Joel M. Neutel

Determinants of Elevated Pulse Pressure in Middle-Aged and Older Subjects With Uncomplicated Systolic Hypertension The Role of Proximal Aortic Diameter and the Aortic Pressure-Flow Relationship

Background—Elevated pulse pressure (PP) is associated with increased cardiovascular risk and is thought to be secondary to elastin fragmentation with secondary collagen deposition and stiffening of the aortic wall, leading to a dilated, noncompliant vasculature. Methods and Results—By use of calibrated tonometry and pulsed Doppler, arterial stiffness and pulsatile hemodynamics were assessed in 128 subjects with uncomplicated systolic hypertension (supine systolic pressure ≥140 mm Hg off medication) and 30 normotensive control subjects of comparable age and gender. Pulse-wave velocity was assessed from tonometry and body surface measurements. Characteristic impedance (Zc) was calculated from the ratio of change in carotid pressure and aortic flow in early systole. Effective aortic diameter was assessed by use of the water hammer equation. Hypertensives were heavier (P <0.001) and had higher PP (P <0.001), which was attributable primarily to higher Zc (P <0.001), especially in women. Pulse-wave velocity was higher in hypertensives (P =0.001); however, this difference was not significant after adjustment for differences in mean arterial pressure (MAP) (P >0.153), whereas increased Zc remained highly significant (P <0.001). Increased Zc in women and in hypertensive men was attributable to decreased effective aortic diameter, with no difference in wall stiffness at comparable MAP and body weight. Conclusions—Elevated PP in systolic hypertension was independent of MAP and was attributable primarily to elevated Zc and reduced effective diameter of the proximal aorta. These findings are not consistent with the hypothesis of secondary aortic degeneration, dilation, and wall stiffening but rather suggest that aortic function may play an active role in the pathophysiology of systolic hypertension.

Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial

IMPORTANCE In phase 2 studies, evolocumab, a fully human monoclonal antibody to PCSK9, reduced LDL-C levels in patients receiving statin therapy. OBJECTIVE To evaluate the efficacy and tolerability of evolocumab when used in combination with a moderate- vs high-intensity statin. DESIGN, SETTING, AND PATIENTS Phase 3, 12-week, randomized, double-blind, placebo- and ezetimibe-controlled study conducted between January and December of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries. INTERVENTIONS Patients (n = 2067) were randomized to 1 of 24 treatment groups in 2 steps. Patients were initially randomized to a daily, moderate-intensity (atorvastatin [10 mg], simvastatin [40 mg], or rosuvastatin [5 mg]) or high-intensity (atorvastatin [80 mg], rosuvastatin [40 mg]) statin. After a 4-week lipid-stabilization period, patients (n = 1899) were randomized to compare evolocumab (140 mg every 2 weeks or 420 mg monthly) with placebo (every 2 weeks or monthly) or ezetimibe (10 mg or placebo daily; atorvastatin patients only) when added to statin therapies. MAIN OUTCOMES AND MEASURES Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) level at the mean of weeks 10 and 12 and at week 12. RESULTS Evolocumab reduced LDL-C levels by 66% (95% CI, 58% to 73%) to 75% (95% CI, 65% to 84%) (every 2 weeks) and by 63% (95% CI, 54% to 71%) to 75% (95% CI, 67% to 83%) (monthly) vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups; the LDL-C reductions at week 12 were comparable. For moderate-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean of 39 to 49 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 33 to 35 mg/dL. Adverse events were reported in 36%, 40%, and 39% of evolocumab-, ezetimibe-, and placebo-treated patients, respectively. The most common adverse events in evolocumab-treated patients were back pain, arthralgia, headache, muscle spasms, and pain in extremity (all <2%). CONCLUSIONS AND RELEVANCE In this 12-week trial conducted among patients with primary hypercholesterolemia and mixed dyslipidemia, evolocumab added to moderate- or high-intensity statin therapy resulted in additional LDL-C lowering. Further studies are needed to evaluate the longer-term clinical outcomes and safety of this approach for LDL-C lowering. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01763866.

Comparative efficacy of olmesartan, losartan, valsartan, and irbesartan in the control of essential hypertension.

In a multicenter, randomized, double‐blind trial, the authors compared the antihypertensive efficacy of once‐daily treatment with the new angiotensin II type 1 receptor blocker (ARB) olmesartan (20 mg) with recommended starting doses of losartan (50 mg), valsartan (80 mg), and irbesartan (150 mg) in 588 patients with a cuff diastolic blood pressure (DBP) of ≥100 and ≥115 mm Hg and a mean daytime DBP of ≥90 mm Hg and <120 mm Hg, as measured by ambulatory blood pressure monitoring. Cuff and ambulatory blood pressures were monitored at baseline and after 8 weeks of treatment. All groups were predominantly white and approximately 62% male, and their mean age was approximately 52 years. In all groups, mean baseline DBP and systolic blood pressure (SBP) were approximately 104 and 157 mm Hg, respectively. The reduction of sitting cuff DBP with olmesartan (11.5 mm Hg), the primary efficacy variable of this study, was significantly greater than with losartan, valsartan, and irbesartan (8.2, 7.9, and 9.9 mm Hg, respectively). Reductions of cuff SBP with the four ARBs ranged from 8.4–11.3 mm Hg and were not significantly different. The reduction in mean 24‐hour DBP with olmesartan (8.5 mm Hg) was significantly greater than reductions with losartan and valsartan (6.2 and 5.6 mm Hg, respectively) and showed a trend toward significance when compared to the reduction in DBP with irbesartan (7.4 mm Hg; p=0.087). The reduction in mean 24‐hour SBP with olmesartan (12.5 mm Hg) was significantly greater than the reductions with losartan and valsartan (9.0 and 8.1 mm Hg, respectively) and equivalent to the reduction with irbesartan (11.3 mm Hg). All drugs were well tolerated. The authors conclude that olmesartan, at its starting dose, is more effective than the starting doses of the other ARBs tested in reducing cuff DBP in patients with essential hypertension.

Omapatrilat Reduces Pulse Pressure and Proximal Aortic Stiffness in Patients With Systolic Hypertension

Background— Increased pulse pressure, an indicator of conduit vessel stiffness, is a strong independent predictor of cardiovascular events in hypertensive cohorts, which suggests that reduction of conduit vessel stiffness may be desirable in hypertension. Methods and Results— We assessed changes in pulse pressure and conduit vessel stiffness in a 12-week double-blind, randomized clinical trial that compared monotherapy with the ACE inhibitor enalapril 40 mg daily (n=87) versus the vasopeptidase (dual ACE and neutral endopeptidase) inhibitor omapatrilat 80 mg daily (n=80) in patients with systolic hypertension. Patients were withdrawn from antihypertensive medications 1 to 2 weeks before enrollment, and systolic pressure was confirmed to be ≥160 mm Hg. With the use of calibrated tonometry and pulsed Doppler, pulsatile hemodynamics were assessed before randomization and at 12 weeks. Characteristic impedance (Zc), a direct measure of the stiffness of the central aorta, was calculated from the ratio of change...

Aortic Diameter, Wall Stiffness, and Wave Reflection in Systolic Hypertension

Systolic hypertension is associated with increased pulse pressure (PP) and increased risk for adverse cardiovascular outcomes. However the pathogenesis of increased PP remains controversial. One hypothesis suggests that aortic dilatation, wall stiffening and increased pulse wave velocity result from elastin fragmentation, leading to a premature reflected pressure wave that contributes to elevated PP. An alternative hypothesis suggests that increased proximal aortic stiffness and reduced aortic diameter leads to mismatch between pressure and flow, giving rise to an increased forward pressure wave and increased PP. To evaluate these two hypotheses, we measured pulsatile hemodynamics and proximal aortic diameter directly using tonometry, ultrasound imaging, and Doppler in 167 individuals with systolic hypertension. Antihypertensive medications were withdrawn for at least 1 week before study. Patients with PP above the median (75 mm Hg) had lower aortic diameter (2.94±0.36 versus 3.13±0.28 cm, P<0.001) and higher aortic wall stiffness (elastance-wall stiffness product: 16.1±0.7 versus 15.7±0.7 ln[dyne/cm], P<0.001) with no difference in augmentation index (19.9±10.4 versus 17.5±10.0%, P=0.12). Aortic diameter and wall stiffness both increased with advancing age (P<0.001). However, an inverse relation between PP and aortic diameter remained significant (P<0.001) in models that adjusted for age, sex, height, and weight and then further adjusted for aortic wall stiffness, augmentation index, and mean arterial pressure. Among individuals with systolic hypertension, increased PP is primarily attributable to increased wall stiffness and reduced aortic diameter rather than premature wave reflection.

Results of Bococizumab, A Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, from a Randomized, Placebo-Controlled, Dose-Ranging Study in Statin-Treated Subjects With Hypercholesterolemia

Bococizumab is a humanized monoclonal antibody binding proprotein convertase subtilisin/kexin type 9, which may be a potential therapeutic option for reducing low-density lipoprotein cholesterol (LDL-C) levels in patients with hypercholesterolemia. In this 24-week, multicenter, double-blind, placebo-controlled, dose-ranging study (NCT01592240), subjects with LDL-C levels≥80 mg/dl on stable statin therapy were randomized to Q14 days subcutaneous placebo or bococizumab 50, 100, or 150 mg or Q28 days subcutaneous placebo or bococizumab 200 or 300 mg. Doses of bococizumab were reduced if LDL-C levels persistently decreased to ≤25 mg/dl. The primary end point was the absolute change in LDL-C levels from baseline to week 12 after placebo or bococizumab administration. Continuation of bococizumab administration through to week 24 enabled the collection of safety data over an extended period. Of the 354 subjects randomized, 351 received treatment (placebo [n=100] or bococizumab [n=251]). The most efficacious bococizumab doses were 150 mg Q14 days and 300 mg Q28 days. Compared with placebo, bococizumab 150 mg Q14 days reduced LDL-C at week 12 by 53.4 mg/dl and bococizumab 300 mg Q28 days reduced LDL-C by 44.9 mg/dl; this was despite dose reductions in 32.5% and 34.2% of subjects at week 10 or 8, respectively. Pharmacokinetic/pharmacodynamic model-based simulation assuming no dose reductions predicted that bococizumab would lower LDL-C levels by 72.2 and 55.4 mg/dl, respectively. Adverse events were similar across placebo and bococizumab groups. Few subjects (n=7; 2%) discontinued treatment because of treatment-related adverse events. In conclusion, bococizumab significantly reduced LDL-C across all doses despite dose reductions in many subjects. Model-based simulations predicted greater LDL-C reduction in the absence of bococizumab dose reduction. The Q14 days regimen is being evaluated in phase 3 clinical trials.

Diagnosis of mild hypertension by ambulatory blood pressure monitoring.

BACKGROUND Between 20% and 30% of patients with clinically diagnosed hypertension have normal blood pressure (BP) values during automated ambulatory 24-hour BP monitoring. It has not been clear, however, whether these patients can be regarded as normotensive or whether they should be treated in the same way as confirmed hypertensive patients. METHODS AND RESULTS Ambulatory BP monitoring was performed in 88 normal control subjects and 171 hypertensive patients (office diastolic BP > or = 90 mm Hg on three visits; never treated or off treatment for more than 6 months). Hypertensive patients were classified as nonconfirmed or white coat (n = 58) if their 24-hour diastolic averages were < 85 mm Hg and at least 15 mm Hg lower than their office values. For comparisons, white coat patients were pair-matched with normal subjects by 24-hour diastolic averages and sex, and by similar age and weight; there were 40 such pairs. White coat patients were likewise pair-matched with confirmed hypertensive patients by identical office BPs (51 pairs). Participants were studied by individualized treadmill testing, Doppler echocardiography, and assays of resting plasma catecholamines, upright plasma renin and aldosterone, and lipid, glucose, and insulin concentrations. Because of the matching, compared with normal subjects, patients with white coat hypertension and normal subjects had identical 24-hour BP averages. The white coat patients exhibited slightly greater variability among individual readings (obtained each 15 minutes) throughout the day [P < .05]), but there were no differences in hemodynamic responses to exercise. Plasma norepinephrine (P < .05), renin and aldosterone (P < .01 for each), and insulin and low-density lipoprotein cholesterol levels (P < .01 for each) were higher in the white coat group, as were left ventricular septal wall (P < .05) and muscle mass (P = .07) echocardiographic measurements. When compared with the confirmed hypertensive patients, the white coat patients had higher renin (P < .01) but were otherwise similar. Within the white coat group, plasma norepinephrine correlated with total cholesterol and triglycerides (P < .05 for each), and aldosterone correlated with left ventricular mass (P < .01); there were no significant correlations within the normal control subject or confirmed hypertension groups. CONCLUSIONS Patients with white coat hypertension differ in metabolic, neuroendocrine, and cardiac findings from normal control subjects and have greater BP variability. These changes appear to be mediated by heightened activity of the sympathetic and renin-angiotensin systems. Although these characteristics could reflect an alerting reaction in the clinic due to awareness of their diagnosis, the white coat hypertensive patients also have evidence for additional, more-sustained differences from normal subjects. Thus, this condition appears to be a true variant of hypertension.

Ventilatory mechanisms of exercise intolerance in chronic heart failure

Mechanisms that have been suggested to underlie the abnormal ventilatory response to exercise in patients with chronic congestive heart failure (CHF) include high pulmonary pressures, ventilation-perfusion mismatching, early metabolic acidosis, and abnormal respiratory control. To evaluate the role that ventilation and gas exchange play in limiting exercise capacity in patients with CHF, data from 33 patients with CHF and 34 normal subjects of similar age who underwent maximal exercise testing were analyzed. Maximal oxygen uptake was higher among normal subjects (31.7 +/- 6 ml/kg/min) than among patients with CHF (17.7 +/- 4 ml/kg/min; p less than 0.001). The ventilatory equivalent for oxygen, expressed as a percentage of maximal oxygen uptake, was 25% to 35% higher among patients with CHF compared with normal subjects throughout exercise (p less than 0.01). A steeper component effect of ventilation on maximal oxygen uptake was observed among normal subjects compared with patients with CHF, which suggests that a significant portion of ventilation in CHF is wasted. Maximal oxygen uptake was inversely related to the ratio of maximal estimated ventilatory dead space to maximal tidal volume (VD/VT) in both groups (r = -0.73, p less than 0.001). Any given oxygen uptake at high levels of exercise among patients with CHF was accompanied by a higher VD/VT, lower tidal volume, and higher respiratory rate compared with normal subjects (p less than 0.01). Relative hyperventilation in patients with CHF started at the beginning of exercise and was observed both below and above the ventilatory threshold, which suggests that the excess ventilation was not directly related to earlier than normal metabolic acidosis. Thus abnormal ventilatory mechanisms contribute to exercise intolerance in CHF, and excess ventilation is associated with both a higher physiologic dead space and an abnormal breathing pattern. The high dead space is most likely due to ventilation-perfusion mismatching in the lungs, which is related to poor cardiac output, and the abnormal breathing pattern appears to be an effort to reduce the elevated work of breathing that is caused by high pulmonary pressures and poor lung compliance.

CONTRASTING CLINICAL PROPERTIES AND EXERCISE RESPONSES IN OBESE AND LEAN HYPERTENSIVE PATIENTS

OBJECTIVES We sought to test whether the differences in activity of the renin-angiotensin and sympathetic nervous systems at rest or during exercise can explain the differing cardiovascular properties and outcomes of lean and obese hypertensive patients. BACKGROUND Although lean hypertensive patients have fewer metabolic abnormalities than obese hypertensive patients, paradoxically they appear to have a poorer cardiovascular prognosis. METHODS To evaluate the heightened risks in lean hypertensive patients, this study compared metabolic, neuroendocrine and cardiovascular characteristics at rest and during a standardized treadmill protocol in obese (body mass index [BMI] = 32.5 +/- 0.3 kg/m2, n = 55) and lean (BMI = 24.3 +/- 0.2 kg/m2, n = 66) hypertensive patients. Normotensive obese (n = 21) and lean (n = 55) volunteers served as control subjects. RESULTS Compared with the lean normotensive subjects, the lean and obese hypertensive patients had greater left ventricular mass index (LVMI) values, but on multivariate analysis, LVMI correlated with plasma renin activity (p < 0.001) and plasma norepinephrine (PNE) (p < 0.01) in the lean but not the obese hypertensive patients. Arterial compliance (stroke volume/pulse pressure ratio) was reduced in the lean hypertensive patients, in whom it correlated (p = 0.033) with PNE. The PNE rose less (22%) in the obese than in the lean (55%) hypertensive patients in response to standing (p < 0.05). Likewise, during treadmill exercise, there were lesser increases in renin (65% vs. 145%, p < 0.01) and epinephrine (200% vs. 500%, p < 0.05) in the obese hypertensive patients. These changes were also less in obese patients than in lean control subjects, indicating attenuated neurohormonal responses to stress in obesity. CONCLUSIONS Compared with obese hypertensive patients, cardiovascular properties in lean hypertensive patients are more dependent on catecholamines and the renin system. The different neuroendocrine responses to dynamic stimuli in lean and obese patients also might help to explain the disparity in their cardiovascular outcomes.

Comparison of ST segment/heart rate index to standard ST criteria for analysis of exercise electrocardiogram.

The objective of our study was to compare the discriminating power of a proposed ST segment/heart rate index with that of a standard method of assessing exercise-induced ST segment depression for diagnosing coronary artery disease. We used a cross-sectional retrospective analysis of exercise test and coronary angiographic data. The study took place in a 1,200-bed Veterans Affairs Medical Center; participants were 328 male patients who had undergone both a sign and symptom-limited treadmill test and coronary angiography. The sensitivity of the ST segment/heart rate index was 54% at a cut point of 0.021 mm/(beats/min), corresponding to a specificity of 73%. The standard visual ST segment analysis had a sensitivity of 58% at this same specificity, which corresponded to an ST segment cut point of 1-mm depression relative to rest (p = NS). Similarly, for diagnosing three-vessel or left main coronary disease, no significant difference was found between the sensitivities or the two measurements at cut points of equivalent specificity. In this consecutive series of patients presenting for routine clinical testing, the ST segment/heart rate index did not improve the diagnostic accuracy of the exercise test for identifying the presence or severity of coronary artery disease relative to standard visual criteria.