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. Summary 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.

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.

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, 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.

Cross-sectional studies in the developed countries document strong relationships among age, systolic blood pressure (SBP) and pulse pressure (PP). There is little information about these trends and their impact in underdeveloped countries with different socioeconomic and lifestyle characteristics. We studied a convenience sample of 572 residents of rural Fontaine, Haiti: 193 males and 379 females (mean, s.d.) age 40.2 (17.1) years and performed intake questionnaires and BP measurements in participants' homes. Income and educational achievement were very low but most-recommended lifestyle factors were very favorable: very high physical activity, low dietary fat, virtually no obesity (body mass index 21.8 (4.9)), and low smoking prevalence. Rough estimates of salt intake were high (~13 g per day) as was the overall prevalence of hypertension: 34.4% (23.4% in males, 40.2% in females). SBP and PP were related closely to age (r=0.28, P<0.001 and r=0.22, P<0.001); for each decade of age, SBP increased by 7.6 mm Hg. Diastolic BP peaked in the 6th decade (polynomial r=0.22, P<0.001) and the nadir of PP occurred in the 3rd decade. We conclude that, despite a favorable profile of lifestyle characteristics and no obesity, the prevalence of hypertension and rate of increase in SBP and PP with age in Haiti are at least as high as those of developed countries.

Background The optimal level of sodium intake remains controversial. Objective To determine whether examination of left ventricular (LV) longitudinal and circumferential strain (LS, CS) 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 Hypertension Genetic Epidemiology study echocardiograms with available urinary sodium data (N = 2,996). We evaluated the association between ESI and LS, CS, and e′ velocity using multivariable-adjusted linear mixed effects models (to account for relatedness among subjects) with linear splines (spline 1: ESI ≤3.7g/day, spline 2: ESI >3.7g/day based upon 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 (SBP) and serum aldosterone on the relationship between ESI and strain and e′ velocity. Results Mean age was 49 ± 14 years, 57% were female, 50% were African American, and 54% had hypertension. The median (25th–75th percentile) ESI was 3.73 (3.24–4.25) g/day. ESI >3.7g/day was associated with larger left atrial and LV 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, LV mass, ejection fraction, and wall motion score index, ESI >3.7g/day was associated with all strain parameters and e′ velocity in (p <0.05 for all comparisons), but ESI ≤3.7g/day was not (p >0.05 for all comparisons). There were significant interactions by potassium excretion for CS. Mediation analysis suggested that SBP explained 14% and 20% of the indirect effects between ESI and LS and e′ velocity, respectively, while 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.

Purpose of review: Right-sided heart failure (HF), which is often present in the setting of advanced HF, 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 HF, could lead to novel therapeutics to ameliorate HF. Here we provide an overview of right-sided HF, 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 sodiumhydrogen exchanger-3 (NHE3) may form a causal link between right ventricular (RV) dysfunction, splanchnic congestion, and worsening HF. These include: (1) an anaerobic environment in enterocytes, resulting in reduced intracellular pH; (2) increased sodium absorption by the gut via NHE3; (3) decreased pH at the intestinal brush border thus altering the gut microbiome profile; (4) increased bacterial synthesis of trimethylamine N-oxide; and (5) decreased bacterial synthesis of short-chain fatty acids causing abnormal intestinal barrier function.Summary: Splanchnic congestion in the setting of right-sided HF may serve an important role in the pathogenesis of advanced HF, and further exploration of these mechanisms may lead to new therapeutic advances.

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