Visceral Congestion in Heart Failure: Right Ventricular Dysfunction, Splanchnic Hemodynamics, and the Intestinal Microenvironment.

PURPOSE OF REVIEW: Visceral venous congestion of the gut may play a key role in the pathogenesis of right-sided heart failure (HF) and cardiorenal syndromes. Here, we review the role of right ventricular (RV) dysfunction, visceral congestion, splanchnic hemodynamics, and the intestinal microenvironment in the setting of right-sided HF. We review recent literature on this topic, outline possible mechanisms of disease pathogenesis, and discuss potential therapeutics. RECENT FINDINGS: There are several mechanisms linking RV-gut interactions via visceral venous congestion which could result in (1) hypoxia and acidosis in enterocytes, which may lead to enhanced sodium-hydrogen exchanger 3 (NHE3) expression with increased sodium and fluid retention; (2) decreased luminal pH in the intestines, which could lead to alteration of the gut microbiome which could increase gut permeability and inflammation; (3) alteration of renal hemodynamics with triggering of the cardiorenal syndrome; and (4) altered phosphate metabolism resulting in increased pulmonary artery stiffening, thereby increasing RV afterload. A wide variety of therapeutic interventions that act on the RV, pulmonary vasculature, intestinal microenvironment, and the kidney could alter these pathways and should be tested in patients with right-sided HF. The RV-gut axis is an important aspect of HF pathogenesis that deserves more attention. Modulation of the pathways interconnecting the right heart, visceral congestion, and the intestinal microenvironment could be a novel avenue of intervention for right-sided HF.

Association of blood pressure variability with Endothelin-1 by menopause status among Black women: findings from the Jackson Heart Study.

TO THE EDITOR: Postmenopausal women have a higher risk of hypertension compared with premenopausal women possibly related to increased endothelial dysfunction in the setting of lower levels of circulating estrogen. Using data from 660 women in the Jackson Heart Study (JHS), postmenopausal women had higher daytime, nighttime and 24 h systolic blood pressure variability (BPV) compared with premenopausal women, and higher nighttime systolic BPV was associated with higher endothlin-1 (a marker of endothelial dysfunction) in postmenopausal women (ß = 0.27 [0.05, 0.50], p = 0.019), even after adjustment for possible confounders including age. These findings highlight the relevance of menopause status to blood pressure variability and the potential role of blood pressure variability in the development of high endothelin-1 in postmenopausal women.

Association of activin A and postpartum blood pressure in peripartum cardiomyopathy.

BACKGROUND: Activin A has been implicated in the pathogenesis of patients with chronic hypertension and heart failure as well as patients with hypertensive disorders of pregnancy (HDP). Whether activin A correlates with blood pressure in patients with peripartum cardiomyopathy (PPCM) and HDP history has not previously been explored. METHODS AND RESULTS: 82 women with PPCM w/ and w/out HDP or hypertension history were selected for analysis from the Investigations in Pregnancy Associated Cardiomyopathy (IPAC) study. Serum biomarkers and blood pressure were assessed at the time of enrollment (median postpartum day 24). Levels of both sFlt-1 (SBP: r 0.47, p = 0.008; DBP: r 0.57, p < 0.001) and activin A (SBP: r 0.59, p < 0.001;DBP: r 0.68, p < 0.001) were noted to significantly correlate with blood pressure in patients with a history of HDP who went on to develop PPCM, but not in patients with chronic hypertension or no hypertensive history. The strongest correlation was between activin A levels and postpartum diastolic blood pressure for the subset with preeclampsia (DBP: r0.82, p < 0.001). This remained significant in multivariable linear regression analysis (DBP: ß = 0.011, p = 0.015). CONCLUSION: In patients with PPCM, activin A and sFlt-1 levels had direct correlations with both systolic (SBP) and diastolic blood pressures (DBP), but only in participants with history of HDP. This correlation was more evident for activin A and strongest with a history of preeclampsia. Our findings suggest that activin A may play an important role in blood pressure modulation in women with HDP who subsequently develop PPCM.

Cardiovascular Health in a Single Community in Rural Haiti: A Cross-sectional Study.

INTRODUCTION: There is a growing burden of cardiovascular disease in low- and middle-income countries and assessment of cardiovascular health (CVH) may identify populations at risk for poor CVH. METHODS: Between July 2014 and August 2014, we performed a household survey from a convenience sample among adult community members in rural northern Haiti. We used a modified World Health Organization STEPwise approach to chronic disease questionnaire to capture self-reported data on tobacco, diet, physical activity, and diabetes, and measured blood pressure and body mass index. We used an adapted American Heart Association definition and thresholds for determining ideal, intermediate, and poor cardiovascular health. We used linear and logistic regression to examine associations between socio-demographic characteristics with CVH score and ideal CVH. RESULTS: Among 540 participants (mean [SD] age = 40.3 [17.1] years, 67% women), there was a high prevalence of poor CVH (n=476, 88.1%) compared with intermediate (n=56, 10.4%) and ideal (n=41, 7.6%) CVH. Ideal metrics for blood pressure (47%) and diet (26%) were least often met, while body weight (84%), physical activity (83%), and smoking (90%) were most often met. Men were associated with better CVH score (0.31, [0.04-0.59]; P=0.03), and being a farmer was associated with ideal CVH (P=0.006). CONCLUSION: In this community-based sample of a farming community in rural Haiti, very few adults had ideal CVH. Higher CVH score was associated with male sex, and farming as a primary occupation. Women and non-farmers may represent at-risk subgroups within this population. Blood pressure and diet may represent possible areas for improvement.

Presentation, Treatment, and Outcome of Survivors of In-Hospital Versus Out-of-Hospital Sudden Cardiac Arrest.

We examined the baseline characteristics, rates of implantable cardioverter defibrillator implantation, and long-term all-cause mortality for survivors of in-hospital (IHSCA) versus out-of-hospital (OHSCA) sudden cardiac arrest (SCA). A total of 1,433 SCA survivors (807 IHSCA and 626 OHSCA) from 2002 to 2012 were followed through February 2017. Baseline characteristics and potential triggers of SCA, including significant electrolyte and metabolic abnormalities and acute myocardial infarction and ischemia, were collected. Adjusted survival analyses were performed using a multivariate Cox model. The presence of SCA triggers was similar between IHSCA and OHSCA patients (39% vs 35%, p = 0.3), but OHSCA was more likely associated with cardiac ischemia and drug abuse, whereas IHSCA was more associated with new antiarrhythmic drugs (p <0.05). OHSCA survivors were more likely to receive an implantable cardioverter defibrillator (38% vs 18%, p <0.001). Over a median follow-up of 3.6 years, 674 (47%) patients died. After adjusting for unbalanced baseline characteristics, survival was similar between IHSCA and OHSCA survivors (hazard ratio 1.1, 95% confidence interval 0.9 to 1.3, p = 0.4). In conclusion, survivors of IHSCA and OHSCA differed in baseline characteristic, potential SCA triggers, and treatment interventions but their adjusted survival was comparable.

Diffuse right ventricular fibrosis in heart failure with preserved ejection fraction and pulmonary hypertension.

AIMS: While right ventricular (RV) dysfunction is associated with worse prognosis in co-morbid pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF), the mechanisms driving RV dysfunction are unclear. We evaluated the extent and clinical correlates of diffuse RV myocardial fibrosis in PH-HFpEF, as measured by cardiovascular magnetic resonance-derived extracellular volume (ECV). METHODS AND RESULTS: We prospectively enrolled participants with PH-HFpEF (n = 14), pulmonary arterial hypertension (PAH; n = 13), and controls (n = 8). All participants underwent high-resolution cardiovascular magnetic resonance, and case subjects (PH-HFpEF and PAH) additionally underwent right heart catheterization. T1 mapping was performed using high-resolution modified look-locker inversion recovery with a 1 × 1 mm2 in-plane resolution. RV free wall T1 values were quantified, and ECV was calculated. Participants with PH-HFpEF were older and carried higher rates of hypertension and obstructive sleep apnoea than those with PAH. While RV ECV was similar between PH-HFpEF and PAH (33.1 ± 8.0 vs. 34.0 ± 4.5%; P = 0.57), total pulmonary resistance was lower in PH-HFpEF compared with PAH [PH-HFpEF: 5.68 WU (4.70, 7.66 WU) vs. PAH: 8.59 WU (8.14, 12.57 WU); P = 0.01]. RV ECV in PH-HFpEF was associated with worse indices of RV structure (RV end-diastolic volume: r = 0.67, P = 0.01) and RV function (RV free wall strain: r = 0.59, P = 0.03) but was not associated with RV afterload (total pulmonary resistance: r = 0.08, P = 0.79). Conversely, there was a strong correlation between RV ECV and RV afterload in PAH (r = 0.57, P = 0.04). CONCLUSIONS: Diffuse RV fibrosis, as measured by ECV, is present in PH-HFpEF and is associated with adverse RV structural and functional remodelling but not degree of pulmonary vasculopathy. In PH-HFpEF, diffuse RV fibrosis may occur out of proportion to the degree of RV afterload.

The role of splanchnic congestion and the intestinal microenvironment in the pathogenesis of advanced heart failure.

PURPOSE OF REVIEW: Right-sided heart failure, which is often present in the setting of advanced heart failure, is associated with cardiac cachexia, the cardiorenal syndrome, and adverse outcomes. Improved understanding of venous congestion of the splanchnic circulation, which may play a key role in the pathogenesis of right-sided heart failure, could lead to novel therapeutics to ameliorate heart failure. Here we provide an overview of right-sided heart failure, splanchnic hemodynamics, fluid homeostasis, and the intestinal microenvironment. We review recent literature to describe pathophysiologic mechanisms and possible therapeutics. RECENT FINDINGS: Several possible mechanisms centered around upregulation of sodium-hydrogen exchanger-3 (NHE3) may form a causal link between right ventricular dysfunction, splanchnic congestion, and worsening heart failure. These include an anaerobic environment in enterocytes, resulting in reduced intracellular pH; increased sodium absorption by the gut via NHE3; decreased pH at the intestinal brush border thus altering the gut microbiome profile; increased bacterial synthesis of trimethylamine N-oxide; and decreased bacterial synthesis of short-chain fatty acids causing abnormal intestinal barrier function. SUMMARY: Splanchnic congestion in the setting of right-sided heart failure may serve an important role in the pathogenesis of advanced heart failure, and further exploration of these mechanisms may lead to new therapeutic advances.

Implications of Initial Recorded Rhythm on Cardioverter-Defibrillator Insertion and Subsequent All-Cause Mortality in Sudden Cardiac Arrest Survivors.

Sudden cardiac arrest (SCA) rhythms have been traditionally divided into shockable [ventricular tachycardia (VT)/ventricular fibrillation (VF)] and nonshockable [(asystole (ASY)/pulseless electrical activity (PEA)] rhythms. It is unclear if the specific rhythm has implications on patient management and outcomes. We evaluated 1,433 patients who were admitted with SCA from 2000 to 2012 and were discharged alive. Of those, 1,123 patients had a recorded initial SCA rhythm. Subjects included were >18 years of age, and without an implantable cardioverter-defibrillator (ICD) in place at the time of the event. The likelihood of receiving an ICD for each SCA rhythm and the time to death were analyzed. Of the overall cohort of 1,123 SCA survivors (age of 62 ± 15 years; 39.2% women; 56.3% in-hospital SCA; 83% white; 67% coronary artery disease), 355 (31.6%) received an ICD, and 493 (43.9%) died over a mean follow-up of 3.8 ± 3.2 years. Patients with VF (n = 254, 43.6%) or VT (n = 83, 43.9%) were more likely to receive ICD therapy compared with those with ASY (n = 9, 5.3%) or PEA (n = 9, 4.8%; p <0.001). All-cause mortality was lower in VF patients compared with the other groups (p <0.0001). ICD therapy was associated with lower risk of death in the VF group (hazard ratio [HR] 0.61 [0.45 to 0.83]; p = 0.002) and strong trends toward less mortality in patients with VT (HR 0.64 [0.40 to 1.03]; p = 0.07) and ASY (HR 0.39 [0.12 to 1.31]; p = 0.13) but not in those with PEA (HR 0.93 [0.39 to 2.23]; p = 0.88). In conclusion, long-term survival in post-SCA patients is influenced by initial SCA rhythm. Although SCA survivors with shockable rhythms were more likely to receive ICDs, the ICD was associated with lower risk of death in most patients, including those with ASY. In conclusion, our data suggest that a more detailed SCA rhythm classification has important implications to patient management and long-term survival in this population.

Advances in the pharmacotherapy of chronic heart failure with preserved ejection fraction: an ideal opportunity for precision medicine.

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF), which comprises approximately 50% of all heart failure patients, is a challenging and complex clinical syndrome that is often thought to lack effective treatments. Areas covered: Despite the common mantra that HFpEF has no effective treatments, closer inspection of HFpEF clinical trials reveals that several of the drugs tested are associated with benefits in exercise capacity and quality of life, and reduction in heart failure hospitalization. Here we review major randomized controlled trials in HFpEF, focusing on renin-angiotensin-aldosterone system antagonists, organic nitrates, digoxin, beta-blockers, and phosphodiesterase-5 inhibitors. In addition, we review several classes of drugs currently in development for HFpEF such as neprilysin inhibitors, inorganic nitrates (nitrites), and soluble guanylate cyclase stimulators. Expert opinion: HFpEF should not be viewed as lacking effective treatments. While there have been no breakthrough clinical trials showing a reduction in mortality, several existing medications are likely to benefit specific subgroups of HFpEF patients. HFpEF is now well known to be a heterogeneous syndrome; thus, the clinical management of HFpEF patients and future HFpEF clinical trials will both likely require a nuanced, phenotype-specific approach instead of a one-size-fits-all tactic. Drug development for HFpEF therefore represents an exciting opportunity for personalized medicine.

Association of Estimated Sodium Intake With Adverse Cardiac Structure and Function: From the HyperGEN Study.

BACKGROUND: The optimal level of sodium intake remains controversial. OBJECTIVES: This study sought to determine whether examination of left ventricular longitudinal strain (LS), circumferential strain, and e' velocity can provide insight into thresholds for the detrimental effects of estimated sodium intake (ESI) on subclinical cardiovascular disease. METHODS: We performed speckle-tracking analysis on HyperGEN (Hypertension Genetic Epidemiology Network) study echocardiograms with available urinary sodium data (N = 2,996). We evaluated the associations among ESI and LS, circumferential strain, and e' velocity using multivariable-adjusted linear mixed-effects models (to account for relatedness among subjects) with linear splines (spline 1: ESI ≤3.7 g/day, spline 2: ESI >3.7 g/day based on visual inspection of fractional polynomial plots of the association between ESI and indices of strain and e' velocity). We performed mediation analysis to understand the indirect effects of systolic blood pressure and serum aldosterone on the relationship between ESI and strain and e' velocity. RESULTS: Mean age of participants was 49 ± 14 years, 57% were female, 50% were African American, and 54% had hypertension. The median ESI was 3.73 (interquartile range: 3.24, 4.25) g/day. ESI >3.7 g/day was associated with larger left atrial and left ventricular dimensions (p < 0.05). After adjusting for speckle-tracking analyst, image quality, study site, age, sex, smoking status, alcohol use, daily blocks walked, diuretic use, estimated glomerular filtration rate, left ventricular mass, ejection fraction, and wall motion score index, ESI >3.7 g/day was associated with both strain parameters and e' velocity (p < 0.05 for all comparisons), but ESI ≤3.7 g/day was not (p > 0.05 for all comparisons). There were significant interactions by potassium excretion for circumferential strain. Mediation analysis suggested that systolic blood pressure explained 14% and 20% of the indirect effects between ESI and LS and e' velocity, respectively, whereas serum aldosterone explained 19% of the indirect effects between ESI and LS. CONCLUSIONS: ESI >3.7 g/day is associated with adverse cardiac remodeling and worse systolic strain and diastolic e' velocity.