.39) and r 2 (range, 0.02 to 0.94) were highly variable and often very different than those derived for the composite and group regressions. Conclusions— Within individual subjects the noninvasive indices E/e′ and E/Vp do not reliably track changes in left-sided filling pressures as these pressures vary, precluding the use of these techniques in research studies with healthy volunteers or the titration of medical therapy in patients with HFpEF.

Contemporary patterns of fractional flow reserve and intravascular ultrasound use among patients undergoing percutaneous coronary intervention in the United States: insights from the National Cardiovascular Data Registry.

To the Editor: The use of fractional flow reserve (FFR) and intravascular ultrasound (IVUS) to assess intermediate coronary stenoses (defined as 40% to 70% stenosis) has been associated with improved procedural and clinical outcomes ([1,2][1]) in patients undergoing percutaneous coronary

Characterization of Static and Dynamic Left Ventricular Diastolic Function in Patients With Heart Failure With a Preserved Ejection Fraction

Background—Congestive heart failure in the setting of a preserved left ventricular (LV) ejection fraction is increasing in prevalence among the senior population. The underlying pathophysiologic abnormalities in ventricular function and structure remain unclear for this disorder. We hypothesized that patients with heart failure with preserved ejection fraction (HFPEF) would have marked abnormalities in LV diastolic function with increased static diastolic stiffness and slowed myocardial relaxation compared with age-matched healthy controls. Methods and Results—Eleven highly screened patients (4 men, 7 women) aged 73±7 years with HFPEF were recruited to participate in this study. Thirteen sedentary healthy controls (7 men, 6 women) aged 70±4 years also were recruited. All subjects underwent pulmonary artery catheterization with measurement of cardiac output, end-diastolic volumes, and pulmonary capillary wedge pressures at baseline; cardiac unloading (lower-body negative pressure or upright tilt); and cardiac loading (rapid saline infusion). The data were used to define the Frank-Starling and LV end-diastolic pressure-volume relationships. Doppler echocardiographic data (tissue Doppler velocities, isovolumic relaxation time, propagation velocity of early mitral inflow , E/A-wave ratio) were obtained at each level of cardiac preload. Compared with healthy controls, patients with HFPEF had similar LV contractile function and static LV compliance but reduced LV chamber distensibility with elevated filling pressures and slower myocardial relaxation as assessed by tissue Doppler imaging. Conclusions—In this small, highly screened patient population with hemodynamically confirmed HFPEF, increased end-diastolic static ventricular stiffness relative to age-matched controls was not a universal finding. Nevertheless, patients with HFPEF, even when well compensated, had elevated filling pressures, reduced distensibility, and increased diastolic wall stress compared with controls. In contrast, LV relaxation as assessed by tissue Doppler variables appeared consistently impaired in patients with HFPEF.

Persistent Sympathetic Activation During Chronic Antihypertensive Therapy: A Potential Mechanism for Long Term Morbidity?

Previous studies have demonstrated that antihypertensive treatment resets baroreflex control of heart rate (HR) and increases cardiac vagal baroreflex sensitivity. However, it is uncertain whether baroreflex control of muscle sympathetic nerve activity (MSNA) also resets after treatment. We tested the hypothesis that chronic antihypertensive therapy alters baroreflex regulation of MSNA in patients with untreated moderate hypertension. Seven newly diagnosed patients with systolic blood pressure (BP) of 159±5 mm Hg (mean±SE) and diastolic BP of 103±4 mm Hg were studied before and after 1 to 2 weeks ´ and 3 months (chronic) of antihypertensive treatment with losartan–hydrochlorothiazide (Hyzaar). MSNA and hemodynamics were measured supine, during a Valsalva maneuver (VM), and at 70° head-up tilt (HUT) for 10 minutes. Data were compared with those obtained in 7 age-matched healthy controls. We found that Hyzaar lowered mean BP acutely and chronically by 20±4 and 23±3 mm Hg (both P<0.01) but did not change HR. Supine MSNA increased by 43±11% and 34±11% after acute and chronic treatment (both P<0.01). However, MSNA responses to VM and HUT did not differ after treatment compared with before treatment, indicating unchanged reflex control. These data indicate that sympathetic neural activity was augmented substantially by antihypertensive treatment with Hyzaar, consistent with an ongoing baroreflex unloading, and did not return to baseline or “reset” after 3 months of therapy. We speculate that persistent and marked sympathetic activation by the baroreflex may be a potential mechanism for hypertension that is refractory to antihypertensive therapy and may provide a target mechanism for persistent morbidity despite adequate BP control.

Advanced glycation end products and diabetic cardiovascular disease.

Advanced glycation end products (AGEs) are formed by a nonenzymatic reaction of sugar moieties (eg, glucose, fructose, glycolytic adducts) with the free amino groups on amino acid residues of proteins. A growing body of data demonstrate that AGEs are intimately involved in the pathophysiology of cardiovascular disease by stimulating inflammation, contributing to atheroma formation, and modulating vascular stiffness. The role of AGEs as potential biomarkers for disease presence and prognosis in patients with diabetes mellitus remains an active area of study. Epidemiologic and angiographic studies suggest that AGE levels may be related to the presence and extent of atherosclerosis, and may predict future outcomes in select populations. The present review summarizes the relevant evidence supporting the role of advanced glycation in promoting atherosclerosis and the epidemiologic studies demonstrating an association between AGEs and diabetic cardiovascular disease.

Differential expression of oxidation-specific epitopes and apolipoprotein(a) in progressing and ruptured human coronary and carotid atherosclerotic lesions.

The relationships between oxidation-specific epitopes (OSE) and lipoprotein (a) [Lp(a)] and progressive atherosclerosis and plaque rupture have not been determined. Coronary artery sections from sudden death victims and carotid endarterectomy specimens were immunostained for apoB-100, oxidized phospholipids (OxPL), apo(a), malondialdehyde-lysine (MDA), and MDA-related epitopes detected by antibody IK17 and macrophage markers. The presence of OxPL captured in carotid and saphenous vein graft distal protection devices was determined with LC-MS/MS. In coronary arteries, OSE and apo(a) were absent in normal coronary arteries and minimally present in early lesions. As lesions progressed, apoB and MDA epitopes did not increase, whereas macrophage, apo(a), OxPL, and IK17 epitopes increased proportionally, but they differed according to plaque type and plaque components. Apo(a) epitopes were present throughout early and late lesions, especially in macrophages and the necrotic core. IK17 and OxPL epitopes were strongest in late lesions in macrophage-rich areas, lipid pools, and the necrotic core, and they were most specifically associated with unstable and ruptured plaques. Specific OxPL were present in distal protection devices. Human atherosclerotic lesions manifest a differential expression of OSEs and apo(a) as they progress, rupture, and become clinically symptomatic. These findings provide a rationale for targeting OSE for biotheranostic applications in humans.

Effects of Heat Stress on Thermoregulatory Responses in Congestive Heart Failure Patients

Background— Clinical observations suggest that tolerance to heat stress may be impaired in patients with cardiovascular diseases, particularly those associated with impaired ventricular function and congestive heart failure (CHF). However, thermoregulatory function during a controlled heat stress challenge in patients with CHF has not been studied. Methods and Results— To test the hypothesis that thermoregulatory responses are attenuated in such patients, we assessed cutaneous vasodilation and sweat rate in patients with stable class II–III CHF and in matched healthy subjects during passive whole-body heating. Whole-body heating induced a similar increase in internal temperature (≈0.85°C) in both groups. The sweating responses in patients with CHF were not significantly different from that in control subjects. In contrast, the elevation in forearm cutaneous vascular conductance in patients with CHF was reduced by nearly 50% relative to the control subjects (3.8±0.8 versus 6.9±1.0 mL/100 mL tissue per minute per 100 mm Hg, P=0.04). Moreover, maximal cutaneous vasodilator capacity to direct local heating in patients with CHF was also significantly lower than in control subjects, suggesting that vascular remodeling may be limiting cutaneous vasodilation during hyperthermia. Conclusions— These observations suggest that patients with CHF exhibit attenuated cutaneous vasodilator responses to both whole-body and local heating, whereas sweating responses are preserved. Attenuated cutaneous vasodilation may be a potential mechanism for heat intolerance in patients with CHF.

Cardiovascular effects of 1 year of progressive endurance exercise training in patients with heart failure with preserved ejection fraction

BACKGROUND Heart failure with preserved ejection fraction (HFpEF) is a disease of the elderly with cardiovascular stiffening and reduced exercise capacity. Exercise training appears to improve exercise capacity and cardiovascular function in heart failure with reduced ejection fraction. However, it is unclear whether exercise training could improve cardiovascular stiffness, exercise capacity, and ventricular-arterial coupling in HFpEF. METHODS Eleven HFpEF patients and 13 healthy controls underwent invasive measurements with right heart catheterization to define Starling and left ventricular (LV) pressure-volume curves; secondary functional outcomes included Doppler echocardiography, arterial stiffness, cardiopulmonary exercise testing with cardiac output measurement, and ventricular-arterial coupling assessed by the dynamic Starling mechanism. Seven of 11 HFpEF patients (74.9 ± 6 years; 3 men/4 women) completed 1 year of endurance training followed by repeat measurements. Pulmonary capillary wedge pressures and LV end-diastolic volumes were measured at baseline during decreased and increased cardiac filling. LV compliance was assessed by the slope of the pressure-volume curve. Beat-to-beat LV end-diastolic pressure (estimated from pulmonary arterial diastolic pressure) and stroke volume index were obtained, and spectral transfer function analysis was used to assess the dynamic Starling mechanism. RESULTS Before training, HFpEF patients had reduced exercise capacity, distensibility and dynamic Starling mechanism but similar LV compliance and end-diastolic volumes compared to controls albeit with elevated filling pressure and increased wall stress. One year of training had little effect on LV compliance and volumes, arterial stiffness, exercise capacity or ventricular-arterial coupling. CONCLUSION Contrary to our hypothesis, 1 year of endurance training failed to impart favorable effects on cardiovascular stiffness or function in HFpEF.