Right Ventricular and Pulmonary Vascular Function are Influenced by Age and Volume Expansion in Healthy Humans.

BACKGROUND: Patients with heart failure (HF) often show signs of right ventricular (RV) dysfunction. The RV function of coupled with the pulmonary circulation (tricuspid annular plane systolic excursion [TAPSE]/pulmonary arterial systolic pressure [PASP]) has been shown to divide HF patients into distinct prognostic strata, but less is known about which factors influence this prognostic marker, and whether those factors can be modified. We sought to obtain normative values and discern the individual effects of age, sex, and fluid overload on RV function. METHODS AND RESULTS: Sixty healthy subjects aged 20-80 years were enrolled in this prospective study. Right heart catheterization with hemodynamic measurements were performed at rest after a rapid saline solution infusion (10 mL/kg, 150 mL/min). Linear regression and Spearman correlation models were used to estimate associations between TAPSE/PASP and relevant variables. In healthy persons of all ages, the median (5th-95th percentiles) normative TASPE-PASP ratio was 1.25 (0.81-1.78) mm/mm Hg. The correlation between progressive age and declining TAPSE/PASP was significant (r = -0.35; P = .006). Sex did not influence TAPSE/PASP (P = .30). Rapid fluid expansion increased central venous pressure from 5 ± 2 mm Hg to 11 ± 4 mm Hg after fluid infusion (P < .0001). This resulted in a 32% decrease in the TAPSE-PASP ratio after fluid infusion, compared to baseline (P < .0001). CONCLUSIONS: The TAPSE-PASP ratio was affected by age, but not sex. TAPSE/PASP is not only a reflection of intrinsic RV function and pulmonary vascular coupling, but fluid status also dynamically affects this index of RV function. Normative values with invasive measurements were obtained for future assessment of HF patients.

Layer-specific deformation analysis in severe aortic valve stenosis, primary mitral valve regurgitation, and healthy individuals validated against invasive hemodynamic measurements of heart function.

AIM: Speckle tracking echocardiography is considered valuable in assessing left ventricular (LV) function. The method has been refined to assess deformation in different myocardial layers, but the effect of volume vs pressure overload on this pattern is unknown. The aim was to test whether layer-specific myocardial strain (LSS) obtained by speckle tracking echocardiography exhibits different patterns in conditions with different loading conditions. METHODS AND RESULTS: Forty patients with asymptomatic severe aortic stenosis (AS) (AVA 0.81 ± 0.15 cm2 , LV ejection fraction [LVEF] 66% ± 7%), 43 patients with asymptomatic or mildly symptomatic significant primary mitral regurgitation (MR) (effective regurgitant orifice (ERO) 0.51 (IQR 0.37-0.67) cm2 , LVEF 70% ± 7%), and 23 healthy individuals (LVEF 65% ± 6%) were enrolled. Echocardiography and right heart catheterization were performed in all patients. In MR, strain values in each myocardial layer (endocardial/global longitudinal strain (GLS)/epicardial) were higher (25.0% ± 3.4%/21.6% ± 2.9%/18.8% ± 2.6%) compared to healthy individuals (22.6% ± 3.2%/19.6% ± 2.9%/17.1% ± 2.6%) and AS (20.5% ± 2.8%/17.7% ± 2.5%/14.0% ± 5.6%), P < .001. All 3 groups exhibited a similar LSS pattern with highest values in the endocardial and lowest values in the epicardial layer. The epicardial-endocardial strain ratio was lower in AS (0.72 ± 0.04) than in MR (0.75 ± 0.04, P = .04). Global longitudinal strain (GLS) correlated significantly with LV wall stress (r = .39, P = .0003) but not with LV stroke work or contractility. CONCLUSION: Layer-specific myocardial strain (LSS) patterns differed in patients with severe AS, significant MR, and healthy individuals with highest values in MR. Strain irrespective of layer assessed was associated with LV wall stress but seemed less related to contractility and unrelated to stroke work in the setting of normal LVEF.

Mitral valve regurgitation in twins: Concordance and survival.

BACKGROUND: Smaller observational studies have suggested familial clustering of mitral regurgitation (MR). Using a large twin cohort, the aims were to assess MR concordance rates and assess mortality in MR twins and unaffected cotwins. METHODS: Through the Danish Twin Registry, twins with an International Classification of Diseases, Eighth Revision and Tenth Revision diagnosis code of MR born 1880-1989 were identified and proband-wise concordance rates were calculated. To assess whether having a cotwin with MR affected survival, 10 matched twins without MR (n = 5,575) were selected for each MR twin (n = 562), and all-cause mortality rates were assessed. RESULTS: Among the 87,432 twins alive January 1, 1977, or later, 494 (0.57%) MR individuals were identified. Six MR concordant pairs were found, of which 3 were monozygotic. Proband-wise concordance rate when accounting for right censoring and competing risk of death was 0.12 (95% CI 0.04-0.32) for monozygotic twins and 0.03 (95% CI 0.01-0.09) for dizygotic twins. Mortality was significantly higher among the affected twins with MR within discordant twin pairs where both were alive at the date of MR diagnosis (sex-adjusted hazard ratio [HR] 2.57, 95% CI 1.86-3.54). Overall there was no increased mortality risk for unaffected cotwins to MR cases compared with matched controls (HR 1.02, 95% CI 0.90-1.17) except for first year of life (HR 1.92, 95% CI 1.10-3.36) and for monozygotic twins older than 65 years (HR 1.49, 95% CI 1.07-2.08). CONCLUSION: Although there is a familial aggregation of MR, the absolute risk is low, even for monozygotic cotwins to affected twins. The study found increased mortality in MR twins compared with their unaffected cotwins. Overall no excess mortality was observed in the unaffected cotwins except for first year of life and for monozygotic cotwins older than 65 years.

Pressure-flow responses to exercise in aortic stenosis, mitral regurgitation and diastolic dysfunction.

BACKGROUND: Haemodynamic exercise testing is important for evaluating patients with dyspnoea on exertion and preserved ejection fraction. Despite very different pathologies, patients with pressure (aortic stenosis (AS)) and volume (mitral regurgitation (MR)) overload and diastolic dysfunction after recent acute myocardial infarction (AMI) reach similar filling pressure levels with exercise. The pressure-flow relationships (the association between change in cardiac output (∆CO) and change in pulmonary arterial wedge pressure (∆PAWP) may provide insight into haemodynamic adaptation to exercise in these groups. METHODS AND RESULTS: One hundred sixty-eight subjects aged >50 years with a left ventricular ejection fraction of ≥50% underwent invasive exercise testing. They were enrolled in four different studies: AS (40 patients), AMI (52 patients), MR (43 patients) and 33 healthy subjects. Haemodynamic data were measured at rest, at 25 W, 75 W and at peak exercise. In all groups, PAWP increased with exercise. The greatest increase was observed in patients with AMI (from 12.7±3.9 mm Hg to 33.1±8.2 mm Hg, p<0.0001) and patients with AS (from 11.8±3.9 mm Hg to 31.4±6.1 mm Hg, p<0.0001), and the smallest was observed in healthy subjects (from 8.3±2.4 mm Hg to 21.1±7.5 mm Hg, p<0.0001). In all groups, the relative pressure increase was greatest at the beginning of the exercise. CO increased most in healthy patients (from 5.3±1.1 to 16.0±3.0 L/min, p<0.0001) and least in patients with AS (from 5.3±1.2 L/min to 12.4±2.6 L/min, p<0.0001). The pressure-flow relationships (∆PAWP/∆CO) and differed among groups (p=0.02). In all groups, the pressure-flow relationship was steepest in the initial phase of the exercise test. The AMI and AS groups (2.3±1.2 mm Hg/L/min and 3.0±1.3 mm Hg/L/min, AMI and AS, respectively) had the largest overall pressure-flow relationship; the healthy group had the smallest initially and at peak exercise (1.3±1.1 mm Hg/L/min) followed by MR group (1.9±1.4 mm Hg/L/min). CONCLUSION: The pressure-flow relationship was steepest in the initial phase of the exercise test in all groups. The pressure-flow relationship differs between groups. TRIAL REGISTRATION NUMBERS: NCT01974557, NCT01046838, NCT02961647 and NCT02395107.

Hemodynamic Characteristics in Significant Symptomatic and Asymptomatic Primary Mitral Valve Regurgitation at Rest and During Exercise.

BACKGROUND: In severe asymptomatic primary mitral valve regurgitation without risk factors, surgery strategy is controversial. We sought to clarify whether being symptomatic corresponds to the hemodynamic burden and reduced exercise capacity. A better understanding of this may contribute to optimize timing of surgery. METHODS AND RESULTS: Subjects with asymptomatic (New York Heart Association functional class I, n=29) or symptomatic (New York Heart Association functional class II and III, n=28) significant primary mitral valve regurgitation (effective regurgitant orifice, ≥0.30 cm2; left ventricular ejection fraction, >60%) were included. Right heart catheterization during rest and exercise, echocardiography, magnetic resonance imaging, and peak oxygen consumption test was performed. Symptomatic subjects had significantly higher pulmonary capillary wedge pressure at rest (14±4 versus 11±3 mm Hg; P=0.003) and at maximal exercise (30±6 versus 25±7 mm Hg; P=0.02) and higher mean pulmonary artery pressure (PAP) at rest (22±7 versus 18±4 mm Hg; P=0.005) and maximal exercise (46±8 versus 39±7 mm Hg; P=0.005) than asymptomatic subjects. Among asymptomatic subjects with normal resting value, exercise testing revealed a systolic PAP >60 mm Hg in 34%. Also the reverse response with minimal increase in pulmonary capillary wedge pressure and mean PAP during exercise was seen, especially in asymptomatic subjects. Among symptomatic subjects, we found a significant inverse correlation between resting mean PAP and left ventricular ejection fraction (r=-0.52; P=0.02) and right ventricular ejection fraction (r=-0.67; P<0.01). Peak oxygen consumption was equal and normal in both groups and correlated with left ventricular stroke volume but not with pulmonary capillary wedge pressure. CONCLUSIONS: Symptoms in patients with severe mitral valve regurgitation relate to congestion (pulmonary capillary wedge pressure and PAP), but not to peak oxygen consumption, which is determined by forward left ventricular stroke volume. Exercise testing reveals a higher mitral valve regurgitation burden in apparently asymptomatic patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02961647.

Cardiac remodelling and haemodynamic characteristics in primary mitral valve regurgitation.

Objective: To assess the association between cardiac morphology and function assessed with cardiac MRI (CMRI) and haemodynamics at rest and during exercise in patients with primary mitral regurgitation (MR). Methods: In an observational study, subjects with significant primary MR (N = 46) with effective regurgitant orifice ≥ 0.30 cm2 and left ventricular (LV) ejection fraction > 60% were examined with right heart catheterisation during rest and exercise and CMRI at rest. End-diastolic pressure volume relationship (EDPVR) was assessed using a single beat method using pulmonary capillary wedge pressure (PCWP) and end-diastolic volume. Patients were divided according to normal PCWP at rest (> 12 mm Hg) and with exercise (> 28 mm Hg). Results: Resting regurgitant volume correlated positively with resting PCWP, (r = 0.42, p = 0.002). However, with exercise no association between PCWP and regurgitant volume was seen (r = 0.09, p = 0.55). At rest left atrial (LA) maximal, minimal and volume index at atrial contraction correlated positively with PCWP (r = 0.60; r = 0.55; r = 0.58, all p < 0.001); in contrast none of these correlated with exercise PCWP (all p > 0.2). EDPVR in patients with high PCWP at rest was shifted towards higher volumes for the same pressures. The opposite was seen for patients with high PCWP during exercise where estimated volumes were smaller for the same pressure than patients with normal exercise PCWP. Conclusion: In patients with significant MR the degree of regurgitation and LA dilatation is associated with resting PCWP. However, with exercise this association disappears. Estimation of EDPVR suggests lower LV compliance in patients where PCWP is increased with exercise. Clinical trial registration: URL: https://clinicaltrials.gov/ct2/show/NCT02961647?term=HEMI&rank=1. ID: NCT02961647.

The Influence of Age on Hemodynamic Parameters During Rest and Exercise in Healthy Individuals.

OBJECTIVES: In this study, the authors sought to obtain hemodynamic estimates across a wide age span and in both sexes for future reference and compare these estimates with current guideline diagnostic hemodynamic thresholds for abnormal filling pressure and pulmonary hypertension. BACKGROUND: At present, the influence of age on hemodynamic function is largely unknown. Because many diseases with proposed cardiac impact are more prevalent in the older population, it is pivotal to know how hemodynamic parameters are affected by age itself to discern the influence of disease from that of physiological aging. METHODS: Sixty-two healthy participants, evenly distributed with respect to age (20 to 80 years) and sex (32 women/30 men), were prospectively enrolled in the study. Participants were all deemed healthy by medical history, echocardiography, exercise test, spirometry, blood tests, and electrocardiogram. Participants had hemodynamic parameters measured using right heart catheterization during rest, passive leg raise, and incremental exercise. RESULTS: During rest, all hemodynamic parameters were similar between age groups, apart from blood pressure. During leg raise and incremental exercise, there was augmented filling pressure (p < 0.0001) and diminished cardiac output (p = 0.001) and hence a higher pressure:flow ratio (pulmonary artery pressure/capillary wedge pressure to cardiac output) with progressive age, evident from the earliest ages. All indexed hemodynamic measures were similar between sexes. The diagnostic threshold (pulmonary capillary wedge pressure ≥25 mm Hg) currently used during exercise testing to diagnose abnormal left ventricular filling pressure was measured in 30% of our healthy elderly participants. CONCLUSIONS: Cardiac aging was progressive without sex differences in healthy participants. The hemodynamic reference values obtained suggest that the diagnostic threshold for abnormal filling pressure should be individually determined according to age of the patient.

Relation of Left Atrial Size, Cardiac Morphology, and Clinical Outcome in Asymptomatic Aortic Stenosis.

Left atrial (LA) dilation in asymptomatic severe aortic stenosis (AS) may be an indicator of advanced disease. We aimed to investigate the association between LA volume index and left ventricular (LV) morphology assessed with cardiac magnetic resonance imaging (cMRI), and to assess the association with cardiac events. Ninety-two asymptomatic patients with aortic valve area <1 cm2, aortic peak jet velocity >3.5 m/s, and ejection fraction ≥50% were prospectively enrolled and divided according to echocardiographic-derived LA volume index <35 ml/m2. Patients underwent echocardiography, cMRI, exercise testing, and were followed for the composite end point of death, readmission, or aortic valve replacement. Aortic valve area index was similar (0.45 ± 0.08 cm2/m2 vs 0.45 ± 0.09 cm2/m2, p = 0.85) in patients with a dilated and normal LA. On cMRI patients with dilated LA were characterized by higher LV mass index (73 ± 17 g/m2 vs 66 ± 16 g/m2, p = 0.03), increased right ventricle (70 ± 14 ml/m2 vs 63 ± 12 ml/m2, p = 0.01) and LV end-diastolic volume index (84 ± 18 ml/m2 vs 77 ± 16 ml/m2, p = 0.05), and higher brain natriuretic peptide. Late enhancement pattern was similar. During follow-up 20 events were recorded in patients with LA dilation compared with 8 in patients with normal LA (adjusted hazard ratio 2.77, 95% confidence interval 1.19 to 6.46, p = 0.02); also B-type natriuretic peptide >125 pg/ml was associated with adverse outcome (adjusted hazard ratio 3.63, 95% confidence interval interval 1.28 to 10.32, p = 0.02). LA dilation is associated with LV remodeling and provides prognostic information in severe asymptomatic AS.

Sudden cardiac death in asymptomatic aortic stenosis: is the valve to blame?

An active 68-year-old man with asymptomatic severe aortic stenosis and normal functional capacity on a conventional bicycle exercise test underwent a haemodynamic stress test with simultaneous invasive haemodynamic monitoring and echocardiography during supine bicycle testing as part of a research project. With exercise, the patient developed pulmonary venous hypertension and mild regional wall motion abnormalities on echocardiography. The patient terminated the test due to exhaustion. In the recovery period, he developed sustained ventricular tachycardia and became unconscious. No symptoms were present during exercise or prior to cardiac arrest. The following coronary angiogram revealed significant 2-vessel disease, and the patient subsequently underwent successful aortic valve replacement and coronary-artery bypass graft surgery.

Association Between Left Atrial Dilatation and Invasive Hemodynamics at Rest and During Exercise in Asymptomatic Aortic Stenosis.

BACKGROUND: Transition from an asymptomatic to symptomatic state in severe aortic stenosis is often difficult to assess. Identification of a morphological sign of increased hemodynamic load may be important in asymptomatic aortic stenosis to identify patients at risk. METHODS AND RESULTS: Thirty-nine patients with asymptomatic severe aortic stenosis (aortic valve area <1 cm2, peak jet velocity >3.5 m/s) underwent exercise testing with simultaneous invasive hemodynamic monitoring and Doppler echocardiography. Cardiac index, pulmonary artery pressure, and pulmonary capillary wedge pressure (PCWP) were recorded. Patients were followed up for the composite end point of death, unplanned hospitalization, or aortic valve replacement. Patients were stratified into 2 groups according to left atrial (LA) volume index ≥35 mL/m2. In 25 patients (64%) LA volume index was ≥35 mL/m2. Aortic valve area was similar between groups (0.81±0.15 versus 0.84±0.18 cm2; P=0.58). PCWP was higher at rest and during exercise in patients with LA volume index ≥35 mL/m2 (P<0.01), despite similar cardiac index. At rest, PCWP was <12 mm Hg in 11 patients (44%) with LA dilatation, whereas PCWP was <25 mm Hg in 1 patient (4%) with exercise. LA volume index and E/e' predicted exercise PCWP>30 mm Hg with areas under the receiver operating curve of 0.75 and 0.84, respectively. During follow-up, 14 cardiac events were recorded. LA volume was associated with a hazard ratio of 1.90 (95% confidence interval, 0.92-4.15). CONCLUSIONS: LA size reflects hemodynamic burden in patients with asymptomatic severe aortic stenosis. Quantitative measurements of LA and diastolic function are associated with left ventricular filling pressures with exercise and could be used to identify asymptomatic patients with increased hemodynamic burden. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02395107.

Early changes in left atrial volume after acute myocardial infarction. Relation to invasive hemodynamics at rest and during exercise.

BACKGROUND: Dilatation of left atrium (LA) reflects chronic LA pressure or volume overload that possesses considerable prognostic information. Little is known regarding the interaction between LA remodeling after acute myocardial infarction (MI) and left atrial pressure at rest and during exercise. The objective was to assess changes in LA volume early after MI in patients with diastolic dysfunction and the relation to invasive hemodynamics and natriuretic peptides. METHODS: 62 patients with left ventricle ejection fraction (LVEF)≥45%, diastolic E/e'>8 and LA volume index >34ml/m2 within 48h of MI were enrolled. After 1 and 4months blood sampling, echocardiography and right heart catheterization were performed during exercise test. RESULTS: LA remodeling was considered in patients with a change from mild (35-41ml/m2), to severe (>48ml/m2) dilatation after 4months (Found in 22 patients (35%)). Patients with LA remodeling were characterized by lower a' (1month 8.9±2.0 vs. 10.4±2.5cm/s, p=0.002; 4month 8.8±2.0 vs. 10.4±2.4cm/s, p=0.007) and higher MR-proANP (1month 162±64 vs. 120±44pg/l, p=0.005; 4months 175±48 vs. 129±56pg/l, p=0.002). With exercise, pulmonary artery pressure, right atrial pressure and pulmonary capillary wedge pressure increased markedly in all patients. There were however, no significant differences in filling pressure at rest or during exercise irrespective of whether LA remodeling occurred. CONCLUSION: Contrary to our hypothesis early LA dilatation after MI was weakly associated with resting and exercise induced changes in LA pressure overload. The dilatation was however associated with lower e' and higher MR-proANP.