Influence of altitude on hypertension phenotypes and responses to antihypertensive therapy: Review of the literature and design of the INTERVENCION trial.

Systemic arterial hypertension constitutes the leading cause of mortality worldwide, and affects people living at different altitudes above sea level (AASL). AASL has a major impact on cardiovascular function and various biologic pathways that regulate blood pressure-related phenotypes, but whether it affects the clinical response to antihypertensive therapy is unknown. The hemodynamic adaptations observed among lowlanders acutely exposed to high altitude (HA) is distinct from those observed among HA dwellers. However, the phenotypic patterns of hypertension and the response to standard antihypertensive agents among adults chronically exposed to different AASL are poorly understood. The authors describe the protocol for the INTERVENCION trial, a randomized clinical trial designed to assess the effects of three first-line antihypertensive monotherapies (a thiazide diuretic, an angiotensin receptor blocker, and a calcium channel blocker) on peripheral and central blood pressure, in-office blood pressure, and ambulatory blood pressure hemodynamics of hypertensive patients living at different AASL (low altitude, intermediate altitude, and high altitude). The primary end point is the reduction in 24-hour brachial systolic blood pressure. The INTERVENCION trial will provide the first clinical trial data regarding the influence of AASL on the response to antihypertensive monotherapy, as well as the hemodynamic characteristics of arterial hypertension at different AASL.

Evaluation of ventricular-arterial coupling by impedance cardiography in healthy volunteers.

BACKGROUND: The interplay between cardiac function and the arterial system is currently defined as ventricular-arterial coupling (VAC) and it is an expression of global cardiovascular efficiency. VAC involves a variety of complex interactions between the heart and the vasculature. A basic index of VAC is the ratio of effective arterial elastance (Ea)/ end-systolic elastance (Ees). While this is often done with echocardiography, obtaining Ea/Ees using impedance cardiography is feasible, although this possibility has not been explored so far. OBJECTIVE: The aim of this study was to compare the Ea/Ees values obtained using echocardiography and impedance cardiography. APPROACH: Two independent operators estimated Ea/Ees in 91 (41 ± 14 years old, women 51%) untreated apparently healthy individuals using (1) Doppler echocardiography with the single-beat method developed by Chen et al (2001 J. Am. Coll. Cardiol. 38 2028-34); and (2) data provided by impedance cardiography. The differences between Ea/Ees values were compared and correlation between both methods was estimated. MAIN RESULTS: Although Ea and Ees values calculated by impedance cardiography were lower than those estimated by echocardiography (-0.201 ± 0.457 mmHg ml-1 and -0.193 ± 0.413 mmHg ml-1), Ea/Ees ratio values were similar. Thus, there was no significant difference between the mean values of Ea/Ees estimated by impedance cardiography or echocardiography (Ea/Ees impedance cardiography - Ea/Ees echocardiography = -0.015 ± 0.096, p  = 0.150). Ea/Ees values calculated by both methods were highly correlated (r = 0.85, p  < 0.001), as well as the pre-ejection and left ventricular ejection time (r = 0.83 and r = 0.91, respectively). SIGNIFICANCE: In healthy individuals, estimation of Ea/Ees by impedance cardiography yielded similar values to those obtained using echocardiography.

Hemodynamic Patterns Identified by Impedance Cardiography Predict Mortality in the General Population: The PREVENCION Study.

Background Blood pressure is determined by the interactions between the heart and arterial properties, and subjects with identical blood pressure may have substantially different hemodynamic determinants. Whether arterial hemodynamic indices quantified by impedance cardiography ( ICG ), a simple operator-independent office procedure, independently predict all-cause mortality in adults from the general population, and specifically among those who do not meet criteria for American College of Cardiology/American Heart Association stage 2 hypertension, is currently unknown. Methods and Results We studied 1639 adults aged 18 to 80 years from the general population. We used ICG to measure hemodynamic parameters and metrics of cardiac function. We assessed the relationship between hemodynamic parameters measured at baseline and all-cause mortality over a mean follow-up of 10.9 years. Several ICG parameters predicted death. The strongest predictors were total arterial compliance index (standardized hazard ratio=0.38; 95% confidence interval=0.31-0.46; P<0.0001) and indices of cardiac contractility: velocity index (standardized hazard ratio=0.45; 95% confidence interval=0.37-0.55; P<0.0001) and acceleration index (standardized hazard ratio=0.44; 95% confidence interval=0.35-0.55; P<0.0001). These remained independently predictive of death after adjustment for multiple confounders, as well as systolic and diastolic blood pressure. Among subjects without stage 2 hypertension (n=1563), indices of cardiac contractility were independently predictive of death and identified a subpopulation (25% of non-stage-2 hypertensives) that demonstrated a high 10-year mortality risk, equivalent to that of stage 2 hypertensives. Conclusions Hemodynamic patterns identified by ICG independently predict mortality in the general population. The predictive value of ICG applies even in the absence of American College of Cardiology/American Heart Association stage 2 hypertension and identifies higher-risk individuals who are in earlier stages of the hypertension continuum.

Carotid Artery Wall Thickness in Obese and Nonobese Adults With Obstructive Sleep Apnea Before and Following Positive Airway Pressure Treatment.

Study objectives: Debate persists as to whether obstructive sleep apnea (OSA) is an independent risk factor for atherosclerosis. The purpose of this study was to compare carotid intima-media thickness (IMT), an early sign of atherosclerosis, in obese and nonobese adults with OSA before and following positive airway pressure (PAP) treatment. Methods: A total of 206 adults newly diagnosed with OSA with an apnea-hypopnea index (AHI) of 15-75 events/hour and 53 controls with AHI <10 were studied. Waist circumference was used to classify participants as obese and nonobese. Bilateral common carotid artery B-mode ultrasound was performed at baseline to assess IMT, arterial diameter, arterial-wall mass, and circumferential wall stress. Measurements were repeated in 118 participants with OSA who completed a 4-month PAP treatment and had an average daily use over that period of ≥4 hours/day. Results: No significant differences in carotid IMT, diameter, or arterial-wall mass were present at baseline between participants with OSA and controls stratified by waist circumference, after adjusting for other cardiovascular risk factors. In participants with OSA, who had adequate PAP adherence over the 4-month treatment, carotid artery diameter significantly increased (mean change [95% confidence interval] = 0.13 [0.06, 0.20] mm; p = .0004), but no significant changes in carotid IMT, arterial-wall mass, and circumferential stress were observed in obese and nonobese participants. Conclusions: Regardless of obesity status, carotid IMT is not increased in adults with moderate to severe OSA versus controls and does not change following 4 months of PAP treatment.

Dislipidemia aterogénica en Latino América: prevalencia, causas y tratamiento / Atherogenic dislipidemia in Latin America: prevalence, causes and treatment

En las guías clínicas actuales, la dislipidemia aterogénica (DA) es una entidad escasamente atendida. Debido a las frecuentes alteraciones en los lípidos asociados a la DA en Latino América (LA), se organizó un grupo de expertos que se ha denominado Academia Latino Americana para el estudio de los Lípidos (ALALIP) para generar un documento con análisis de su prevalencia y ofrecer recomendaciones prácticas. Se utilizó la metodología Delphi modificada, con revisión comprensiva de la literatura con énfasis en aquellas publicaciones con implicaciones para LA. Subsecuentemente, se desarrollaron preguntas claves para ser discutidas. En LA no existe un estudio global sobre los factores de riesgo que representan a la totalidad de la población. El análisis sistemático de las encuestas nacionales de salud y de los estudios sistemáticos de cohorte muestran consistentemente una alta prevalencia de las anormalidades lipídicas que definen la DA. La concentración baja del colesterol unido a las lipoproteínas de alta densidad (C-HDL) varía entre 34,1% a 53,3% y la de triglicéridos (TG) elevados del 25,5% al 31,2%, con mayor prevalencia entre los hombres. Múltiples causas se han reconocidos, como alta ingesta de alimentos de mayor densidad calórica, contenido de colesterol, grasas trans, sedentarismo y cambios epigenéticos. La DA bien puede ser tratada con los cambios terapéuticos del estilo de vida (CTEV) con incremento en la actividad física, ejercicio regular y dieta baja en carbohidratos y alta en ácidos grasos poliinsaturados, tales como los ácidos grasos omega-3 como intervención primaria. De ser necesario, esta estrategia sera suplementada con terapia farmacológica como la monoterapia con estatinas o la combinación de fibratos/ácidos grasos omega-3. Las anormalidades lipídicas que definen la DA tienen una elevada prevalencia en LA; su interacción con un estilo de vida no saludable, herencia y cambios epigenéticos están ligados a sus posibles causas. La DA es una causa importante de riesgo cardiovascular residual (RCVR) que debe ser diagnosticada y tratada. Es importante y necesario diseñar un estudio global de factores de riesgo en LA para conocer la real prevalencia de la DA.

In the current clinical guidelines, atherogenic dyslipidemia (AD) is a poorly recognized entity. Due to the frequent lipid alterations associated with AD in Latin America (LA), we organized a group of experts named Latin American Academy for the study of Lipids (ALALIP), to generate a document for analyzing its prevalence and to offer practical recommendations. Using the Delphi methodology, we conducted a comprehensive literature review, with emphasis on those publications with implications for LA. Subsequently we developed key questions to be discussed. In LA there is no a global study on risk factors that represent the entire population. The systematic analysis of national health surveys and regional cohort studies showed a consistent high prevalence of the lipid abnormalities that define AD. Low high density lipoprotein cholesterol (HDL-C) ranges from 34.1% to 53.3% and elevated triglycerides (TG) from 25.5% to 31.2%, more prevalent in men. There are multiple causes: high consumption of foods with a high caloric density, cholesterol and trans fats, sedentary lifestyle and epigenetic changes. AD must be well treated with therapeutic changes in lifestyle with increased in physical activities, regular exercise and a diet with a low proportion of carbohydrates y rich in poliunsatured fatty acid, such as omega-3 fatty acid as primary intervention. If needed, this strategie must be supplemented with pharmacological therapies such as monotherapy with statins or a combination of fibrates plus omega-3.fatty acid. Lipid abnormalities that define AD have a high prevalence in LA; the interaction between non-healthy lifestyle, inheritance and epigenetic changes, possibly are its cause. AD is an important cause of cardiovascular residual risk (CVRR), that must be diagnosed and treated. It is important and neccesary to design a global study of risk factors in LA to know the true prevalence of AD.

Atherogenic Dyslipidemia in Latin America: Prevalence, causes and treatment: Expert's position paper made by The Latin American Academy for the Study of Lipids (ALALIP) Endorsed by the Inter-American Society of Cardiology (IASC), the South American Society of Cardiology (SSC), the Pan-American College of Endothelium (PACE), and the International Atherosclerosis Society (IAS).

This is an executive summary made by a group of experts named Latin American Academy for the study of Lipids (ALALIP). In the current clinical guidelines, atherogenic dyslipidemia (AD) is a poorly recognized entity. Due to the frequent lipid alterations associated with AD in Latin America (LA), we organized a group of experts named (ALALIP) to generate a document in order to analyze their prevalence and to offer practical recommendations. METHODOLOGY: using the Delphi methodology, we conducted a comprehensive literature review with emphasis on those publications related to LA. Subsequently, we developed key questions for discussion. As a convention, those recommendations that had a 100% of acceptance were considered unanimous, those with >80% were consensual, and those with <80% were in disagreement. RESULTS: a systematic analysis of national health surveys and regional cohort studies showed a consistently high prevalence of the lipid abnormalities that define AD: low levels of high-density lipoprotein cholesterol (HDL-C) range from 34.1% to 53.3% and elevated triglycerides (TG) range from 25.5% to 31.2%. These abnormalities could be related to high consumption of food with a high caloric density, cholesterol and trans fats, a sedentary lifestyle and perhaps epigenetic changes CONCLUSIONS: lipid abnormalities that define AD have a high prevalence in LA. The interaction between an unfavorable lifestyle, inheritance and epigenetic changes is probably their cause. It is important to design a global study of risk factors in LA to know its true prevalence in the region, its consequences and to derive from its treatment strategies.

Isosorbide Dinitrate, With or Without Hydralazine, Does Not Reduce Wave Reflections, Left Ventricular Hypertrophy, or Myocardial Fibrosis in Patients With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Wave reflections, which are increased in patients with heart failure with preserved ejection fraction, impair diastolic function and promote pathologic myocardial remodeling. Organic nitrates reduce wave reflections acutely, but whether this is sustained chronically or affected by hydralazine coadministration is unknown. METHODS AND RESULTS: We randomized 44 patients with heart failure with preserved ejection fraction in a double-blinded fashion to isosorbide dinitrate (ISDN; n=13), ISDN+hydralazine (ISDN+hydral; n=15), or placebo (n=16) for 6 months. The primary end point was the change in reflection magnitude (RM; assessed with arterial tonometry and Doppler echocardiography). Secondary end points included change in left ventricular mass and fibrosis, measured with cardiac magnetic resonance imaging, and the 6-minute walk distance. ISDN reduced aortic characteristic impedance (mean baseline=0.15 [95% CI, 0.14-0.17], 3 months=0.11 [95% CI, 0.10-0.13], 6 months=0.10 [95% CI, 0.08-0.12] mm Hg/mL per second; P=0.003) and forward wave amplitude (Pf, mean baseline=54.8 [95% CI, 47.6-62.0], 3 months=42.2 [95% CI, 33.2-51.3]; 6 months=37.0 [95% CI, 27.2-46.8] mm Hg, P=0.04), but had no effect on RM (P=0.64), left ventricular mass (P=0.33), or fibrosis (P=0.63). ISDN+hydral increased RM (mean baseline=0.39 [95% CI, 0.35-0.43]; 3 months=0.31 [95% CI, 0.25-0.36]; 6 months=0.44 [95% CI, 0.37-0.51], P=0.03), reduced 6-minute walk distance (mean baseline=343.3 [95% CI, 319.2-367.4]; 6 months=277.0 [95% CI, 242.7-311.4] meters, P=0.022), and increased native myocardial T1 (mean baseline=1016.2 [95% CI, 1002.7-1029.7]; 6 months=1054.5 [95% CI, 1036.5-1072.3], P=0.021). A high proportion of patients experienced adverse events with active therapy (ISDN=61.5%, ISDN+hydral=60.0%; placebo=12.5%; P=0.007). CONCLUSIONS: ISDN, with or without hydralazine, does not exert beneficial effects on RM, left ventricular remodeling, or submaximal exercise and is poorly tolerated. ISDN+hydral appears to have deleterious effects on RM, myocardial remodeling, and submaximal exercise. Our findings do not support the routine use of these vasodilators in patients with heart failure with preserved ejection fraction. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT01516346.

Pharmacokinetics and Pharmacodynamics of Inorganic Nitrate in Heart Failure With Preserved Ejection Fraction.

RATIONALE: Nitrate-rich beetroot juice has been shown to improve exercise capacity in heart failure with preserved ejection fraction, but studies using pharmacological preparations of inorganic nitrate are lacking. OBJECTIVES: To determine (1) the dose-response effect of potassium nitrate (KNO3) on exercise capacity; (2) the population-specific pharmacokinetic and safety profile of KNO3 in heart failure with preserved ejection fraction. METHODS AND RESULTS: We randomized 12 subjects with heart failure with preserved ejection fraction to oral KNO3 (n=9) or potassium chloride (n=3). Subjects received 6 mmol twice daily during week 1, followed by 6 mmol thrice daily during week 2. Supine cycle ergometry was performed at baseline (visit 1) and after each week (visits 2 and 3). Quality of life was assessed with the Kansas City Cardiomyopathy Questionnaire. The primary efficacy outcome, peak O2-uptake, did not significantly improve (P=0.13). Exploratory outcomes included exercise duration and quality of life. Exercise duration increased significantly with KNO3 (visit 1: 9.87, 95% confidence interval [CI] 9.31-10.43 minutes; visit 2: 10.73, 95% CI 10.13-11.33 minute; visit 3: 11.61, 95% CI 11.05-12.17 minutes; P=0.002). Improvements in the Kansas City Cardiomyopathy Questionnaire total symptom (visit 1: 58.0, 95% CI 52.5-63.5; visit 2: 66.8, 95% CI 61.3-72.3; visit 3: 70.8, 95% CI 65.3-76.3; P=0.016) and functional status scores (visit 1: 62.2, 95% CI 58.5-66.0; visit 2: 68.6, 95% CI 64.9-72.3; visit 3: 71.1, 95% CI 67.3-74.8; P=0.01) were seen after KNO3. Pronounced elevations in trough levels of nitric oxide metabolites occurred with KNO3 (visit 2: 199.5, 95% CI 98.7-300.2 µmol/L; visit 3: 471.8, 95% CI 377.8-565.8 µmol/L) versus baseline (visit 1: 38.0, 95% CI 0.00-132.0 µmol/L; P<0.001). KNO3 did not lead to clinically significant hypotension or methemoglobinemia. After 6 mmol of KNO3, systolic blood pressure was reduced by a maximum of 17.9 (95% CI -28.3 to -7.6) mm Hg 3.75 hours later. Peak nitric oxide metabolites concentrations were 259.3 (95% CI 176.2-342.4) µmol/L 3.5 hours after ingestion, and the median half-life was 73.0 (interquartile range 33.4-232.0) minutes. CONCLUSIONS: KNO3 is potentially well tolerated and improves exercise duration and quality of life in heart failure with preserved ejection fraction. This study reinforces the efficacy of KNO3 and suggests that larger randomized trials are warranted. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02256345.

Dislipidemia aterogénica en latino américa: prevalencia, causas y tratamiento / Atherogenic dyslipidemia in Latin America: prevalence, causes and treatment

En las guías clínicas actuales, la dislipidemia aterogénica (DA) es una entidad no muy atendida. Debido a las frecuentes alteraciones en los lípidos asociados a la DA en Latino América (LA). Métodos: organizamos un grupo de expertos denominado Academia Latino Americana para el estudio de los Lípidos (ALALIP) para así generar un documento con análisis de su prevalencia y recomendaciones terapéuticas prácticas. Se utilizó la metodología Delphi modificada, con una revisión integral de la literatura y énfasis en las publicaciones con implicaciones para LA. Subsecuentemente, desarrollamos preguntas claves para ser discutidas. Resultados: En Latinoamérica (LA) no existe un estudio global sobre los factores de riesgo que representan a la totalidad de la población. El análisis sistemático de las encuestas nacionales de salud y de los estudios sistemáticos de cohorte muestran consistentemente una alta prevalencia de las anormalidades lipídicas que definen la DA. La concentración baja del colesterol unido a las lipoproteínas de alta densidad (C-HDL) varía entre 34,1% a 53,3% y la de triglicéridos (TG) elevados del 25,5% al 31,2%, con mayor prevalencia entre los hombres. La DA bien puede ser tratada con los cambios del estilo de vida (CTEV) como ncremento en laactividad física, dieta baja en carbohidratos y alta en ácidos grasos poliinsaturados, tales como los ácidos grasos omega-3 como intervención primaria. De ser necesario, esta estrategia sera suplementada con terapia farmacológica como la monoterapia con estatinas o la combinación de fibratos/ácidos grasos omega-3. Conclusiones: Las anormalidades lipídicas que definen la DA tienen una elevada prevalencia en LA; su interacción con un estilo de vida no saludable, herencia y cambios epigenéticos están ligados a sus posibles causas. La DA es una causa importante de riesgo cardiovascular residual (RCVR) que debe ser diagnosticada y tratada. Es importante y necesario diseñar un estudio global de factores de riesgo en LA para conocer la real prevalencia de la DA(AU)

In the current clinical guidelines, atherogenic Med Interna (Caracas) 2017; 33 (3): 121 - 139 Dislipidemia Aterogénica en Latino América: Prevalencia, causas y tratamiento Carlos I. Ponte-N, Jesús E. Isea-Pérez, Alberto J. Lorenzatti, Patricio López-Jaramillo, Fernando Stuardo Wyss-Q, Xavier Pintó, Fernando Lanas, Josefina Medina, Livia T. Machado-H, Mónica Acevedo, Paola Varleta Alfonso Bryce, Carlos Carrera, Carlos Ernesto Peñaherrera, José Ramón Gómez-M, Alfredo Lozada, Alonso Merchan-V, Daniel Piskorz, Enrique Morales, María Paniagua, Félix Medina-Palomino, Raúl Alejandro Villar-M, Leonardo Cobos, Enrique Gómez-Álvares, Rodrigo Alonso, Juan Colan, Julio Chirinos, Jofre Lara, Vladimir Ullauri, Ildefonso Arocha Documento de la posición de expertos de la Academia Latino Americana para el estudio de los Lípidos (ALALIP) y avalado por la Sociedad Interamericana de Cardiología (SIAC), Sociedad Sur Americana de Cardiología (SSC), el Colegio Panamericano de Endotelio (CPAE) y la Sociedad Internacional de Aterosclerosis (IAS). Publicado en conjunto con las Revistas de la Sociedad Venezolana de Medicina Interna y de la Sociedad Venezolana de ndocrinología y Metabolismo. dyslipidemia (AD) is a poorly recognized entity. Due to the frequent lipid alterations associated with AD in Latin America (LA), we organized a group of experts named Latin American Academy for the study of Lipids (ALALIP), to generate a document to analize it´s prevalence and to offer practical recommendations. Methodology: Using the Delphi methodology, we conducted a comprehensive literature review, with emphasis on those publications with implications for LA. Subsequently we developed key questions to be discussed. Results: In LA There is no a global study on risk factors that represent the entire population. The systematic analysis of national health surveys and regional cohort studies showed a consistent high prevalence of the lipid abnormalities that define AD. Low high density lipoprotein cholesterol (HDL-C) ranges from 34.1% to 53.3% and elevated triglycerides (TG) from 25.5% to 31.2% more prevalent in men. There are multiple causes: high consumption of foods with a high caloric density, cholesterol and trans fats, sedentary lifestyle and epigenetic changes. AD must be well treated with therapeutic changes in lifestyle with increase in physical activities, regular exercise and a diet with a low proportion of carbohydrates and rich in poliunsatured fatty acid, such as omega-3 fatty acids as primary intervention. If needed, this strategy must be supplemented with pharmacological therapies such as monotherapy with statins or a combination of fibrates plus omega-3. fatty acid. conclusions: Lipid abnormalities that define AD have a high prevalence in LA; the interaction between non-healthy lifestyle, inheritance and epigenetic changes, possibly are the cause. AD is an important cause of cardiovascular residual risk (CVRR), that must be diagnosed and treated It is important and necesary to design a global study of risk factors in LA to know the true prevalence of AD(AU)

Heart Failure, Left Ventricular Remodeling, and Circulating Nitric Oxide Metabolites.

BACKGROUND: Stable plasma nitric oxide (NO) metabolites (NOM), composed predominantly of nitrate and nitrite, are attractive biomarkers of NO bioavailability. NOM levels integrate the influence of NO-synthase-derived NO production/metabolism, dietary intake of inorganic nitrate/nitrite, and clearance of NOM. Furthermore, nitrate and nitrite, the most abundant NOM, can be reduced to NO via the nitrate-nitrite-NO pathway. METHODS AND RESULTS: We compared serum NOM among subjects without heart failure (n=126), subjects with heart failure and preserved ejection fraction (HFpEF; n=43), and subjects with heart failure and reduced ejection fraction (HFrEF; n=32). LV mass and extracellular volume fraction were measured with cardiac MRI. Plasma NOM levels were measured after reduction to NO via reaction with vanadium (III)/hydrochloric acid. Subjects with HFpEF demonstrated significantly lower unadjusted levels of NOM (8.0 µmol/L; 95% CI 6.2-10.4 µmol/L; ANOVA P=0.013) than subjects without HF (12.0 µmol/L; 95% CI 10.4-13.9 µmol/L) or those with HFrEF (13.5 µmol/L; 95% CI 9.7-18.9 µmol/L). There were no significant differences in NOM between subjects with HFrEF and subjects without HF. In a multivariable model that adjusted for age, sex, race, diabetes mellitus, body mass index, current smoking, systolic blood pressure, and glomerular filtration rate, HFpEF remained a predictor of lower NOM (ß=-0.43; P=0.013). NOM did not correlate with LV mass, or LV diffuse fibrosis. CONCLUSIONS: HFpEF, but not HFrEF, is associated with reduced plasma NOM, suggesting greater endothelial dysfunction, enhanced clearance, or deficient dietary ingestion of inorganic nitrate. Our findings may underlie the salutary effects of inorganic nitrate supplementation demonstrated in recent clinical trials in HFpEF.

Aging is Associated With an Earlier Arrival of Reflected Waves Without a Distal Shift in Reflection Sites.

BACKGROUND: Despite pronounced increases in central pulse wave velocity (PWV) with aging, reflected wave transit time (RWTT), traditionally defined as the timing of the inflection point (TINF) in the central pressure waveform, does not appreciably decrease, leading to the controversial proposition of a "distal-shift" of reflection sites. TINF, however, is exceptionally prone to measurement error and is also affected by ejection pattern and not only by wave reflection. We assessed whether RWTT, assessed by advanced pressure-flow analysis, demonstrates the expected decline with aging. METHODS AND RESULTS: We studied a sample of unselected adults without cardiovascular disease (n=48; median age 48 years) and a clinical population of older adults with suspected/established cardiovascular disease (n=164; 61 years). We measured central pressure and flow with carotid tonometry and phase-contrast MRI, respectively. We assessed RWTT using wave-separation analysis (RWTTWSA) and partially distributed tube-load (TL) modeling (RWTTTL). Consistent with previous reports, TINF did not appreciably decrease with age despite pronounced increases in PWV in both populations. However, aging was associated with pronounced decreases in RWTTWSA (general population -15.0 ms/decade, P<0.001; clinical population -9.07 ms/decade, P=0.003) and RWTTTL (general -15.8 ms/decade, P<0.001; clinical -11.8 ms/decade, P<0.001). There was no evidence of an increased effective reflecting distance by either method. TINF was shown to reliably represent RWTT only under highly unrealistic assumptions about input impedance. CONCLUSIONS: RWTT declines with age in parallel with increased PWV, with earlier effects of wave reflections and without a distal shift in reflecting sites. These findings have important implications for our understanding of the role of wave reflections with aging.

Misinterpretation of the Determinants of Elevated Forward Wave Amplitude Inflates the Role of the Proximal Aorta.

BACKGROUND: The hemodynamic basis for increased pulse pressure (PP) with aging remains controversial. The classic paradigm attributes a predominant role to increased pulse wave velocity (PWV) and premature wave reflections (WRs). A controversial new paradigm proposes increased forward pressure wave amplitude (FWA), attributed to proximal aortic characteristic impedance (Zc), as the predominant factor, with minor contributions from WRs. Based on theoretical considerations, we hypothesized that (rectified) WRs drive the increase in FWA, and that the forward pressure wave does not depend solely on the interaction between flow and Zc (QZc product). METHODS AND RESULTS: We performed 3 substudies: (1) open-chest anesthetized dog experiments (n=5); (2) asymmetric T-tube model-based study; and (3) human study in a diverse clinical population (n=193). Animal experiments demonstrated that FWA corresponds to peak QZc only when WRs are minimal. As WRs increased, FWA was systematically greater than QZc and peaked well after peak flow, analogous to late-systolic peaking of pressure attributable to WRs. T-tube modeling confirmed that increased/premature WRs resulted in increased FWA. Magnitude and timing of WRs explained 80.8% and 74.3% of the variability in the difference between FWA and peak QZc in dog and human substudies, respectively. CONCLUSIONS: Only in cases of minimal reflections does FWA primarily reveal the interaction between peak aortic flow and proximal aortic diameter/stiffness. FWA is strongly dependent on rectified reflections. If interpreted out of context with the hemodynamic principles of its derivation, the FWA paradigm inappropriately amplifies the role of the proximal aorta in elevation of FWA and PP.

Clinical Use of Pulse Wave Analysis: Proceedings From a Symposium Sponsored by North American Artery.

The use of pulse wave analysis may guide the provider in making choices about blood pressure treatment in prehypertensive or hypertensive patients. However, there is little clinical guidance on how to interpret and use pulse wave analysis data in the management of these patients. A panel of clinical researchers and clinicians who study and clinically use pulse wave analysis was assembled to discuss strategies for using pulse wave analysis in the clinical encounter. This manuscript presents an approach to the clinical application of pulse waveform analysis, how to interpret central pressure waveforms, and how to use existing knowledge about the pharmacodynamic effect of antihypertensive drug classes in combination with brachial and central pressure profiles in clinical practice. The discussion was supplemented by case-based examples provided by panel members, which the authors hope will provoke discussion on how to understand and incorporate pulse wave analysis into clinical practice.

Depressive symptoms and carotid intima-media thickness in South American Hispanics: results from the PREVENCION study.

This study aimed to: (1) examine the relationship between depressive symptoms and subclinical atherosclerosis, measured by carotid intima-media thickness (IMT); and, (2) Determine the moderating effect of gender in this relationship among South American Hispanics. We studied 496 adults enrolled in the population-based PREVENCION study. Carotid IMT was measured with high-resolution ultrasonography. Depressive symptoms were assessed using the Hospital Anxiety and Depression Scale. Mean carotid IMT was 0.66 mm. (SD = 0.17) and mean depression score was 5.6 (SD = 3.5). Depressive symptoms were not associated with carotid IMT (ß = 0.04, p = 0.222) in multivariate analyses. A significant moderating effect of gender was found (ß for interaction = 0.10, p = 0.030), resulting from a significant association between depressive symptoms and carotid IMT in men but not women. Depressive symptoms were associated with subclinical atherosclerosis in South American Hispanic men but not women after controlling for demographic characteristics and traditional cardiovascular risk factors.

Prospective risk factors for increased central augmentation index in men and women.

BACKGROUND: Arterial wave reflections are important determinants of central pressure pulsatility and left ventricular afterload. The augmentation index (AIx) is the most widely used surrogate of arterial wave reflections. Despite multiple cross-sectional studies assessing the correlates of AIx, little prospective data exist regarding changes in AIx over time. We aimed to assess the predictors of changes in AIx over time in adults from the general population. METHODS: We performed radial arterial tonometry assessments a median of 3.18 ± 0.4 years apart on 143 nondiabetic adult participants in the population-based PREVENCION study. Central AIx was obtained using the generalized transfer function of the Sphygmocor device. RESULTS: Predictors of the change in AIx over time were investigated. Among men (n = 67), the change in AIx was predicted by abdominal obesity (standardized ß for waist circumference = 0.34; P = 0.002), impaired fasting glucose (standardized ß = 0.24; P = 0.009), and the change in heart rate (standardized ß = -0.78; P < 0.001). Among women (n = 76), the change in AIx was predicted by non-high-density lipoprotein cholesterol (standardized ß = 0.33; P = 0.001), C-reactive protein levels (standardized ß = 0.24; P = 0.02), change in mean arterial pressure (standardized ß = 0.33; P = 0.001), and change in heart rate (standardized ß = -0.52; P < 0.001). CONCLUSIONS: Metabolic and inflammatory factors predicted changes in AIx over time, with important sex differences. Metabolic factors, such as abdominal obesity and impaired fasting glucose, predicted changes in AIx in men, whereas C-reactive protein and non-high-density lipoprotein cholesterol levels predicted changes in women. Our findings highlight the impact of sex on arterial properties and may guide the design of interventions to favorably impact changes in late systolic pressure augmentation.

Strain improves risk prediction beyond ejection fraction in chronic systolic heart failure.

BACKGROUND: The utility of longitudinal, circumferential, and radial strain and strain rate in determining prognosis in chronic heart failure is not well established. METHODS AND RESULTS: In 416 patients with chronic systolic heart failure, we performed speckle-tracking analyses of left ventricular longitudinal, circumferential, and radial strain and strain rate on archived echocardiography images (30 frames per second). Cox regression models were used to determine the associations between strain and strain rate and risk of all-cause mortality, cardiac transplantation, and ventricular-assist device placement. The area under the time-dependent ROC curve (AUC) was also calculated at 1 year and 5 years. Over a maximum follow-up of 8.9 years, there were 138 events (33.2%). In unadjusted models, all strain and strain rate parameters were associated with adverse outcomes (P<0.001). In multivariable models, all parameters with the exception of radial strain rate (P=0.11) remained independently associated, with patients in the lowest tertile of strain or strain rate parameter having a ≈ 2-fold increased risk of adverse outcomes compared with the reference group (P<0.05). Addition of strain to ejection fraction (EF) led to a significantly improved AUC at 1 year (0.697 versus 0.633, P=0.032) and 5 years (0.700 versus 0.638, P=0.001). In contrast, strain rate did not provide incremental prognostic value to EF alone. CONCLUSIONS: Longitudinal and circumferential strain and strain rate, and radial strain are associated with chronic heart failure prognosis. Strain provides incremental value to EF in the prediction of adverse outcomes, and with additional study may be a clinically relevant prognostic tool.

Metabolic syndrome as an underlying disease entity and its relationship to subclinical atherosclerosis in Andean Hispanics.

BACKGROUND: The question of whether the metabolic syndrome truly reflects a single disease entity with a common underlying pathology remains unclear. In this study, we assess whether metabolic syndrome represents an underlying disease construct in a large population-based sample of Andean Hispanic adults and examine its relationship to subclinical atherosclerosis. METHODS: The study sample was comprised of 2513 participants. Confirmatory factor analysis (CFA) was used to identify a metabolic syndrome latent factor using waist circumference, systolic and diastolic blood pressure, high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), and glucose levels as indicators. The relationship with subclinical atherosclerosis, measured by carotid intima media thickness (cIMT), was assessed using structural equation modeling. RESULTS: Results supported the proposed structure of the metabolic syndrome latent factor evidenced by adequate fit indexes. HDL-C did not significantly load on the metabolic syndrome latent factor (standardized factor loading=0.01, P=0.88). The metabolic syndrome latent factor was significantly associated with cIMT in women (B=0.007, P<0.001) and men (B=0.008, P<0.001) after controlling for age, low-density lipoprotein cholesterol and smoking. CONCLUSIONS: Our findings suggest that metabolic syndrome components, such as waist circumference, blood pressure, TGs, and glucose levels, but not HDL-C, share a common underlying pathophysiology that may contribute to the progression of atherosclerosis in Andean Hispanics. Its longitudinal association with cardiovascular disease should be the focus of future research.