Brian P. Shapiro

Acute and Chronic Ventricular-Arterial Coupling in Systole and Diastole. Insights From an Elderly Hypertensive Model

Aging and hypertension lead to arterial remodeling and tandem increases in arterial (Ea) and ventricular (LV) systolic stiffness (ventricular-arterial [VA] coupling). Age and hypertension also predispose to heart failure with normal ejection fraction (HFnlEF), where symptoms during hypertensive urgencies or exercise are common. We hypothesized that: (1) chronic VA coupling also occurs in diastole, (2) acute changes in Ea are coupled with shifts in the diastolic and systolic pressure-volume relationships (PVR), and (3) diastolic VA coupling reflects changes in LV diastolic stiffness rather than external forces or relaxation. Old chronically hypertensive (OHT, n=8) and young normal (YNL, n=7) dogs underwent assessment of PVR (caval occlusion) and of aortic pressure, dimension, and flow, at baseline and during changes in afterload and preload. Concomitant changes in the slope/position of PVR were accounted for by calculating systolic (ESV200) and diastolic (EDV20) volumes at common pressures (capacitance). OHT displayed marked vascular remodeling. Indices reflecting the pulsatile component of Ea (aortic stiffness and systemic arterial compliance) were more impaired in OHT at any distending pressure. In both groups, acute increases in Ea were associated with decreases in ESV200 and EDV20. However, at any load, OHT had lower ESV200 and EDV20, associated with LV remodeling and myocardial endothelin activation. Acute changes in EDV20 were not mediated by changes in relaxation or external forces. These observations provide insight into the mechanisms whereby arterial remodeling and acute and chronic VA coupling in both systole and diastole may predispose to and interact with increases in load to cause HFnlEF.

Use of Plasma Brain Natriuretic Peptide Concentration to Aid in the Diagnosis of Heart Failure

Plasma concentration of brain natriuretic peptide (BNP), as measured by the Triage BNP Test, is approved by the Food and Drug Administration to aid in the diagnosis of heart failure. This diagnostic test is available in many institutions. The purpose of this article is to help the physician know the appropriate time to order this test and to aid in interpreting results. To achieve this goal, we review the physiology of BNP, clinical studies that support its use for diagnosing heart failure, and confounding variables to consider when BNP is being used clinically. We show that the BNP test can be extremely helpful when used in the correct clinical setting.

Advanced Glycation End Products Accumulate in Vascular Smooth Muscle and Modify Vascular but Not Ventricular Properties in Elderly Hypertensive Canines

Background— Advanced glycation end products (AGEs) are believed to increase left ventricular (LV) and vascular stiffness, in part via cross-linking proteins. We determined whether and where AGEs were increased in elderly hypertensive nondiabetic dogs and whether an AGE cross-link breaker (ALT-711) improved vascular or ventricular function. Methods and Results— Elderly dogs with experimental hypertension (old hypertensives [OH]) were randomized to receive ALT-711 (OH+ALT group; n=11; 1 mg/kg PO) or not (OH group; n=11) for 8 weeks. Conscious blood pressure measurements (weekly), echocardiography (week 8), and anesthetized study (week 8) with LV pressure–volume analysis and aortic pressure–dimension and pressure–flow assessment over a range of preloads and afterloads were performed. In LV and aorta from OH, OH+ALT, and young normal dogs, AGE content (immunohistochemistry and Western analysis for N&egr;-(carboxymethyl)lysine [CML]) was assessed. Aortic CML content was markedly increased in OH and OH+ALT dogs compared with young normal dogs. CML was localized to aortic and aortic vasa vasorum smooth muscle but not to collagen or elastin. CML was essentially undetectable in young normal, OH, or OH+ALT myocardium but was visible in large vessels in the LV. ALT-711 therapy was associated with lower blood pressure and pulse pressure, decreased systemic vascular resistance, increased aortic distensibility and arterial compliance, and, notably, significant aortic dilatation. Neither LV systolic nor diastolic function was different in OH+ALT versus OH dogs. Conclusions— In elderly hypertensive canines, AGE accumulation and AGE cross-link breaker effects were confined to the vasculature without evidence of myocardial accumulation or effects. The lack of AGE accumulation in collagen-rich areas suggests that the striking vascular effects may be mediated by mechanisms other than collagen cross-linking.

Mineralocorticoid signaling in transition to heart failure with normal ejection fraction

Heart failure with normal ejection fraction occurs in elderly patients with hypertensive heart disease. We hypothesized that, in such patients, mineralocorticoid receptor activation accelerates the types of ventricular and vascular remodeling and dysfunction believed important in the transition to heart failure. We tested this hypothesis by administering deoxycorticosterone acetate (DOCA) without salt loading or nephrectomy to elderly dogs with experimental hypertension. Elderly dogs were made hypertensive by renal wrapping. After 5 weeks, dogs were randomly assigned to DOCA (1 mg/kg per day IM; old hypertensive [OH]+DOCA; n=11) or not (OH; n=11) for 3 weeks. At week 8, conscious echocardiography and hemodynamic assessment under anesthesia were performed. DOCA resulted in further increases in conscious blood pressure (P<0.05) without increases in cardiac output or diastolic volume. In the conscious state, effective arterial elastance (P<0.05) and systemic vascular resistance (P=0.06) were increased, and systemic arterial compliance (P<0.05) was decreased in OH+DOCA animals. After anesthesia, instrumentation, and autonomic blockade, blood pressure was lower, whereas left ventricular (LV) systolic elastance, LV diastolic stiffness, and ex vivo myofiber diastolic stiffness were increased in OH+DOCA animals. LV collagen was increased in OH+DOCA animals (P<0.05 for all), but LV mass, LV brain natriuretic peptide, and titin isoform profiles were not. Neither aortic stiffness nor aortic structure was altered in OH+DOCA animals. These findings suggest that age and hypertensive heart disease enhance sensitivity to exogenous mineralocorticoid administration and that mineralocorticoid receptor activation could contribute to the transition to heart failure in elderly persons by promoting increases in LV diastolic and systolic stiffness.

Titin Isoforms, Extracellular Matrix, and Global Chamber Remodeling in Experimental Dilated Cardiomyopathy Functional Implications and Mechanistic Insight

Background—Altered titin isoforms may modify cardiac function in heart failure (HF), but the nature of isoform switches and associated functional implications are not well defined. Limited studies have reported an increased compliant isoform (N2BA) expression in human systolic HF. Titin may also modulate stretch-regulated responses such as myocardial natriuretic peptide production. Methods and Results—We characterized titin isoform expression and extracellular matrix in all 4 cardiac chambers and the left ventricular (LV) epicardium and endocardium in normal dogs (n=6) and those with HF (n=6) due to tachypacing and characterized functional implications at the LV myofiber and chamber level. Recognizing the potential for uncoupling of the extracellular matrix and cardiomyocyte in tachypacing, myocardial natriuretic peptide production, a molecular marker of stretch-regulated responses, was also assessed. All chambers were dilated in HF, but the extracellular matrix was not increased. HF dogs had markedly lower N2BA in the atria and right ventricle. In failing LVs, N2BA was decreased only in the epicardium, where myofiber passive stiffness was increased. However, LV chamber mechanics were driven by the marked LV dilatation, with no increase in LV diastolic stiffness. Natriuretic peptide concentrations increased markedly in the endocardium in relation to increases in LV wall stress. Conclusions—Tachypacing HF is characterized by decreases in compliant titin isoform expression in the atria, right ventricle, and LV epicardium. However, LV chamber mechanics are principally determined by geometric and extracellular matrix changes rather than titin-based myofiber stiffness in this model. Stretch-regulated myocardial responses (natriuretic peptide production) appeared intact, suggesting that the mechanotransduction role of titin was not impaired in HF.

Indexes of von willebrand factor as biomarkers of aortic stenosis severity (from the biomarkers of aortic stenosis severity [BASS] study)

We correlated von Willebrand factor (VWF) activity indexes and brain natriuretic peptide (BNP) with measures of aortic stenosis (AS) severity, bleeding, symptoms, and freedom from death or aortic valve replacement. Patients with AS (n = 66 [16 mild, 20 moderate, and 30 severe]) and aortic valve replacement (n = 21) were assessed with VWF antigen, VWF latex agglutination immunoturbidic activity, platelet function analyzer collagen plus adenosine diphosphate (PFA-CADP), VWF multimer ratio, and BNP level after echocardiography. In patients with AS, the mean gradient correlated with BNP (Spearman r = 0.29, p = 0.02), VWF latex agglutination immunoturbidic activity/VWF antigen ratio (r = -0.41, p <0.001), PFA-CADP (r = 0.49, p <0.001), and VWF multimer ratio (r = -0.76, p <0.001). The area under the curve for detection of severe AS was 0.62 (95% confidence interval [CI] 0.48 to 0.77) by elevated BNP, 0.81 (95% CI 0.69 to 0.92) by PFA-CADP closure time, 0.69 (95% CI 0.55 to 0.82) by VWF latex agglutination immunoturbidic activity/VWF antigen ratio, and 0.86 (95% CI 0.76 to 0.95) by VWF multimer ratio. For the VWF multimer ratio, a threshold of 0.15 yielded a sensitivity and specificity for severe AS of 77% and positive predictive value of 74%. Bleeding (in 14%) was associated with a prolonged PFA-CADP time and reduced VWF latex agglutination immunoturbidic activity/VWF antigen ratio. Symptoms were associated with elevated BNP and low Duke Activity Status Index score. In 66 patients with AS, freedom from death (n = 4) or aortic valve replacement (n = 22) was associated with PFA-CADP (p = 0.003), VWF high-molecular-weight multimers (p = 0.009), and VWF latex agglutination immunoturbidic activity/VWF antigen ratio (p <0.001) but not BNP (p = 0.32). In severe AS versus aortic valve replacement, the PFA-CADP and VWF multimer ratio differed (p <0.001), but BNP and the VWF latex agglutination immunoturbidic activity/VWF antigen ratio did not. In conclusion, the VWF activity indexes were associated with AS severity and bleeding and were predictive of cardiovascular outcomes.

Echocardiographic Assessment of Estimated Right Atrial Pressure and Size Predicts Mortality in Pulmonary Arterial Hypertension

BACKGROUND Elevated mean right atrial pressure (RAP) measured by cardiac catheterization is an independent risk factor for mortality. Prior studies have demonstrated a modest correlation with invasive and noninvasive echocardiographic RAP, but the prognostic impact of estimated right atrial pressure (eRAP) has not been previously evaluated in patients with pulmonary arterial hypertension (PAH). METHODS A retrospective analysis of 121 consecutive patients with PAH based on right-sided heart catheterization and echocardiography was performed. The eRAP was calculated by inferior vena cava diameter and collapse using 2005 and 2010 American Society of Echocardiography (ASE) definitions. Accuracy and correlation of eRAP to RAP was assessed. Kaplan-Meier survival analysis by eRAP, right atrial area, and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) risk criteria as well as univariate and multivariate analysis of echocardiographic findings was performed. RESULTS Elevation of eRAP was associated with decreased survival time compared with lower eRAP (P < .001, relative risk = 7.94 for eRAP > 15 mm Hg vs eRAP ≤ 5 mm Hg). Univariate analysis of echocardiographic parameters including eRAP > 15 mm Hg, right atrial area > 18 cm², presence of pericardial effusion, right ventricular fractional area change < 35%, and at least moderate tricuspid regurgitation was predictive of poor survival. However, multivariate analysis revealed that eRAP > 15 mm Hg was the only echocardiographic risk factor that was predictive of mortality (hazard ratio = 2.28, P = .037). CONCLUSIONS Elevation of eRAP by echocardiography at baseline assessment was strongly associated with increased risk of death or transplant in patients with PAH. This measurement may represent an important prognostic component in the comprehensive echocardiographic evaluation of PAH.

Shear stress-associated acquired von Willebrand syndrome in patients with mitral regurgitation

Mitral valve regurgitation is associated with an acquired hemostatic defect.

Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization

OBJECTIVE To compare corifollitropin alfa with recombinant FSH treatment in terms of the vital pregnancy rate in older patients undergoing IVF. DESIGN Phase 3 randomized, double-blind, noninferiority trial. SETTING Multicenter trial. PATIENT(S) A total of 1,390 women aged 35-42 years. INTERVENTION(S) A single injection of 150 μg of corifollitropin alfa or daily 300 IU of recombinant FSH for the first 7 days then daily recombinant FSH until three follicles reach ≥17 mm in size. Ganirelix was started on stimulation day 5 up to and including the day of recombinant hCG administration. If available, two good quality embryos were transferred on day 3. MAIN OUTCOME MEASURE(S) Vital pregnancy rate (PR), number of oocytes, and live birth rate. RESULT(S) Vital PRs per started cycle were 23.9% in the corifollitropin alfa group and 26.9% in the recombinant FSH group, with an estimated difference (95% confidence interval) of -3.0% (-7.4 to 1.4). The mean (SD) number of recovered oocytes per started cycle was 10.7 (7.2) and 10.3 (6.8) in the corifollitropin alfa and the recombinant FSH groups, respectively, with an estimated difference of 0.5 (-0.2 to 1.2). The live birth rates per started cycle were 21.3% in the corifollitropin alfa group and 23.4% in the recombinant FSH group, with an estimated difference (95% confidence interval) -2.3% (-6.5 to 1.9). The incidence of serious adverse events was 0.4% versus 2.7% in the corifollitropin alfa and recombinant FSH groups, respectively, and of ovarian hyperstimulation syndrome (OHSS; all grades) was 1.7% in both groups. CONCLUSION(S) Treatment with corifollitropin alfa was proven noninferior to daily recombinant FSH with respect to vital PRs, number of oocytes retrieved, and live birth rates, and was generally well tolerated. CLINICAL TRIAL REGISTRATION NUMBER NCT01144416.

Effect of Intensive Blood Pressure Lowering on Left Ventricular Hypertrophy in Patients With Hypertension

Background: It is currently unknown whether intensive blood pressure (BP) lowering beyond that recommended would lead to more lowering of the risk of left ventricular hypertrophy (LVH) in patients with hypertension and whether reducing the risk of LVH explains the reported cardiovascular disease (CVD) benefits of intensive BP lowering in this population. Methods: This analysis included 8164 participants (mean age, 67.9 years; 35.3% women; 31.2% blacks) with hypertension but no diabetes mellitus from the SPRINT trial (Systolic Blood Pressure Intervention Trial): 4086 randomly assigned to intensive BP lowering (target SBP <120 mm Hg) and 4078 assigned to standard BP lowering (target SBP <140 mm Hg). Progression and regression of LVH as defined by Cornell voltage criteria derived from standard 12-lead ECGs recorded at baseline and biannually were compared between treatment arms during a median follow-up of 3.81 years. The effect of intensive (versus standard) BP lowering on the SPRINT primary CVD outcome (a composite of myocardial infarction, acute coronary syndrome, stroke, heart failure, and CVD death) was compared before and after adjustment for LVH as a time-varying covariate. Results: Among SPRINT participants without baseline LVH (n=7559), intensive (versus standard) BP lowering was associated with a 46% lower risk of developing LVH (hazard ratio=0.54; 95% confidence interval, 0.43–0.68). Similarly, among SPRINT participants with baseline LVH (n=605, 7.4%), those assigned to the intensive (versus standard) BP lowering were 66% more likely to regress/improve their LVH (hazard ratio=1.66; 95% confidence interval, 1.31–2.11). Adjustment for LVH as a time-varying covariate did not substantially attenuate the effect of intensive BP therapy on CVD events (hazard ratio of intensive versus standard BP lowering on CVD, 0.76 [95% confidence interval, 0.64–0.90] and 0.77 [95% confidence interval, 0.65–0.91] before and after adjustment for LVH as a time-varying covariate, respectively). Conclusions: Among patients with hypertension but no diabetes mellitus, intensive BP lowering (target systolic BP <120 mm Hg) compared with standard BP lowering (target systolic BP <140 mm Hg) resulted in lower rates of developing new LVH in those without LVH and higher rates of regression of LVH in those with existing LVH. This favorable effect on LVH did not explain most of the reduction in CVD events associated with intensive BP lowering in the SPRINT trial. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062.Background:It is currently unknown whether intensive blood pressure (BP) lowering beyond that recommended would lead to more lowering of the risk of left ventricular hypertrophy (LVH) in patients w...