Borlaug, Barry A.

Introduction: Pulmonary hypertension (PH), defined as an elevated mean pulmonary artery pressure, has been consistently associated with adverse outcomes in hospitalized patients. Limited epidemiologic data exist regarding PH in the cardiac intensive care unit (CICU) population. We used transthoracic echocardiography (TTE) to describe the prevalence, etiology, and outcomes of PH in the CICU. Hypothesis: PH will be associated with higher in-hospital mortality in CICU patients. Methods: CICU patients admitted from 2007 to 2018 who had right ventricular systolic pressure (RVSP) measured via TTE within 1 day of CICU admission were included. PH was defined as an estimated RVSP >35 mmHg. Predictors of in-hospital mortality were determined using multivariable logistic regression. Results: We included 5042 patients with a mean age of 69.4±14.8 (41% females); 81.1% had an admission diagnosis of acute coronary syndrome or heart failure. PH was present in 3085 (61%); the majority (68%) of patients with PH had left heart failure, and 29% had lung disease. In-hospital mortality occurred in 8% and was higher in patients with PH (11% vs. 4%, adjusted OR 1.40, 95% CI 1.03-1.92, p =0.03). PH was associated with higher in-hospital mortality in patients with acute coronary syndrome, heart failure or cardiac arrest (all p <0.01), but not in patients with cardiogenic shock, respiratory failure or sepsis ( Figure ). In-hospital mortality increased as a function of higher RVSP in each admission diagnosis group (adjusted 1.18 per 10 mmHg higher in the entire cohort, 95% CI 1.09-1.28, p <0.001). Conclusions: PH by TTE is very common in the CICU population and remains associated with a higher risk of death during hospitalization even after adjustment. TTE assessment of right heart hemodynamics can predict mortality in CICU patients, with variability across common admission diagnoses. This highlights the importance of PH determined by TTE in hospitalized patients with cardiac critical illness.

Background: The relationship between blood volume and pressure in the vascular system can be described in terms of unstressed and stressed blood volume. Stressed blood volume determines venous pressure and provides preload back to the heart, which regulates the generation of cardiac output (CO) via the Frank-starling mechanism. Whether sodium-glucose cotransporter-2 (SGLT2i) favorably modifies stressed blood volume is not known. Hypothesis: To investigate the effect of SGLT2i (empagliflozin) on the hemodynamic estimated stressed blood volume (eSBV) in HFrEF patients compared to placebo. Methods: A post hoc analysis of investigator-initiated, double-blinded, placebo-controlled, randomized trial. Seventy patients were assigned to empagliflozin of 10 mg or matching placebo once daily for 12 weeks. Patients underwent right heart catheterization at rest and during exercise at baseline and follow-up. Outcome was change in eSBV after 12 weeks of empagliflozin treatment at each level of exercise. We conducted computer-modelling simulations based on invasive hemodynamic assessment to measure eSBV. Results: HFrEF patients with mean age was 57 years, mean ejection fraction 27%, 47 (71%) on diuretics were randomized. After 12 weeks treatment exercise eSBV was significantly reduced at 0 watt, 25 watt and 25 % of maximal exercise watt, compared to placebo [(0 watt; –258 mL, 95% CI –476 to –39, p=0.021); (25 watt; –301 mL, 95% CI –561 to –40, p=0.024); and (25% of peak exercise watt; –262 mL, 95% CI –490 to –34, p=0.024)]. There was no effect on rest, or at peak exercise eSBV [(Rest; –75 ml, 95% confidence interval [CI] –279 to 130; p=0.47); and (Peak; –96 mL, 95% CI –444 to 251, p=0.59)]. This was consistent among patients with and without type 2 diabetes, etiology of HFrEF, and diuretic usage (Figure 1). Conclusion: Empagliflozin may contribute to shift blood from the effective circulatory beds to the venous reservoir in reducing filling pressure and eSBV, but maintaining CO.

Introduction: Peripheral factors contribute to exercise limitations in heart failure (HF) with preserved ejection fraction (HFpEF) and may be related to excess regional adiposity. Slowed oxygen uptake (VO 2 ) kinetics are common in HF with reduced ejection fraction (HFrEF) and reflect peripheral O 2 transport impairments and abnormal muscle metabolic control. Differences in VO 2 kinetics between HFpEF and HFrEF may reveal phenotype-specific impairments in peripheral O 2 transport but remain unknown. Hypothesis: We hypothesized that VO 2 kinetics are slower in HFpEF (compared to HFrEF) and associated with greater leg adiposity. Methods: Patients with HFpEF (n=12; 3 women; 66±6 yrs; 29±3 kg/m 2 ; ejection fraction: 59±5%), HFrEF (n=12; 3 women; 62±9 yrs; 28±4 kg/m 2 ; ejection fraction: 37±8%), and controls (n=12; 3 women; 65±5 yrs; 28±3 kg/m 2 ) cycled at 20 W for 5 minutes prior to a maximal exercise test to determine VO 2peak . Age, sex, and BMI were matched by design and were not different among groups (p>0.05). A monoexponential function with a time delay was used to describe the VO 2 transition from rest to 20 W and calculate the O 2 deficit. Leg fat mass was measured via dual energy X-ray absorptiometry. Results: VO 2peak was lower in HFpEF (18.6±6.2 mL/kg/min) and HFrEF (19.0±3.7 mL/kg/min) compared to controls (26.0±3.1; both p<0.05). Amplitude (HFpEF: 507±97 mL/min; HFrEF: 443±91 mL/min; controls: 477±117 mL/min) and time delay (HFpEF: 16±9 s; HFrEF: 11±7 s; controls: 11±6 s) were not different among groups (p>0.05). The time constant was slower in HFrEF compared to controls (45±9 s vs. 32±6 s; p=0.03) and further slowed in HFpEF (66±18 s; p<0.001). The O 2 deficit was significantly greater in HFpEF (895±201 mL) and HFrEF (649±131 mL) compared to controls (590±125 mL; both p<0.05). There were no differences in percent leg fat mass among groups (HFpEF: 33±8%; HFrEF: 31±6%; controls: 34±9%) and no associations were detected between percent leg fat mass and any VO 2 parameters (all p>0.05). Conclusions: Patients with HFpEF exhibited slower VO 2 kinetics compared to HFrEF with no association to leg adiposity. These data suggest differences in peripheral O 2 transport and intramuscular metabolic control abnormalities between HF phenotypes.

Introduction: Heart failure patients with preserved ejection fraction (HFpEF) may exhibit inspiratory muscle dysfunction potentially contributing to exercise intolerance. Activation of neural afferents in response to inspiratory muscle contraction (metaboreflex) elicits increases in mean arterial pressure (MAP) and leg vascular resistance (LVR) through enhanced sympathetic outflow leading to decreases in leg blood flow (LBF) in healthy humans. It is unknown if HFpEF patients exhibit exaggerated cardiovascular responses to inspiratory muscle metaboreflex activation. Hypothesis: We hypothesize that patients with HFpEF will exhibit a greater increase in MAP and LVR with a decrease in LBF during inspiratory muscle metaboreflex activation than controls. Methods: HFpEF patients (n=15, 10M/5W, 69±10 yrs; 33±4 kg/m2) and controls (n=14; 10M/4W; 70±8 yrs; 28±4 kg/m2) performed inspiratory resistive breathing tasks (IRBT) at 2% and 60% of their maximal inspiratory pressure. During the IRBTs, the breathing frequency was 20 breaths/min with a 50% duty cycle. At rest and during the IRBTs, MAP was measured by photoplethysmography, venous norepinephrine was measured, LBF was measured by near-infrared spectroscopy and indocyanine green dye injections, and LVR was calculated. Results: During the 2% IRBT, there were no differences between groups in the changes from rest in MAP (HFpEF: 2±4 vs. CTL: 3±4 mmHg) or LBF (HFpEF: 1±14 vs. CTL: 1±12%) (both, p>0.05). During the 60% IRBT, venous norepinephrine increased from rest in HFpEF and controls (p<0.05), while no differences existed between groups (p>0.05). During the 60% IRBT, HFpEF patients, compared to controls, exhibited a greater increase from rest in MAP (HFpEF: 16±7 vs. CTL: 10±6 mmHg) and LVR (HFpEF: 76±45 vs. CTL: 32±19%) coupled with a greater decrease in LBF (HFpEF: -32±14 vs. CTL: -17±9%) (all, p<0.05). Conclusions: These data indicate that patients with HFpEF exhibit exaggerated cardiovascular responses with inspiratory muscle metaboreflex activation compared to healthy individuals. These findings have important implications for the integrative physiology of exercise in HFpEF patients.

Introduction: Arteriovenous fistulas(AVF) have been associated with high output heart failure but little is known about their effect on patients initiating hemodialysis. We sought to describe echocardiographic changes and identify those with incident heart failure after AVF creation. Methods: This was a retrospective analysis of all patients undergoing AVF creation over a 15 year period from 2000-2014 at the Mayo Clinic in Rochester, MN. Patients undergoing echocardiogram <3 months (median 40 days) before AVF creation and >6 months (median 2.5 years) following surgery were included. Patients with independent modifiers of LV structural changes (such as revascularization or myocardial infarction) were excluded by chart review. Clinical heart failure was defined by Framingham criteria. Results: From 2000-2014, 2236 patients underwent creation of AVFs and 137 patients met inclusion criteria. There was a longitudinal decrease in systolic function as evident by a drop in ejection fraction(-2%, p=0.047) with decrease in s’ tissue Doppler velocity(-0.6 cm/s, p=0.055) and increase in HR(+5 beats/min, p=0.003). There was also an increase in the prevalence of RV dilation(20 to 40%, p=0.002) and RV dysfunction(12 to 29%, p=0.002). With initiation of dialysis and decrease in weight (-7.3kg) and estimated plasma volume (-303ml) (both p<0.0001), there was a decrease in LV end diastolic dimension (-2mm, p=0.006). Despite better volume control, left atrial volume index increased (+5ml/m2, p=0.004). On multivariate Cox regression, worsening RV dilation [HR 1.8 (1.06-3.09),p=0.03] was independently associated with mortality. Incident heart failure developed in 43%(28/65) with no pre-existing HF, of whom 75% had HFPEF and 25% HFrEF. The development of new systolic HF (but not HFPEF) was associated with increased age and sex adjusted mortality [HR 3.0(1.0-7.9), p=0.045]. Conclusions: AVF creation is associated with worsening biventricular function and left atrial and RV dilatation, despite reduction in LV size. These changes are coupled with high incidence of new, unexplained heart failure. Further research is needed to identify the hemodynamic mechanisms underlying heart failure development in patients with ESRD requiring dialysis access.

Introduction: The incidence of heart failure (HF) is higher in black than in white Americans, but the causes are unclear. We proposed that ethnic differences in ventricular-arterial interaction may contribute to this differential HF risk. Methods: We studied measures of arterial elastance (Ea) and left ventricle (LV) end-systolic elastance (Ees) in 5767 community-based elderly participants (76±5 years, 41% male, 22% black) who underwent echocardiography in the Atherosclerosis Risk in Community (ARIC) Study. Results: Black participants were more frequently women (66 vs 57%) and had a higher prevalence of obesity (46 vs 31%), hypertension (94 vs 80%), and diabetes mellitus (47 vs 34%). Adjusting for these baseline differences, the prevalence of LV hypertrophy was similar, but Ea, Ees and Ea/Ees ratio were higher in blacks than whites, particularly in black women (Figure). Ea was positively associated with LV mass index and E/e’ ratio in blacks, but not in whites (p for interaction < 0.001). Conclusion: These community-based data demonstrate that ventricular-arterial stiffening is greater in black than white Americans, coupled with more ventricular remodeling and dysfunction. The heightened afterload dependence in blacks suggests greater potential for risk reduction with anti-hypertensive therapy.

Introduction: Assessment of cardiac function during exercise is critical in the clinical evaluation of patients with heart failure with preserved (HFpEF) or reduced (HFrEF) ejection fraction. Direct invasive measurement of cardiac power (CP) and stroke work (SW) are robust measures of cardiac function. Non-invasive gas exchange based surrogates may provide practical means of assessing cardiac function in clinical and research settings; however, the relationship between invasive and non-invasive measurement of CP or SW during exercise is unclear in HFpEF and HFrEF. We aimed to assess relationships between invasive and non-invasive measures of CP and SW during exercise in HFpEF and HFrEF. Methods: HFpEF (n=47) and HFrEF (n=29) (age 71±10 vs 55±10 yrs; EF% 62±8 vs 21±6%; BSA 2.1±0.3 vs 2.1±0.2 m 2 ; weight 99±22 vs 87±15 kg; peak work 36±14 vs 37±13 watts (W), respectively; all p<0.05, except peak work) underwent peak exercise testing during right heart catheterization. Invasive measurement of cardiac pressures, hemodynamics, and arterial pressures were recorded at rest, 20 W, and peak work. Continuous measurement of HR and VO 2 occurred from rest to peak work via 12-lead ECG and metabolic measurement system, respectively. Invasive measurements were calculated as, CP=(MAP–RAP) x Q x 2.22х10 -3 ; SW=(MAP–PCWP) x SV I x 0.133; and non-invasive as, CP=VO 2 x MAP; SW=VO 2 /HR x MAP. All indices adjusted for body surface area. Results: At rest, there were moderate relationships between invasive and non-invasive measures of CP and SW in HFpEF (r=0.56 and 0.48) and HFrEF (0.57 and 0.73), respectively (all p<0.05). At 20 W, relationships between invasive and non-invasive measures of CP and SW strengthened in HFpEF (r=0.74 and 0.69) and HFrEF (0.74 and 0.72), respectively (all p<0.05). The relationships noted between invasive and non-invasive measures of CP and SW at 20 W persisted at peak work in HFpEF (r=0.74 and 0.67) and HFrEF (0.78 and 0.69), respectively (all p<0.05). Conclusion: These data suggest that non-invasive estimates of CP and SW correlate closely with invasive measures and may be reasonable surrogates for these indices during peak exercise testing in both HFpEF and HFrEF patients.

Introduction: Invasive measurement of cardiac power (CP) and stroke work (SW) during exercise are robust indices of cardiac function and relate to syndrome severity and prognosis in heart failure patients with preserved (HFpEF) or reduced (HFrEF) ejection fraction. Because invasive measurement via catheterization laboratories are not always readily available, non-invasive cardiopulmonary exercise testing to estimate cardiac function is routinely performed in the clinical evaluation of HFpEF and HFrEF. However, it is unknown how VO 2 relates with CP and SW in HFpEF vs HFrEF. We compared relationships between CP and SW with VO 2 at rest and peak exercise in HFpEF vs HFrEF. Methods: 30 HFpEF and 32 HFrEF (EF: 62±2 vs 22±1%; males: 17 vs 30; age: 70±2 vs 55±2 yrs; BMI: 34±1 vs 28±1 kg/m 2 ; wt: 98±4 vs 86±3 kg (all p<0.05)) participated in exercise testing during right heart catheterization. Oxygen consumption (VO 2 ) was measured continuously from rest to peak work. Invasive measures at rest and peak work included mean radial arterial pressure (MAP), right atrial pressure (RAP), and pulmonary capillary wedge pressure (PCWP). We calculated CP=(MAP–RAP) x Q I x 2.22х10 -3 and SW=(MAP–PCWP) x SV I x 0.133. Results: At rest, R 2 between VO 2 and CP or SW were not different between HFpEF (CP=0.41, SW=0.30) and HFrEF (CP=0.39, SW=0.15). Slopes did not differ significantly between HFpEF (CP=0.13, SW=0.01) and HFrEF (CP=0.16, SW=0.01) for regressions between VO 2 and CP or SW; but, fitted intercepts of the regression showed significantly higher intercepts in HFrEF (CP=0.89, SW=1.16) vs HFpEF (CP=0.05, SW=0.27) for VO 2 vs CP and SW, respectively. At peak exercise, R 2 between VO 2 and CP or SW were not different between HFpEF (CP=0.48, SW=0.64) and HFrEF (CP=0.70, SW=0.67). Slopes did not differ between HFpEF (CP=0.18, SW=0.02) and HFrEF (CP=0.15, SW=0.02) for regressions between VO 2 and CP or SW, whereas the fitted intercepts the slope of the regression were significantly higher in HFrEF (CP=5.1, SW=4.4) vs HFpEF (CP=3.2, SW=2.0) for VO 2 vs CP and SW, respectively. Conclusion: Our data suggest that despite lower VO 2 relative to CP and SW in HFpEF, both the strength of relationship and rate of increase in VO 2 relative to CP and SW are similar between HFpEF and HFrEF at rest and peak exercise.

Patients with HFrEF exhibit severe exercise intolerance. One of the primary peripheral mechanisms contributing to exercise intolerance in patients with HFrEF is locomotor muscle group III/IV afferent feedback. However, it is unknown whether these afferents impact the central and peripheral responses during submaximal cycling exercise. Herein, we demonstrate that inhibition of locomotor muscle group III/IV afferent feedback elicited increases in stroke volume during submaximal exercise in HFrEF, but not in healthy controls.