Predictive capacity of a genetic risk score for coronary artery disease in assessing recurrences and cardiovascular mortality among patients with myocardial infarction.

Aim: This study aimed to evaluate the capacity of a genetic risk score (GRS) for coronary artery disease (CAD) independent of classical cardiovascular risk factors to assess the risk of recurrence in patients with first myocardial infarction. The secondary aim was to determine the predictive value of this GRS. Methods: We performed a meta-analysis of individual data from three studies, namely, a prospective study including 75 patients aged <55 years, a prospective study including 184 patients with a mean age of 60.5 years, and a case-control study (77 cases and 160 controls) nested in a cohort of patients with first myocardial infarction. A GRS including 12 CAD genetic variants independent of classical cardiovascular risk factors was developed. The outcome was a composite of cardiovascular mortality and recurrent acute coronary syndrome. Results: The GRS was associated with a higher risk of recurrence [hazard ratio = 1.24; 95% confidence interval (CI): 1.04-1.47]. The inclusion of the GRS in the clinical model did not increase the model's discriminative capacity (change in C-statistic/area under the curve: 0.009; 95% CI: -0.007 to 0.025) but improved its reclassification (continuous net reclassification index: 0.29; 95% CI: 0.08-0.51). Conclusion: The GRS for CAD, independent of classical cardiovascular risk factors, was associated with a higher risk of recurrence in patients with first myocardial infarction. The predictive capacity of this GRS identified a subgroup of high-risk patients who could benefit from intensive preventive strategies.

Machine Learning to Optimize the Echocardiographic Follow-Up of Aortic Stenosis.

BACKGROUND: Disease progression in patients with mild-to-moderate aortic stenosis is heterogenous and requires periodic echocardiographic examinations to evaluate severity. OBJECTIVES: This study sought to explore the use of machine learning to optimize aortic stenosis echocardiographic surveillance automatically. METHODS: The study investigators trained, validated, and externally applied a machine learning model to predict whether a patient with mild-to-moderate aortic stenosis will develop severe valvular disease at 1, 2, or 3 years. Demographic and echocardiographic patient data to develop the model were obtained from a tertiary hospital consisting of 4,633 echocardiograms from 1,638 consecutive patients. The external cohort was obtained from an independent tertiary hospital, consisting of 4,531 echocardiograms from 1,533 patients. Echocardiographic surveillance timing results were compared with the European and American guidelines echocardiographic follow-up recommendations. RESULTS: In internal validation, the model discriminated severe from nonsevere aortic stenosis development with an area under the receiver-operating characteristic curve (AUC-ROC) of 0.90, 0.92, and 0.92 for the 1-, 2-, or 3-year interval, respectively. In external application, the model showed an AUC-ROC of 0.85, 0.85, and 0.85, for the 1-, 2-, or 3-year interval. A simulated application of the model in the external validation cohort resulted in savings of 49% and 13% of unnecessary echocardiographic examinations per year compared with European and American guideline recommendations, respectively. CONCLUSIONS: Machine learning provides real-time, automated, personalized timing of next echocardiographic follow-up examination for patients with mild-to-moderate aortic stenosis. Compared with European and American guidelines, the model reduces the number of patient examinations.

Mean Velocity of the Pulmonary Artery as a Clinically Relevant Prognostic Indicator in Patients with Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Right ventricular (RV) to pulmonary circulation (PC) coupling can stratify prognosis in heart failure (HF). In this study, we assessed the prognostic role of the mean velocity of the pulmonary artery (mvPA) determined by cardiac magnetic resonance (CMR) in HF with preserved ejection fraction (HFpEF). METHODS: Inclusion of 58 HFpEF outpatients that underwent CMR with measurement of RV-PC coupling parameters including mvPA between 2016 and 2019. The primary combined endpoint was a composite of HF readmissions and all-cause mortality. RESULTS: Optimal cut-off value of mvPA calculated by receiver operating curve for the prediction of the primary endpoint was 9 cm/s. Over a median follow-up of 23 months (interquartile range: 24), 21 patients met the primary endpoint. The primary endpoint was more frequent in patients with mvPA ≤ 9 cm/s, as indicated by Kaplan-Meier survival curves; Log-Rank: 9.193, p = 0.02, regardless of RV dysfunction. On Cox multivariate analysis, mvPA ≤ 9 cm/s emerged as an independent prognostic predictor of the primary endpoint (HR: 4.11, 95% CI: 1.28-13.19, p = 0.017), together with left atrial area by CMR (HR: 1.08, 95% CI: 1.01-1.24, p = 0.034). CONCLUSIONS: In our HFpEF cohort, mvPA was associated with a higher rate of the primary endpoint, regardless of RV function, thus enabling identification of patients at higher risk of cardiovascular events before structural damage onset.

Non-selective beta-blockers impair global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites.

BACKGROUND & AIMS: The safety of non-selective ß-blockers (NSBBs) has been questioned in refractory ascites (RA). We studied the effects of NSBBs on cardiac systolic function, systemic hemodynamics, and renal perfusion pressure (RPP) and function in patients with diuretic-responsive ascites (DRA) and RA. METHODS: We performed a prospective pre-post repeated-measures study in cirrhotic patients, 18 with DRA and 20 with RA on NSBBs for variceal bleeding prophylaxis. Systolic function (by ejection intraventricular pressure difference [EIVPD]), hepatic venous pressure gradient (HVPG), cardiopulmonary pressures, RPP, and sympathetic activation were measured at baseline and after 4 weeks of propranolol. RESULTS: EIVPD was elevated at baseline (RA 4.5 [2.8-5.7] and DRA 4.2 [3.1-5.7] mmHg; normal 2.4-3.6 mmHg) and directly related to the severity of vasodilation and sympathetic activation. NSBBs led to similar reductions in heart rate and HVPG in both groups. NSBBs reduced EIPVD in RA but not in DRA (-20% vs. -2%, p <0.01). In RA, the NSBB-induced reduction in EIPVD correlated with the severity of vasodilation and with higher plasma nitric oxide, norepinephrine and IL-6 (r >0.40, all p <0.05). NSBBs reduced RPP in both groups, but impaired renal function only in patients with RA. Reduced EIPVD correlated with decreases in RPP and estimated glomerular filtration rate (r >0.40, all p <0.01). After NSBB treatment, RPP dropped below the threshold of renal flow autoregulation in 11 of the 20 (55%) patients with RA, including the 4 fulfilling the criteria for HRS-AKI. CONCLUSION: Renal perfusion and function depend critically on systolic function and sympathetic hyperactivation in RA. NSBBs blunt the sympathetic overdrive, hamper cardiac output, lower RPP below the critical threshold and impair renal function. ß-blockade should be used cautiously or even avoided in patients with RA. LAY SUMMARY: We have identified the mechanisms by which non-selective beta-blockers could impair survival in patients with refractory ascites. We show that peripheral vasodilation and sympathetic activation lead to increased left ventricle systolic function in patients with cirrhosis and ascites, which acts as an adaptive mechanism to maintain renal perfusion. When ascites becomes refractory, this compensatory cardiac response to vasodilation is critically dependent on sympathetic hyperactivation and is hardly able to maintain renal perfusion. In this setting, ß-blockade blunts the sympathetic overdrive of cardiac function, hampers cardiac output, lowers renal perfusion pressure below the critical threshold and impairs renal function.

Blood Stasis Imaging Predicts Cerebral Microembolism during Acute Myocardial Infarction.

BACKGROUND: Cardioembolic stroke is a major source of mortality and disability worldwide. The authors hypothesized that quantitative characterization of intracardiac blood stasis may be useful to determine cardioembolic risk in order to personalize anticoagulation therapy. The aim of this study was to assess the relationship between image-based metrics of blood stasis in the left ventricle and brain microembolism, a surrogate marker of cardiac embolism, in a controlled animal experimental model of acute myocardial infarction (AMI). METHODS: Intraventricular blood stasis maps were derived from conventional color Doppler echocardiography in 10 pigs during anterior AMI induced by sequential ligation of the mid and proximal left anterior descending coronary artery (AMI-1 and AMI-2 phases). From these maps, indices of global and local blood stasis were calculated, such as the average residence time and the size and ratio of contact with the endocardium of blood regions with long residence times. The incidence of brain microemboli (high-intensity transient signals [HITS]) was monitored using carotid Doppler ultrasound. RESULTS: HITS were detected in 0%, 50%, and 90% of the animals at baseline and during AMI-1 and AMI-2 phases, respectively. The average residence time of blood in the left ventricle increased in parallel. The residence time performed well to predict microemboli (C-index = 0.89, 95% CI, 0.75-1.00) and closely correlated with the number of HITS (R = 0.87, P < .001). Multivariate and mediation analyses demonstrated that the number of HITS during AMI phases was best explained by stasis. Among conventional echocardiographic variables, only apical wall motion score weakly correlated with the number of HITS (R = 0.3, P = .04). Mural thrombosis in the left ventricle was ruled out in all animals. CONCLUSIONS: The degree of stasis of blood in the left ventricle caused by AMI is closely related to the incidence of brain microembolism. Therefore, stasis imaging is a promising tool for a patient-specific assessment of cardioembolic risk.

The Biological Bases of Group 2 Pulmonary Hypertension.

Pulmonary hypertension (PH) is a potentially fatal condition with a prevalence of around 1% in the world population and most commonly caused by left heart disease (PH-LHD). Usually, in PH-LHD, the increase of pulmonary pressure is only conditioned by the retrograde transmission of the left atrial pressure. However, in some cases, the long-term retrograde pressure overload may trigger complex and irreversible biomechanical and biological changes in the pulmonary vasculature. This latter clinical entity, designated as combined pre- and post-capillary PH, is associated with very poor outcomes. The underlying mechanisms of this progression are poorly understood, and most of the current knowledge comes from the field of Group 1-PAH. Treatment is also an unsolved issue in patients with PH-LHD. Targeting the molecular pathways that regulate pulmonary hemodynamics and vascular remodeling has provided excellent results in other forms of PH but has a neutral or detrimental result in patients with PH-LHD. Therefore, a deep and comprehensive biological characterization of PH-LHD is essential to improve the diagnostic and prognostic evaluation of patients and, eventually, identify new therapeutic targets. Ongoing research is aimed at identify candidate genes, variants, non-coding RNAs, and other biomarkers with potential diagnostic and therapeutic implications. In this review, we discuss the state-of-the-art cellular, molecular, genetic, and epigenetic mechanisms potentially involved in PH-LHD. Signaling and effective pathways are particularly emphasized, as well as the current knowledge on -omic biomarkers. Our final aim is to provide readers with the biological foundations on which to ground both clinical and pre-clinical research in the field of PH-LHD.

The natural matching of harmonic responses in the pulmonary circulation.

KEY POINTS: The right ventricle of the mammal heart is highly sensitive to the afterload imposed by a combination of the pulmonary circulation and the retrograde contribution of the left heart. Right ventricular afterload can be analysed in terms of pulmonary artery input impedance, which we were able to decompose as the result of the harmonic frequency responses of the pulmonary vessels and the left heart attached in series. Using spectral methods, we found a natural matching between the pulmonary vasculature and the left chambers of the heart. This coupling implies that the upstream transmission of the left heart frequency-response has favourable effects on the pulmonary tree. This physiological mechanism protects the right ventricle against acute changes in preload, and its impairment may be a relevant contribution to right ventricle dysfunction in pulmonary hypertension. ABSTRACT: The right ventricle (RV) of the mammal heart is highly sensitive to the afterload imposed by the pulmonary circulation, and the left heart (LH) retrogradely contributes significantly to this vascular load. Transmission-line theory anticipates that the degree of matching between the frequency responses of the pulmonary vasculature and the LH should modulate the global right haemodynamic burden. We measured simultaneous high-fidelity flow (pulmonary artery) and pressure (pulmonary artery and left atrium) in 18 healthy minipigs under acute haemodynamic interventions. From these data, we decomposed the impedance spectra of the total right-circulation system into the impedance of the pulmonary vessels and the harmonic response of the LH. For frequencies above the first harmonic, total impedance was below the pulmonary impedance during all phases (P < 0.001; pooled phases), demonstrating a favourable effect of the LH harmonic response on RV pulsatile load: the LH harmonic response was responsible for a 20% reduction of pulse pulmonary artery pressure (P < 0.001 vs. a theoretical purely-resistive response) and a 15% increase of pulmonary compliance (P = 0.009). This effect on compliance was highest during acute volume overload. In the normal right circulation, the longitudinal impedance of the pulmonary vasculature is matched to the harmonic response of the LH in a way that efficiently reduces the pulmonary pulsatile vascular load. This source of interaction between the right and left circulations of mammals protects the RV against excessive afterload during acute volume transients and its disruption may be an important contributor to pulmonary hypertension.

Age-Dependence of Flow Homeostasis in the Left Ventricle.

Background: Intracardiac flow homeostasis requires avoiding blood stasis and platelet activation during its transit through the cardiac chambers. However, the foundations of intraventricular blood washout and its exposure to shear stresses have been poorly addressed. We aimed to characterize and quantify these features in a wide population of healthy subjects and assess the relationships of these indices with age. Methods: We used color-Doppler echocardiography and custom post-processing methods to study 149 healthy volunteers from 26 days to 80 years old. From the intraventricular flow-velocity fields we obtained personalized maps of (1) the residence time of blood in the LV, and (2) the shear index, a metric accounting for the strongest occurrence of shear stresses inside the chamber. From these maps we derived quantitative indices of the overall intraventricular blood washout and shear exposure. We addressed the age-dependence of these indices and analyzed their relationship with age-related changes in filling-flow. Results: The entire intraventricular blood pool was replaced before 8 cycles. Average residence time of blood inside the LV was <3 cycles in all subjects and followed an inverse U-shape relationship with age, increasing from median (IQR) of 1.0 (0.7 to 1.2) cycles in the 1st year of life to 1.8 (1.4-2.2) cycles in young adults (17-30 years old), becoming shorter again thereafter. Shear index showed no relation with age and was bounded around 20 dyn·s/cm2. Regions with the longest residence time and highest shear index were identified near the apex. Differences in the degree of apical penetration of the filling waves and the duration of the late-filling phase explained the age-dependence of residence time ( R adj 2 = 0.48, p < 0.001). Conclusions: In average, blood spends 1 to 3 beats inside the LV with very low shear stress rates. The apical region is the most prone to blood stasis, particularly in mid-aged adults. The washout of blood in the normal LV is age-dependent due to physiological changes in the degree of apical penetration of the filling waves.

Valve area and the risk of overestimating aortic stenosis.

OBJECTIVE: To obtain reference values of aortic valve area (AVA) in a large population and to infer the risk of overestimating aortic stenosis (AS) when focusing on flow-corrected indices of severity. METHODS: We prospectively measured indices of AS in all consecutive echocardiograms performed in a large referral cardiac imaging laboratory for 1 year. We specifically analysed the distribution of AVA, indexed AVA and velocity ratio (Vratio) in patients with and without AS, the latter defined as the coexistence of valvular outflow obstruction (Vmax ≥2.5 m/s) and morphological findings of valve degeneration. RESULTS: 16 156 echocardiograms were analysed, 14 669 of which did not show valvular obstruction (peak jet velocity <2.5 m/s). In the latter group, AVA was 2.6±0.7 cm2 in 8190 studies with normal valves and 2.3±0.7 cm2 in 6479 studies with aortic sclerosis (AScl). There was a relatively wide overlap between values of AVA, indexed AVA and velocity ratio between studies of patients with AScl and AS. Values of AVA ≤1.0 cm2 were found in 0.5% of studies with normal valves and 1.8% of studies with AScl. These proportions were 3.1% and 9.3% for AVA ≤1.5 cm2, respectively. Vratio ≤0.25 were found in 0.1% of patients without obstruction. Risk factors for a small AVA in patients without obstruction were AScl, female sex, small body surface area, low ejection fraction and mitral regurgitation. CONCLUSIONS: Normal values of continuity-equation derived AVA are smaller than previously considered. AVA values below cutoffs of moderate or severe AS can be found in patients without the disease. Flow-corrected indices may overestimate AS in patients with low gradients, particularly in the presence of well-identified risk factors.

Impact of acute hypertension transients on diastolic function in patients with heart failure with preserved ejection fraction.

AIM: To address the mechanisms responsible for the increase in LV filling pressures induced by acute hypertension transients in patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Multiple-beat pressure-volume loops were recorded during inferior vena cava occlusion in 39 HFpEF patients and 20 controls during handgrip and atrial pacing. We measured the contribution of relaxation, elastic recoil, and stiffness to instantaneous diastolic pressure using a novel processing method. Fibrosis was quantified from endomyocardial biopsies. HFpEF patients showed higher diastolic pressures and stiffness constant than controls (P < 0.05 for all). As opposed to controls, all intrinsic global diastolic properties were sensitive to acute changes in systolic pressure in the HFpEF group. In fact, the stiffness constant increased by more than 50% during handgrip in HFpEF patients (P < 0.05), tightly related to changes in systolic pressure (fixed-effect = 0.26 mm Hg per mm Hg [95% CI = 0.15-0.37]; P < 0.0001). Incomplete relaxation contributed to increasing pressure before atrial contraction, but changes in end-diastolic pressure was mostly caused by the increase in stiffness. The degree of pressure-sensitivity of stiffness correlated with myocardial collagen volume and crosslinking (R = 0.40 to 0.82 for all). CONCLUSION: Acute chamber stiffening is the main mechanism responsible for rising late-diastolic pressures when HFpEF patients undergo hypertension transients. This stiffening behaviour is related to impaired dynamic systolic-diastolic interactions and correlates with matrix remodelling. Ventricular-vascular relationships are a promising target in HFpEF and should be taken into account when assessing diastolic function.

The Functional Significance of Paradoxical Low-Gradient Aortic Valve Stenosis: Hemodynamic Findings During Cardiopulmonary Exercise Testing.

OBJECTIVES: The goal of this study was to determine the functional impact of paradoxical low-gradient aortic stenosis (PLGAS) and clarify whether the relevance of the valvular obstruction is related to baseline flow. BACKGROUND: Establishing the significance of PLGAS is particularly challenging. METHODS: Twenty symptomatic patients (77 ± 6 years of age; 17 female subjects) with PLGAS (mean gradient 28 ± 6 mm Hg; aortic valve area 0.8 ± 0.1 cm2; ejection fraction 66 ± 7%) underwent cardiopulmonary exercise testing combined with right-heart catheterization and Doppler echocardiographic measurements. RESULTS: Aortic valve area increased by 84 ± 23% (p < 0.001) and, in 70% of subjects, it reached values >1.0 cm2 at peak exercise. Stroke volume index and blood pressure increased by 83 ± 56% and 26 ± 16%, respectively (both p < 0.0001). Peak oxygen consumption inversely correlated with the rate of increase in pulmonary capillary wedge pressure (PCWP) (PCWP slope: R = -0.61; p = 0.004). In turn, the PCWP slope was determined by changes in the valvular and vascular load but not by the rest of the indices of aortic stenosis. The functional impact of PLGAS was also not related to baseline flow. Agreement between Doppler echocardiography and the Fick technique was good up to intermediate workload. CONCLUSIONS: In symptomatic patients with PLGAS, the capacity to dynamically reduce vascular and valvular loads determines the effect of exercise on PCWP, which, in turn, conditions the functional status. A critically fixed valvular obstruction may not be the main mechanism of functional impairment in a large proportion of patients with PLGAS. Exercise echocardiography is suitable to study the dynamics of PLGAS.

A clinical method for mapping and quantifying blood stasis in the left ventricle.

In patients at risk of intraventrcular thrombosis, the benefits of chronic anticoagulation therapy need to be balanced with the pro-hemorrhagic effects of therapy. Blood stasis in the cardiac chambers is a recognized risk factor for intracardiac thrombosis and potential cardiogenic embolic events. In this work, we present a novel flow image-based method to assess the location and extent of intraventricular stasis regions inside the left ventricle (LV) by digital processing flow-velocity images obtained either by phase-contrast magnetic resonance (PCMR) or 2D color-Doppler velocimetry (echo-CDV). This approach is based on quantifying the distribution of the blood Residence Time (TR) from time-resolved blood velocity fields in the LV. We tested the new method in illustrative examples of normal hearts, patients with dilated cardiomyopathy and one patient before and after the implantation of a left ventricular assist device (LVAD). The method allowed us to assess in-vivo the location and extent of the stasis regions in the LV. Original metrics were developed to integrate flow properties into simple scalars suitable for a robust and personalized assessment of the risk of thrombosis. From a clinical perspective, this work introduces the new paradigm that quantitative flow dynamics can provide the basis to obtain subclinical markers of intraventricular thrombosis risk. The early prediction of LV blood stasis may result in decrease strokes by appropriate use of anticoagulant therapy for the purpose of primary and secondary prevention. It may also have a significant impact on LVAD device design and operation set-up.

Técnicas de imagen en la insuficiencia cardiaca aguda / Imaging techniques in acute heart failure

En los últimos años las técnicas de imagen han revolucionado el diagnóstico de la insuficiencia cardiaca. Ante un cuadro clínico compatible con descompensación aguda, la instauración precoz de las medidas generales y el tratamiento etiológico determina en gran medida el pronóstico. Dada su rentabilidad diagnóstica y su portabilidad, la exploración con ultrasonidos se ha convertido en una herramienta fundamental en este contexto, y actualmente se encuentra en todos los ámbitos médicos que rodean al paciente crítico. La resonancia magnética cardiaca y la tomografía computarizada permiten caracterizar en detalle múltiples aspectos previamente inasequibles de la anatomía y la función cardiacas. Esto permite guiar y monitorizar la mayor parte de las decisiones terapéuticas en esta población de una forma completamente no invasiva. El presente artículo tiene por objeto revisar la utilidad de las técnicas de imagen clínicamente relevantes en el contexto de un episodio agudo de insuficiencia cardiaca. Se enfatizan con especial detalle sus indicaciones y limitaciones, y se proporcionan las bases para interpretar adecuadamente sus resultados (AU)

In recent years, imaging techniques have revolutionized the diagnosis of heart failure. In patients with a clinical picture of acute decompensation, prognosis is largely determined by early implementation of general measures and treatment of the underlying cause. Given its diagnostic yield and portability, ultrasound has become an essential tool in the setting of acute heart failure, and is currently found in all medical departments involved in the care of the critically ill patient. Cardiac magnetic resonance and computed tomography allow detailed characterization of multiple aspects of cardiac structure and function that were previously unavailable. This helps guide and monitor many of the treatment decisions in the acute heart failure population in an entirely noninvasive way. This article aims to review the usefulness of the imaging techniques that are clinically relevant in the context of an episode of acute heart failure. We discuss the indications and limitations of these techniques in detail and describe the general principles for the appropriate interpretation of results (AU)