Sex and age interaction in fundamental circulatory volumetric variables at peak working capacity

Background Whether the fundamental hematological and cardiac variables determining cardiorespiratory fitness and their intrinsic relationships are modulated by major constitutional factors, such as sex and age remains unresolved. Methods Transthoracic echocardiography, central hemodynamics and pulmonary oxygen (O2) uptake were assessed in controlled conditions during submaximal and peak exercise (cycle ergometry) in 85 healthy young (20–44 year) and older (50–77) women and men matched by age-status and moderate-to-vigorous physical activity (MVPA) levels. Main outcomes such as peak left ventricular end-diastolic volume (LVEDVpeak), stroke volume (SVpeak), cardiac output (Qpeak) and O2 uptake (VO2peak), as well as blood volume (BV), BV–LVEDVpeak and LVEDVpeak–SVpeak relationships were determined with established methods. Results All individuals were non-smokers and non-obese, and MVPA levels were similar between sex and age groups (P ≥ 0.140). BV per kg of body weight did not differ between sexes (P ≥ 0.118), but was reduced with older age in men (P = 0.018). Key cardiac parameters normalized by body size (LVEDVpeak, SVpeak, Qpeak) were decreased in women compared with men irrespective of age (P ≤ 0.046). Older age per se curtailed Qpeak (P ≤ 0.022) due to lower heart rate (P < 0.001). In parallel, VO2peak was reduced with older age in both sexes (P < 0.001). The analysis of fundamental circulatory relationships revealed that older women require a higher BV for a given LVEDVpeak than older men (P = 0.024). Conclusions Sex and age interact on the crucial circulatory relationship between total circulating BV and peak cardiac filling, with older women necessitating more BV to fill the exercising heart than age- and physical activity-matched men.

Blood withdrawal acutely impairs cardiac filling, output and aerobic capacity in proportion to induced hypovolemia in middle-aged and older women

Blood donation entails acute reductions of cardiorespiratory fitness in healthy men. Whether these effects can be extrapolated to blood donor populations comprising women remains uncertain. The purpose of this study was to comprehensively assess the acute impact of blood withdrawal on cardiac function, central hemodynamics and aerobic capacity in women throughout the mature adult lifespan. Transthoracic echocardiography and O2 uptake were assessed at rest and throughout incremental exercise (cycle ergometry) in healthy women (n = 30, age: 47–77 yr). Left ventricular end-diastolic volume (LVEDV), stroke volume (SV), cardiac output (Q̇) and peak O2 uptake (V̇O2peak), and blood volume (BV) were determined with established methods. Measurements were repeated following a 10% reduction of BV within a week period. Individuals were non-smokers, non-obese and moderately fit (V̇O2peak = 31.4 ± 7.3 mL·min–1·kg–1). Hematocrit and BV ranged from 38.0 to 44.8% and from 3.8 to 6.6 L, respectively. The standard 10% reduction in BV resulted in 0.5 ± 0.1 L withdrawal of blood, which did not alter hematocrit (P = 0.953). Blood withdrawal substantially reduced cardiac LVEDV and SV at rest as well as during incremental exercise (≥10% decrements, P ≤ 0.009). Peak Q̇ was proportionally decreased after blood withdrawal (P < 0.001). Blood withdrawal induced a 10% decrement in V̇O2peak (P < 0.001). In conclusion, blood withdrawal impairs cardiac filling, Q̇ and aerobic capacity in proportion to the magnitude of hypovolemia in healthy mature women. Novelty: The filling of the heart and therefore cardiac output are impaired by blood withdrawal in women. Oxygen delivery and aerobic capacity are reduced in proportion to blood withdrawal.

In Search of Clinical Impact: Advanced Monitoring Technologies in Daily Heart Failure Care

Despite significant advances in the management of heart failure (HF), further improvement in the outcome of this chronic and progressive disease is still considered a major unmet need. Recurrent hospitalizations due to decompensated HF frequently occur, resulting in increased morbidity and mortality rates. Past attempts at early detection of clinical deterioration were mainly based on monitoring of signs and symptoms of HF exacerbation, which have mostly given disappointing results. Extensive research of the pathophysiology of HF decompensation has indicated that hemodynamic alterations start days prior to clinical manifestation. Novel technologies aim to monitor these minute hemodynamic changes, allowing time for therapeutic interventions to prevent hemodynamic derangement and HF exacerbation. The latest noticeable advancements include assessment of lung fluid volume, wearable devices with integrated sensors, and microelectromechanical systems-based implantable devices for continuous measurement of cardiac filling pressures. This manuscript will review the rationale for monitoring HF patients and discuss previous and ongoing attempts to develop clinically meaningful monitoring devices to improve daily HF health care, with particular emphasis on the recent advances and clinical trials relevant to this evolving field.

Pulmonary Congestion Assessment in Heart Failure: Traditional and New Tools

Congestion related to cardiac pressure and/or volume overload plays a central role in the pathophysiology, presentation, and prognosis of heart failure (HF). Most HF exacerbations are related to a progressive rise in cardiac filling pressures that precipitate pulmonary congestion and symptomatic decompensation. Furthermore, persistent symptoms and signs of congestion at discharge or among outpatients are strong predictors of an adverse outcome. Pulmonary congestion is also one of the most important diagnostic and therapeutic targets in chronic heart failure. The aim of this review is to analyze the importance of clinical, instrumental, and biochemical evaluation of congestion in HF by describing old and new tools. Lung ultrasonography (LUS) is an emerging method to assess pulmonary congestion. Accordingly, we describe the additive prognostic role of chest ultrasound with respect to traditional clinical and X-ray assessment in acute and chronic HF setting.

The 2021 Carl Ludwig Lecture. Unsympathetic autonomic regulation in heart failure: patient-inspired insights

Defined as a structural or functional cardiac abnormality accompanied by symptoms, signs or biomarkers of altered ventricular pressures or volumes, heart failure also is a state of autonomic disequilibrium. A large body of evidence affirms that autonomic disturbances are intrinsic to heart failure; that basal or stimulated sympathetic nerve firing or neural norepinephrine (NE) release more often than not exceed homeostatic need, such that an initially adaptive adrenergic or vagal reflex response, becomes maladaptive; and, that the magnitude of such maladaptation predicts prognosis. This Ludwig lecture develops two theses: that the elucidation and judiciously targeted amelioration of maladaptive autonomic disturbances offers opportunities to complement contemporary guideline-based heart failure therapy; and, that serendipitous single-participant insights, acquired in the course of experimental protocols with entirely different intent, can generate novel insight, inform mechanisms, and launch entirely new research directions. I précis 6 elements of our current synthesis of the causes and consequences of maladaptive sympathetic disequilibrium in heart failure, shaped by patient-inspired epiphanies: arterial baroreceptor reflex modulation; excitation stimulated by increased cardiac filling pressure; paradoxical muscle sympathetic activation as a peripheral neurogenic constraint on exercise capacity; renal sympathetic restraint of natriuresis; co-existing sleep apnea; and, augmented chemoreceptor reflex sensitivity, then conclude by envisaging translational therapeutic opportunities.

Inferring the Frank–Starling Curve From Simultaneous Venous and Arterial Doppler: Measurements From a Wireless, Wearable Ultrasound Patch

The Frank–Starling relationship is a fundamental concept in cardiovascular physiology, relating change in cardiac filling to its output. Historically, this relationship has been measured by physiologists and clinicians using invasive monitoring tools, relating right atrial pressure (Pra) to stroke volume (SV) because the Pra-SV slope has therapeutic implications. For example, a critically ill patient with a flattened Pra-SV slope may have low Pra yet fail to increase SV following additional cardiac filling (e.g., intravenous fluids). Provocative maneuvers such as the passive leg raise (PLR) have been proposed to identify these “fluid non-responders”; however, simultaneously measuring cardiac filling and output via non-invasive methods like ultrasound is cumbersome during a PLR. In this Hypothesis and Theory submission, we suggest that a wearable Doppler ultrasound can infer the Pra-SV relationship by simultaneously capturing jugular venous and carotid arterial Doppler in real time. We propose that this method would confirm that low cardiac filling may associate with poor response to additional volume. Additionally, simultaneous assessment of venous filling and arterial output could help interpret and compare provocative maneuvers like the PLR because change in cardiac filling can be confirmed. If our hypothesis is confirmed with future investigation, wearable monitors capable of monitoring both variables of the Frank–Starling relation could be helpful in the ICU and other less acute patient settings.

Hydraulic force is a novel mechanism of diastolic function that may contribute to decreased diastolic filling in HFpEF and facilitate filling in HFrEF

It is a previously unrecognized physiological mechanism of the heart that diastolic filling occurs with the help of hydraulics. In patients with heart failure with preserved ejection fraction, atrial dilatation may cause the net hydraulic force to work against cardiac filling, thus further augmenting diastolic dysfunction. In contrast, it may work favorably in patients with dilated ventricles, as in heart failure with reduced ejection fraction.

Plasma Clearance of B-Type Natriuretic Peptide (BNP) before and after Bariatric Surgery for Morbid Obesity

Background Obese patients have lower plasma concentrations of the cardiac natriuretic peptides (NPs) than their age- and sex-matched counterparts. This may reflect lower production and/or increased peptide clearance. It is unclear whether NP bioactivity is affected by obesity. Methods We studied the effects of obesity on B-type natriuretic peptide (BNP) clearance and bioactivity by comparing results from standardized intravenous infusions of BNP administered 2 weeks before and 6 months after bariatric surgery in 12 consecutive patients with morbid obesity (body mass index, BMI &gt; 35 kg/m2). Anthropometric, clinical, neurohormonal, renal, and echocardiographic variables were obtained pre- and postsurgery. Pre- vs postsurgery calculated intrainfusion peptide clearances were compared. Results BMI (44.3 ± 5.0 vs 33.9 ± 5.2 kg/m2, P &lt; 0.001) and waist circumference (130.3 ± 11.9 vs 107.5 ± 14.7 cm, P &lt; 0.001) decreased substantially after bariatric surgery. Calculated plasma clearance of BNP was reduced (approximately 30%) after surgery. Though not controlled for, sodium intake was presumably lower after bariatric surgery. Despite this, preinfusion endogenous plasma NP concentrations did not significantly differ between pre- and postsurgery studies. The ratio of plasma N-terminal (NT)-proBNP to 24 h urine sodium excretion was higher postsurgery (P = 0.046; with similar nonsignificant findings for BNP, atrial NP (ANP) and NT-proANP), indicating increased circulating NPs for a given sodium status. Mean plasma NP concentrations for given calculated end-systolic wall stress and cardiac filling pressures (as assessed by echocardiographic E/e’) rose slightly, but not significantly postsurgery. Second messenger, hemodynamic, renal, and neurohormonal responses to BNP were not altered between studies. Conclusion Obesity is associated with increased clearance, but preserved bioactivity, of BNP.

Abstract 16922: Extremely Elevated Natriuretic Peptide is Associated With Incident Dialysis in Chronic Heart Failure Patients With Acute Kidney Injury

Introduction: NT-proBNP has been widely used as a diagnostic and prognostic marker for both acute and chronic HF. Previous studies suggested that impaired renal function was the major contributor of an extreme elevation of NT-proBNP levels in patients with chronic HF rather than elevated cardiac filling pressure. Therefore, extremely elevated NT-proBNP levels may provide prognostic value in patients with cardiorenal syndrome. Hypothesis: Extremely elevated NT-proBNP levels are predictive of incident dialysis and dialysis dependence in chronic HF patients developing AKI Methods: Electronic medical records of 478 adult chronic HF patients admitted to the Cleveland Clinic between 2011 and 2016, who developed AKI during the hospital stay and had baseline NT-proBNP before renal consultation were reviewed. We analyzed the association between baseline NT-proBNP and incident dialysis, and dialysis dependence. Dialysis dependence was defined as patients undergoing dialysis within 72 hours of discharge. Results: Mean age was 67.6±13.3 years, 55.9% were male, and 37.7% had CKD. There were no significant differences in baseline characteristics and serum creatinine between patients with and without incident dialysis. Median NT-proBNP was 7,994 pg/mL (IQR; 3,109-19,357 pg/mL). There were 207 (43.3%) patients required dialysis, and 138 patients (66.7%) became dialysis dependent. Higher NT-proBNP was associated with increased risk of incident dialysis (Q 4 vs 1, OR 1.85, 95% C.I. 1.10-3.09, P =0.020), and dialysis dependence (Q4 vs 1, OR 2.96, 95% C.I. 1.25-7.00, P =0.014). However, in multivariate analysis adjusting for age, gender, hypertension, and baseline creatinine, only the association between NT-proBNP and incident dialysis remained statistically significant (Q4 vs 1, OR 1.77, 95% C.I. 1.03-3.02, P =0.038, Figure). Conclusions: Extremely elevated NT-proBNP was independently associated with incident dialysis in chronic HF patients developing AKI.