Ratio of Mixed Venous Oxygen Saturation-to-Pulmonary Capillary Wedge Pressure: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program

Background: Hemodynamic values from right heart catheterization aid diagnosis and clinical decision-making but may not predict outcomes. Mixed venous oxygen saturation percentage and pulmonary capillary wedge pressure relate to cardiac output and congestion, respectively. We theorized that a novel, simple ratio of these measurements could estimate cardiovascular prognosis. Methods: We queried Veterans Affairs’ databases for clinical, hemodynamic, and outcome data. Using the index right heart catheterization between 2010 and 2016, we calculated the ratio of mixed venous oxygen saturation-to-pulmonary capillary wedge pressure, termed ratio of saturation-to-wedge (RSW). The primary outcome was time to all-cause mortality; secondary outcome was 1-year urgent heart failure presentation. Patients were stratified into quartiles of RSW, Fick cardiac index (CI), thermodilution CI, and pulmonary capillary wedge pressure alone. Kaplan-Meier curves and Cox proportional hazards models related comparators with outcomes. Results: Of 12 019 patients meeting inclusion criteria, 9826 had values to calculate RSW (median 4.00, interquartile range, 2.67–6.05). Kaplan-Meier curves showed early, sustained separation by RSW strata. Cox modeling estimated that increasing RSW by 50% decreases mortality hazard by 19% (estimated hazard ratio, 0.81 [95% CI, 0.79–0.83], P <0.001) and secondary outcome hazard by 28% (hazard ratio, 0.72 [95% CI, 0.70–0.74], P <0.001). Among the 3793 patients with data for all comparators, Cox models showed RSW best associated with outcomes (by both C statistics and Bayes factors). Furthermore, pulmonary capillary wedge pressure was superior to thermodilution CI and Fick CI. Multivariable adjustment attenuated without eliminating the association of RSW with outcomes. Conclusions: In a large national database, RSW was superior to conventional right heart catheterization indices at assessing risk of mortality and urgent heart failure presentation. This simple calculation with routine data may contribute to clinical decision-making in this population.

MiR-150 Attenuates Maladaptive Cardiac Remodeling Mediated by Long Noncoding RNA MIAT and Directly Represses Profibrotic Hoxa4

Background: MicroRNA-150 (miR-150) plays a protective role in heart failure (HF). Long noncoding RNA, myocardial infarction–associated transcript (MIAT) regulates miR-150 function in vitro by direct interaction. Concurrent with miR-150 downregulation, MIAT is upregulated in failing hearts, and gain-of-function single-nucleotide polymorphisms in MIAT are associated with increased risk of myocardial infarction (MI) in humans. Despite the correlative relationship between MIAT and miR-150 in HF, their in vivo functional relationship has never been established, and molecular mechanisms by which these 2 noncoding RNAs regulate cardiac protection remain elusive. Methods: We use MIAT KO (knockout), Hoxa4 (homeobox a4) KO, MIAT TG (transgenic), and miR-150 TG mice. We also develop DTG (double TG) mice overexpressing MIAT and miR-150. We then use a mouse model of MI followed by cardiac functional, structural, and mechanistic studies by echocardiography, immunohistochemistry, transcriptome profiling, Western blotting, and quantitative real-time reverse transcription-polymerase chain reaction. Moreover, we perform expression analyses in hearts from patients with HF. Lastly, we investigate cardiac fibroblast activation using primary adult human cardiac fibroblasts and in vitro assays to define the conserved MIAT/miR-150/HOXA4 axis. Results: Using novel mouse models, we demonstrate that genetic overexpression of MIAT worsens cardiac remodeling, while genetic deletion of MIAT protects hearts against MI. Importantly, miR-150 overexpression attenuates the detrimental post-MI effects caused by MIAT. Genome-wide transcriptomic analysis of MIAT null mouse hearts identifies Hoxa4 as a novel downstream target of the MIAT/miR-150 axis. Hoxa4 is upregulated in cardiac fibroblasts isolated from ischemic myocardium and subjected to hypoxia/reoxygenation. HOXA4 is also upregulated in patients with HF. Moreover, Hoxa4 deficiency in mice protects the heart from MI. Lastly, protective actions of cardiac fibroblast miR-150 are partially attributed to the direct and functional repression of profibrotic Hoxa4 . Conclusions: Our findings delineate a pivotal functional interaction among MIAT, miR-150, and Hoxa4 as a novel regulatory mechanism pertinent to ischemic HF.

Intermittent Occlusion of the Superior Vena Cava to Improve Hemodynamics in Patients With Acutely Decompensated Heart Failure: The VENUS-HF Early Feasibility Study

Background: Reducing congestion remains a primary target of therapy for acutely decompensated heart failure. The VENUS-HF EFS (VENUS-Heart Failure Early Feasibility Study) is the first clinical trial testing intermittent occlusion of the superior vena cava with the preCARDIA system, a catheter mounted balloon and pump console, to improve decongestion in acutely decompensated heart failure. Methods: In a multicenter, prospective, single-arm exploratory safety and feasibility trial, 30 patients with acutely decompensated heart failure were assigned to preCARDIA therapy for 12 or 24 hours. The primary safety outcome was a composite of major adverse cardiovascular and cerebrovascular events through 30 days. Secondary end points included technical success defined as successful preCARDIA placement, treatment, and removal and reduction in right atrial and pulmonary capillary wedge pressure. Other efficacy measures included urine output and patient-reported symptoms. Results: Thirty patients were enrolled and assigned to receive the preCARDIA system. Freedom from device- or procedure-related major adverse events was observed in 100% (n=30/30) of patients. The system was successfully placed, activated and removed after 12 (n=6) or 24 hours (n=23) in 97% (n=29/30) of patients. Compared with baseline values, right atrial pressure decreased by 34% (17±4 versus 11±5 mm Hg, P <0.001) and pulmonary capillary wedge pressure decreased by 27% (31±8 versus 22±9 mm Hg, P <0.001). Compared with pretreatment values, urine output and net fluid balance increased by 130% and 156%, respectively, with up to 24 hours of treatment ( P <0.01). Conclusions: We report the first-in-human experience of intermittent superior vena cava occlusion using the preCARDIA system to reduce congestion in acutely decompensated heart failure. PreCARDIA treatment for up to 24 hours was well tolerated without device- or procedure-related serious or major adverse events and associated with reduced filling pressures and increased urine output. These results support future studies characterizing the clinical utility of the preCARDIA system. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03836079.

Heart Failure Spending Function: An Investment Framework for Sequencing and Intensification of Guideline-Directed Medical Therapies

Heart failure with reduced ejection fraction is managed with increasing numbers of guideline-directed medical therapies (GDMT). Benefits tend to be additive. Burdens can also be additive. We propose a heart failure spending function as a conceptual framework for tailored intensification of GDMT that maximizes therapeutic opportunity while limiting adverse events and patient burden. Each patient is conceptualized to have reserve in physiological and psychosocial domains, which can be spent for a future return on investment. Key domains are blood pressure, heart rate, serum creatinine, potassium, and out-of-pocket costs. For each patient, GDMT should be initiated and intensified in a sequence that prioritizes medications with the greatest expected cardiac benefit while drawing on areas where the patient has ample reserves. When reserve is underspent, patients fail to gain the full benefit of GDMT. Conversely, when a reserve is fully spent, addition of new drugs or higher doses that draw upon a domain will lead to patient harm. The benefit of multiple agents drawing upon varied physiological domains should be balanced against cost and complexity. Thresholds for overspending are explored, as are mechanisms for implementing these concepts into routine care, but further health care delivery research is needed to validate and refine clinical use of the spending function. The heart failure spending function also suggests how newer therapies may be considered in terms of relative value, prioritizing agents that draw on different spending domains from existing GDMT.