Elena Libhaber

Evaluation of Bromocriptine in the Treatment of Acute Severe Peripartum Cardiomyopathy A Proof-of-Concept Pilot Study

Background— Peripartum cardiomyopathy (PPCM) is a potentially life-threatening heart disease that occurs in previously healthy women. We identified prolactin, mainly its 16-kDa angiostatic and proapoptotic form, as a key factor in PPCM pathophysiology. Previous reports suggest that bromocriptine may have beneficial effects in women with acute onset of PPCM. Methods and Results— A prospective, single-center, randomized, open-label, proof-of-concept pilot study of women with newly diagnosed PPCM receiving standard care (PPCM-Std; n=10) versus standard care plus bromocriptine for 8 weeks (PPCM-Br, n=10) was conducted. Because mothers receiving bromocriptine could not breast-feed, the 6-month outcome of their children (n=21) was studied as a secondary end point. Blinded clinical, hemodynamic, and echocardiographic assessments were performed at baseline and 6 months after diagnosis. Cardiac magnetic resonance imaging was performed 4 to 6 weeks after diagnosis in PPCM-Br patients. There were no significant differences in baseline characteristics, including serum 16-kDa prolactin levels and cathepsin D activity, between the 2 study groups. PPCM-Br patients displayed greater recovery of left ventricular ejection fraction (27% to 58%; P=0.012) compared with PPCM-Std patients (27% to 36%) at 6 months. One patient in the PPCM-Br group died compared with 4 patients in the PPCM-Std group. Significantly fewer PPCM-Br patients (n=1, 10%) experienced the composite end point of poor outcome defined as death, New York Heart Association functional class III/IV, or left ventricular ejection fraction <35% at 6 months compared with the PPCM-Std patients (n=8, 80%; P=0.006). Cardiac magnetic resonance imaging revealed no intracavitary thrombi. Infants of mothers in both groups showed normal growth and survival. Conclusions— In this trial, the addition of bromocriptine to standard heart failure therapy appeared to improve left ventricular ejection fraction and a composite clinical outcome in women with acute severe PPCM, although the number of patients studied was small and the results cannot be considered definitive. Larger-scale multicenter and blinded studies are in progress to test this strategy more robustly.

Reversal of IFN-γ, oxLDL and prolactin serum levels correlate with clinical improvement in patients with peripartum cardiomyopathy

Peripartum cardiomyopathy (PPCM) is characterized by acute onset of heart failure of unknown aetiology. We aimed to identify mechanisms involved in initiation and progression of the disease.

Obesity promotes left ventricular concentric rather than eccentric geometric remodeling and hypertrophy independent of blood pressure.

BACKGROUND As it is uncertain whether excess adiposity promotes primarily concentric or eccentric left ventricular hypertrophy (LVH), we aimed to determine at a population level, the independent relationship between waist circumference (WC) and LV geometric changes and the potential hemodynamic mechanisms thereof. METHODS We assessed the relations between WC and LV end-diastolic diameter (EDD), LV mean wall thickness (MWT = posterior + septal wall thickness/2), LV relative wall thickness (RWT = MWT/EDD), LV mass index (LVMI), concentric LVH (LVMI > 51 g/m2.7 and RWT > 0.45), eccentric LVH (LVMI > 51 g/m2.7 and RWT < 0.45), or concentric LV remodeling (normal LVMI and RWT > 0.45), in 309 never treated for hypertension, randomly recruited adult participants with a high prevalence of excess adiposity ( approximately 25% overweight; 38% obese). Pulse-wave analysis was performed to determine central artery blood pressures (BPs). Two hundred and thirty-one participants had high-quality ambulatory BP monitoring. RESULTS Approximately 7% of participants had concentric LVH, approximately 16% concentric LV remodeling, and approximately 15% eccentric LVH. After adjustments for potential confounders including conventional systolic BP (SBP), WC was related to MWT (partial r = 0.23, P = 0.0001), RWT (partial r = 0.13, P = 0.03), concentric LVH (P < 0.04), concentric LV remodeling (P = 0.02), but not with EDD or eccentric LVH (P = 0.91). Similar outcomes were noted after adjustments for central or 24-h SBP, and for conventional, central, or 24-h pulse pressure. Separate analysis in normotensive subjects revealed similar outcomes. CONCLUSIONS In a population sample with a high prevalence of obesity, excess adiposity promotes concentric, rather than eccentric LV geometric changes, effects which are independent of conventional, central artery or 24-h BP measured on a single occasion.

Nurse-recorded auscultatory blood pressure at a single visit predicts target organ changes as well as ambulatory blood pressure

Aim To determine whether high-quality nurse-recorded auscultatory blood pressure (BP) values obtained at a single visit predict cardiovascular target organ changes as closely as ambulatory BP measurements. Methods In a randomly selected population sample (n = 458, 21% receiving antihypertensive treatment; approximately 40% hypertensive), we compared high-quality single visit nurse-recorded auscultatory BP values to same-day 24-h ambulatory BP in their ability to predict multiple target organ changes [left ventricular mass index (LVMI), left ventricle (LV) mean wall thickness (MWT), early-to-late transmitral velocity ratios (E/A), (echocardiography); log of urinary albumin-to-creatinine ratios (log ACR) (24-h urine samples); large artery dysfunction [carotid-femoral pulse wave velocity (PWV) and central augmentation index (Alc) (applanation tonometry)]. Results Nurse-recorded systolic BP (SBP) measurements obtained at a single visit were as closely associated with LVMI (r = 0.44), LV MWT (r = 0.44), E/A (r = −0.55), log ACR (r = 0.20), PWV (r = 0.62) and AIc (r = 0.41) (P < 0.0001 for all relations) as was 24-h SBP (LVMI; r = 0.33, LV MWT; r = 0.37, E/A; r = −0.35, log ACR; r = 0.24, PWV; r = 0.41, and AIc; r = 0.18, P < 0.001 for all relations) and either day or night SBP. On multivariate regression analysis with both nurse-recorded SBP and 24-h SBP in the same model, nurse-recorded SBP was independently associated with LVMI (P = 0.006), LV MWT (P = 0.03), E/A (P < 0.02), PWV (P < 0.0001) and AIc (P = 0.0002), and 24-h SBP was independently and positively associated with log ACR (P < 0.005), and PWV (P = 0.01). Conclusion One or more, high-quality single visit nurse-recorded auscultatory BP measurements may be equally as effective as ambulatory BP in predicting target organ damage in a population sample of African ancestry.

Predictors of outcome in 176 South African patients with peripartum cardiomyopathy.

Objective Identify novel prognostic factors for patients with peripartum cardiomyopathy (PPCM). Design and setting Prospective cohort study conducted in a single tertiary care centre in South Africa. Patients 176 African women with newly diagnosed PPCM were studied. Interventions Clinical assessment, echocardiography and laboratory results were obtained at baseline and at 6 months. Main outcome measures Poor outcome was defined as the combined end point of death, left ventricular (LV) ejection fraction (LVEF) < 35%, or remaining in New York Heart Association (NYHA) functional class III/IV at 6 months. Complete LV recovery was defined as LVEF ≥55% at 6 months. Results Forty-five (26%) patients had a poor outcome. Multiple logistic regression analysis revealed that, after adjustment for age, NYHA functional class, LVEF and systolic blood pressure, increased left ventricular end systolic dimension (LVESD), lower body mass index (BMI) and lower total cholesterol at baseline were independent predictors of poor outcome (adjusted OR 1.09, 95% CI 1.04 to 1.15, p=0.001; OR 0.89, 95% CI 0.83 to 0.96, p=0.004, and OR 0.50, 95% CI 0.34 to 0.73, p=0.0004, respectively). Thirty (21%) of the 141 surviving patients with echocardiographic follow-up recovered LV function at 6 months. Multiple logistic regression analysis revealed that, after adjustment for NYHA functional class, LVEF and left ventricular end diastolic dimension, older age and smaller LVESD at baseline were predictors of LV recovery (OR 1.08, 95% CI 1.01 to 1.17, p=0.02 and OR 0.92, 95% CI 0.86 to 0.98, p=0.007, respectively). Conclusions This study suggests that increased LVESD, lower BMI and lower serum cholesterol at baseline may be independent predictors of poor outcome in patients with PPCM, while older age and smaller LVESD at baseline appear to be independently associated with a higher chance of LV recovery.

Angiotensinogen Gene Promoter Region Variant Modifies Body Size–Ambulatory Blood Pressure Relations in Hypertension

Background—The extent to which genes modify the relationship between risk factors for hypertension and blood pressure (BP) is unclear. As angiotensinogen is expressed in adipose tissue and angiotensinogen (AGT) gene promoter variants influence the production of angiotensinogen, we evaluated the role of AGT gene variants as potential modifiers of body size–BP relations. Methods and Results—Five hundred twenty-one hypertensives of African origin sampled from a group with a high mean body mass index (BMI) had 24-hour ambulatory BP (ABP) measurements determined off therapy and were genotyped for the AGT –6G→A, –532C→T, –20A→C, and 704T→C (M235T) gene variants. Genotypes were also determined in 547 control subjects of African origin who had a normal clinic BP. The –6A and –532C alleles were concordant with the M235T variant. Although AGT gene variants had no independent effects on either the presence of hypertension or ABP values in hypertensives, the –20A→C polymorphism had a marked influence on the relation between ambulatory systolic BP and BMI. This relation was present in patients homozygous for the –20A allele (n=399, r =0.23, P <0.0001), but absent in those with at least one copy of the –20C allele (n=122, r =0.01, P =0.89). The M235T polymorphism did not impact on the BMI-BP relation. Specificity of the –20A→C polymorphism effect on the BMI-BP relation is further indicated by the lack of effect on the systolic BP–age relation. Conclusion—An AGT gene promoter region variant is an important modifier of the relation between body size and BP. Hence, these data corroborate the notion that genetic modifiers can produce a profound impact on BP-phenotypic relations.

Is prehypertension an independent predictor of target organ changes in young-to-middle-aged persons of African descent?

Aim We sought to determine whether prehypertension (BP = 120–139/80–89 mmHg) is associated with target organ changes independent of confounders. Methods In 771 participants from a population sample of African ancestry, approximately 46% of whom had hypertension, and approximately 30% prehypertension, organ damage was assessed from echocardiography (left ventricular mass indexed to height2.7, the mean of posterior and septal wall thickness and early-to-late transmitral velocity), 24-h urine samples (urinary albumin-to-creatinine ratio), serum creatinine concentrations, and carotid–femoral pulse wave velocity. Ambulatory blood pressure values that met with prespecified quality control criteria were available in 539 participants. Results A greater proportion of hypertensives (P < 0.0001) but not prehypertensives had elevated 24-h blood pressure values as compared with participants with optimal blood pressure values. Before adjustment for confounders, hypertension was associated with all target organ changes (P < 0.0001), and after adjustment, an independent association was noted between hypertension and all target organ changes (P < 0.05–0.005) except albumin-to-creatinine ratio or serum creatinine concentrations. Before adjustment, prehypertension was associated with left ventricular mass indexed to height2.7, mean wall thickness, pulse wave velocity, and early-to-late transmitral velocity (P < 0.05–0.001), but not with other target organ changes. After adjustment, however, prehypertension was not independently associated with target organ changes. Other factors independently associated with target organ changes were age (all target organs), waist circumference (left ventricular mass indexed to height2.7 and early-to-late transmitral velocity) and diabetes mellitus (albumin-to-creatinine ratio and pulse wave velocity). Interactions between prehypertension and any of the alternative risk factors were not independent predictors of target organ changes. Conclusion Although associated with it, prehypertension is not an independent predictor of organ damage in young-to-middle-aged persons of African ancestry.

Interobserver agreement in intrapartum estimation of fetal head station

To determine interobserver agreement in estimation of fetal head station during labor, and the determinants of agreement.

Long-term outcome of Peripartum cardiomyopathy in a population with high seropositivity for Human Immunodeficiency Virus

BACKGROUND Peripartum cardiomyopathy (PPCM) is a rare cardiomyopathy with a high risk of mortality. The present study assessed clinical outcome and mortality over a 2-year period in an African cohort of 80 PPCM patients. METHODS A prospective study over a 2-year period at a tertiary center, where 80 consecutive women presenting with PPCM were enrolled on first diagnosis. Patients obtained standard heart failure therapy. Detailed assessments included echocardiography, NYHA functional class, left ventricular ejection fraction (LVEF), mortality and serum levels for hemoglobin, CRP, IL-6, TNF-alpha, Fas/Apo-1, and T-cell count at each 6-month intervals for 24 months. RESULTS Baseline mean age was 30 ± 7 years; 38% were primigravidas and 34% were co-infected with HIV. NYHA functional class III-IV was present in 89% patients with a mean LVEF of 30 ± 9%. Four patients were lost to follow-up, 9 moved to remote areas, 7 were excluded due to subsequent pregnancy. The 2-year mortality rate was 28%. Eight of 80 (10%) died by 6 months. Mean LVEF of surviving patients was: 44 ± 11% at 6-months, 46 ± 13% at 12-months and 50 ± 14% at 24-months follow-up. Of the 69 patients still enrolled at 6 months 14 (20%) died over the remaining 18-month period, despite functional recovery. No statistically significant difference in LVEF and mortality was observed between PPCM patients with or without HIV co-infection. CONCLUSION The novel finding of this study is the continuous high mortality of PPCM patients occurring beyond 6 months independent of HIV infection and subsequent pregnancy. This finding strongly encourages the need for long-term clinical follow-up and management of women with PPCM.

Contribution of Central and General Adiposity to Abnormal Left Ventricular Diastolic Function in a Community Sample With a High Prevalence of Obesity

The relative independent contribution of excess adiposity, as indexed by measures of central, general, or peripheral adiposity, toward abnormal cardiac diastolic chamber function at a community level is unclear. In 377 randomly selected participants >16 years old from a community sample with a high prevalence of excess adiposity ( approximately 25% overweight and approximately 43% obese), we assessed the independent contribution of the indexes of adiposity to the variation in early-to-late (atrial) transmitral velocity (E/A). After adjustments for a number of confounders, including age, gender, pulse rate, conventional diastolic (or systolic) blood pressure, antihypertensive treatment, left ventricular mass index, and the presence of diabetes mellitus or a hemoglobin A1c level >6.1%; waist circumference was an independent predictor of a reduced E/A (p = 0.0038). Body mass index (p = 0.07), waist-to-hip ratio (p = 0.23), and skinfold thickness (p = 0.37) were not independently associated with E/A, whereas waist circumference was independently associated with E/A, even after adjustments for other adiposity indexes, including body mass index (p <0.05 to 0.005). In contrast to the effects on diastolic function, the waist circumference did not correlate with the left ventricular ejection fraction (p = 0.23). The independent relation between the waist circumference and E/A (standardized beta coefficient -0.14 +/- 0.05, p = 0.0038) was second only to age (standardized beta coefficient -0.57 +/- 0.05, p <0.0001) and similar to blood pressure (standardized beta coefficient -0.11 +/- 0.04, p = 0.0075) in the magnitude of the independent effect on E/A. The inclusion of the relative wall thickness rather than the left ventricular mass index in the regression equation produced similar outcomes. The exclusion of the left ventricular mass index and relative wall thickness from the regression equations or the inclusion of carotid-femoral pulse wave velocity or 24-hour blood pressure as confounders failed to modify the relation between waist circumference and E/A. In conclusion, the waist circumference was second only to age in the impact on an independent association with E/A in a population sample with a high prevalence of excess adiposity. This effect was not accounted for by left ventricular hypertrophy or remodeling, the 24-hour blood pressure, or arterial stiffness.