Measures Of Cardiac Performance Research Articles

Abstract P1013: Identification Of Genetic Links Between Cardiovascular Disease And Insomnia In Drosophila

Cardiovascular disease (CVD) is the leading cause of death worldwide. CVD is associated with insomnia such that insomnia symptoms double the risk of incident CVD. However, how they are related is unknown. Two recent genome-wide association studies (GWAS) identified genetic loci significantly associated with insomnia, including one locus with five nearby genes that are associated with CVD in an independent GWAS. Therefore, we hypothesized that genetic predisposition to insomnia contributes to the development of CVD. To test this and identify causal genes at this locus, we used Drosophila melanogaster, which are well-established model systems for sleep and cardiac studies. To assess the role of these genes on cardiac physiology, we used the cardiac-specific Hand-Gal4 driver to perform genetic knockdown (KD). One-week-old Drosophila progeny were then used for semi-intact microscopic heart preparation followed by high-speed videography to assess cardiac physiology. Similarly, to assess their role in sleep, we used the neuronal-specific Elav-Gal4 driver to perform KD of these genes. Sleep and locomotor activity of one-week-old flies were monitored using the Drosophila Activity Monitoring System. We found that neuronal and cardiac-specific RNAi KD of four genes conserved in Drosophila: Lsn, ATPSynC, Bruce, and Imp, contributes to compromised sleep and cardiac performance, respectively. Cardiac-specific KD of Lsn led to significant cardiac dilation and reduced fractional shortening, a measure of cardiac performance. KD of ATPSynC led to significantly reduced fractional shortening without dilations. Furthermore, Lsn and ATPSynC KD hearts had disrupted actin-containing myofibrillar organization. Suppression of Lsn increased Pericardin deposition, indicative of fibrosis. Also, the cardiac suppression of ATPSynC and Lsn significantly shortened lifespan. Neuronal-specific KD of three genes significantly disrupted sleep. Furthermore, KD of ATPSynC and Lsn in the heart disrupted sleep in a non-cell-autonomous manner. This work provides novel insights into genetic mechanisms linking CVD and insomnia, highlighting the potential importance of these four genes in the development of both diseases.

Myocardial contraction fraction: an underused imaging biomarker

Abstract Funding Acknowledgements Type of funding sources: None. Background The Myocardial contraction fraction (MCF% – stroke volume over myocardial volume) is an alternative/complementary measure of cardiac function to the ejection fraction (EF% – stroke volume over end diastolic volume), (1–2). It is dimensionless, does not need allometric scaling, is easy to compute and intuitive: the stroke volume produced per unit of myocardium, with some data for its utility in different forms of hypertrophy, (3–5). EF limitations (eg HFpEF) are well known. We explored the potential utility of MCF in a variety of cardiac diseases. Purpose To define reference ranges for MCF in normal and disease using a large dataset, exploring sex and age-related differences. To evaluate and compare the potential use of MCF as a prognostic biomarker compared to the more commonly used LVEF. Methods 3 cohorts were used: 1. Health: 3,541 subjects from UK biobank, supplemented by 72 local healthy volunteers (UKB lower age limit is 45) to define normality and age/sex differences. 2. Disease: n=380 with a range of diseases : 125 HCM, 157 Fabry disease (FD) and 26 Transthyretin (TTR) Amyloid. 3. Prognostic cohort: n=1500 patients from a single centre with outcomes (26% death or hospitalisation with heart failure over a median 5.5years follow-up) All CMR images were analysed using a clinically validated artificial intelligence (AI) algorithm for convenience of large-scale analysis (6) to determine MCF and LVEF. Results Health: There was no significant changes in MCF with age but there was a significant sex difference (male 0.94, range 0.68–1.2; female 1.10, range 0.82–1.37 p<0.05)—see figure 1. Disease: MCF values for each disease cohort is shown in figure 2, all with a significant reduction compared to the healthy controls. Values ranged from 0.47 with Amyloid to 0.94 with Fabrys. Outcome: MCF strongly predicted patient outcomes – and was a more powerful predictor than LVEF (LVEF chi-squared=84 vs MCF chi-squared=160). Conclusion MCF is a complementary measure of cardiac performance to LVEF and equally as logical, intuitive and easy to calculate. It is frequently reduced even when LVEF is normal, and is a much stronger predictor of outcome than LVEF.

Cardiac Power Output Is Independently and Incrementally Associated With Adverse Outcomes in Heart Failure With Preserved Ejection Fraction.

Cardiac power output is a measure of cardiac performance, and its prognostic significance has been shown in heart failure (HF) with reduced ejection fraction. Patients with HF with preserved ejection fraction may have altered cardiac performance, but the prognostic relevance of cardiac power output is unknown. This study sought to determine the association between cardiac power output and clinical outcomes in HF with preserved ejection fraction and to compare its prognostic effect to other measures of cardiac performance including ventricular-arterial coupling and mechanical efficiency. Cardiac power output normalized to left ventricular mass was assessed by echocardiography in 408 patients with HF with preserved ejection fraction. Load-independent contractility (end-systolic elastance), arterial elastance, its coupling (arterial elastance/end-systolic elastance), left ventricular global longitudinal strain, and mechanical efficiency (stroke work/pressure-volume area) were also estimated noninvasively. The primary end point was a composite of cardiovascular mortality or HF hospitalization. The primary composite outcome occurred in 84 patients during a median follow-up of 19.4 months. There was a dose-dependent association between cardiac power output and the composite outcomes, in which patients with the lowest tertile of cardiac power output had >3-fold risk than those with the highest tertile (hazard ratio, 3.04 [95% CI, 1.66-5.57]; P=0.0003). In a multivariable model, lower cardiac power output was independently associated with adverse outcomes (hazard ratio, 0.70 per 1 SD [95% CI, 0.49-0.97]; P=0.03). In contrast, left ventricular size, end-systolic elastance, arterial elastance, arterial elastance/end-systolic elastance ratio, and left ventricular mechanical efficiency were not associated with outcomes. Cardiac power output provided an incremental prognostic effect over the model based on clinical (age, gender, diastolic blood pressure, and atrial fibrillation) and echocardiographic markers (left atrial size, pulmonary pressures, global longitudinal strain, and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular tissue velocity; P=0.03). In patients with HF with preserved ejection fraction, cardiac power output was independently and incrementally associated with adverse outcomes whereas other markers of cardiac performance were not.

Oil induced cardiac effects in embryonic sheepshead minnows, Cyprinodon variegatus

Following the Deepwater Horizon oil spill in April 2010, much research has been conducted on the cardiotoxic effects of oil on fish. Sensitive life history stages, such as the embryonic period, have been targeted to elucidate the effects of polycyclic aromatic hydrocarbons (PAHs) on the developing cardiovascular systems of fish. However, much of this research has focused on rapidly developing pelagic species, with little emphasis on estuarine species with longer embryological periods. Moreover, previous studies have used heart rate as the primary endpoint to measure cardiac performance in embryos and larvae; an endpoint that on its own may overlook impairment in cardiac performance. This study aims to fill these knowledge gaps and provide a more holistic approach for assessing the effects of PAHs on cardiac function by exposing sheepshead minnow (Cyprinodon variegatus) embryos to two oil doses (150 and 300 μg/L tPAH nominally) throughout embryonic development and measuring cardiac responses through the identification of cardiotoxic phenotypes (pericardial edema) as well as calculation of cardiac output at 4 days post fertilization. Results of this study show significant increases in pericardial edema at both oil doses relative to controls as well as significantly reduced cardiac output – driven by reductions in ventricular stroke volume. This study is one of the first to assess cardiac output in embryonic fish exposed to oil and methods described here allow for more physiologically relevant measures of cardiac performance in early life stages through established and non-invasive measures.

Outpatient Prescription Practices in Patients with Atrial Fibrillation (From the NCDR PINNACLE Registry)

This study sought to evaluate inappropriate prescribing practices in an atrial fibrillation (AF) population, as outlined by the 2016 ACC/AHA Clinical Performance and Quality Measures for Adults with Atrial Fibrillation or Atrial Flutter document. The 2016 AF quality measures document specified medications to avoid in certain AF populations, including aspirin and anticoagulant combination therapy in patients without cardiovascular disease, and non-dihydropyridine calcium channel blockers in patients with reduced ejection fraction. Using data from the NCDR PINNACLE registry, a national outpatient cardiology practice registry, we assessed rates of inappropriate prescription of two types of medications among AF outpatients from 5/1/2008-5/1/2016. Overall rates of inappropriate prescription and variation by practice were calculated. Patient and practice factors associated with inappropriate prescription were assessed in adjusted analyses. A total of 107,759 of 658,250 (16.4%) patients without cardiovascular disease were inappropriately prescribed an antiplatelet and anticoagulant together, and 5,731 of 150,079 (3.8%) patients with reduced ejection fraction were inappropriately prescribed a non-dihydropyridine calcium channel blocker. Overall, 14.8% of AF patients were prescribed medications that were not recommended. Both patient and practice factors were associated with inappropriate prescribing, and the adjusted practice-level median odds ratio for inappropriate prescription was 1.70 (95% CI: 1.61-1.82), indicating a 70% likelihood that 2 random practices would treat identical AF patients differently. In a large registry of AF patients treated in cardiology practices, overall rates of inappropriate prescription practices, as defined by the 2016 AF quality measures, were relatively low, but significant practice variation was present.

Prognostic value of peak stress cardiac power in patients with normal ejection fraction undergoing exercise stress echocardiography.

Cardiac power is a measure of cardiac performance that incorporates both pressure and flow components. Prior studies have shown that cardiac power predicts outcomes in patients with reduced left ventricular (LV) ejection fraction (EF). We sought to evaluate the prognostic significance of peak exercise cardiac power and power reserve in patients with normal EF. We performed a retrospective analysis in 24885 patients (age 59 ± 13 years, 45% females) with EF ≥50% and no significant valve disease or right ventricular dysfunction, undergoing exercise stress echocardiography between 2004 and 2018. Cardiac power and power reserve (developed power with stress) were normalized to LV mass and expressed in W/100 g of LV myocardium. Endpoints at follow-up were all-cause mortality and diagnosis of heart failure (HF). Patients in the higher quartiles of power/mass (rest, peak stress, and power reserve) were younger and had higher peak blood pressure and heart rate, lower LV mass, and lower prevalence of comorbidities. During follow-up [median 3.9 (0.6-8.3) years], 929 patients died. After adjusting for age, sex, metabolic equivalents (METs) achieved, ischaemia/infarction on stress test results, medication, and comorbidities, peak stress power/mass was independently associated with mortality [adjusted hazard ratio (HR), highest vs. lowest quartile, 0.5, 95% confidence interval (CI) 0.4-0.6, P < 0.001] and HF at follow-up [adjusted HR, highest vs. lowest quartile, 0.4, 95% CI (0.3, 0.5), P < 0.001]. Power reserve showed similar results. The assessment of cardiac power during exercise stress echocardiography in patients with normal EF provides valuable prognostic information, in addition to stress test findings on inducible myocardial ischaemia and exercise capacity.

A novel monoclonal antibody targeting aggregated transthyretin facilitates its removal and functional recovery in an experimental model.

Cardiac amyloidosis typically manifests as heart failure with preserved left ventricular function due to extracellular plaques comprising aggregated TTR. Despite recent success in halting disease progression with a TTR stabilizer and encouraging preliminary findings with TTR silencers, these agents are not targeting preexisting plaques. Herein, we report the development of a novel monoclonal antibody capable of attenuating experimental cardiac amyloidosis. We generated an IgG1 monoclonal antibody against aggregated TTR that immunoprecipitated the protein in the sera of patients with wild-type ATTR (wtATTR) and robustly stained cardiac plaques from patients. The antibody was shown to facilitate aggregated-TTR uptake by various myeloid cells and to protect cardiomyocytes from TTR-inducible toxicity. In a novel in vivo model of wtATTR amyloidosis, the antibody enhanced the disappearance of the pyrophosphate signals attesting for a rapid amyloid deposit removal and degradation and also exhibited improved echocardiographic measures of cardiac performance. Importantly, a capture ELISA developed based on the antibody exhibited higher levels of aggregated TTR in the sera of wtATTR amyloidosis patients as compared to control patients with heart failure suggesting a potential applicability in diagnosis and pharmacodynamic guidance of dosing. We developed a proprietary antibody targeting aggregated TTR that exhibits beneficial effects in a novel experimental wtATTR model and also possesses a potential diagnostic utility. The antibody could potentially be tested as a disease modifying agent in ATTR amyloidosis.

Relationship Between Provider Experience and Cardiac Performance Measures in Outpatients (from the NCDR)

Compliance with cardiac performance measures for guideline-directed medical therapy remains suboptimal. There is a compelling need to identify modifiable factors that influence compliance rates, so that these factors can be addressed as targets of quality improvement. This study examines the relationship between cardiovascular provider experience and compliance with performance measures for outpatients with coronary artery disease (CAD), heart failure, and atrial fibrillation in the PINNACLE Registry. We hypothesize that providers who have been practicing longer, especially those further out from certification who may not be required to recertify, will have lower compliance rates with key cardiac performance measures. Using clinical data from January 1, 2013 to March 31, 2014 in the PINNACLE Registry, we employed a multilevel hierarchical logistic regression analysis to examine the relationship between cardiac performance measures and provider experience, defined by the number of years since initial cardiology board certification (<10 years vs 10 to 20 years vs ≥20 years). We found a significant difference in compliance in 4 out of 9 outpatient cardiac performance measures between providers with different experience levels. Providers with ≥20 years since certification were less compliant with 3 out of the 4 statistically different performance metrics; however, the absolute difference between performance measures by provider experience level was small. In conclusion, performance on several key cardiovascular quality measures demonstrate a statistically significant negative association with physician experience-level defined by years since initial cardiology certification, but the clinical significance of this finding is unclear.

T3 Thyrotoxicosis Induced Dilated Cardiomyopathy

The most recognizable features of hyperthyroidism are those that result from the effects of triiodothyronine (T3) on the heart and cardiovascular system: decreased systemic vascular resistance and increased resting heart rate, left ventricular contractility, blood volume, and cardiac output. Although these measures of cardiac performance are enhanced in hyperthyroidism, the finding of clinical cardiac failure can be somewhat paradoxical. About 6% of thyrotoxic individuals develop symptoms of heart failure, but less than 1% develop dilated -cardiomyopathy with impaired left ventricular systolic function. Heart failure resulting from thyrotoxicosis is due to a tachycardia-mediated mechanism leading to an increased level of cytosolic calcium during diastole with reduced ventricular contractility and diastolic dysfunction, often with tricuspid regurgitation. Pulmonary artery hypertension in thyrotoxicosis is gaining awareness as a cause of isolated right-sided heart failure. In both cases, older individuals are more likely to be affected. Treatment needs to be directed at management of the acute cardiovascular complications, control of the heart rate, and thyroid-specific therapy to restore a euthyroid state that will lead to resolution of the signs and symptoms of heart failure.

Immediate Postnatal Ventricular Performance Is Associated with Mortality in Hypoplastic Left Heart Syndrome.

Right ventricular (RV) function as assessed by deformation has been evaluated prenatally and after palliation in hypoplastic left heart syndrome (HLHS). However, limited data exist about the immediate postnatal cardiac adaptation and RV function in HLHS. We compared echocardiographic measures of cardiac performance in HLHS versus controls in their first week of life. As a secondary objective, we evaluated if markers at the first echocardiogram were associated with mid- and long-term outcomes. Clinical and echocardiographic data of patients with HLHS between 2013 and 2016 were reviewed. The study population was matched with controls whose echocardiograms were obtained due to murmur or rule out coarctation. Speckle-tracking echocardiography was used to assess deformation. Thirty-four patients with HLHS and 28 controls were analyzed. Age at echocardiogram was similar between HLHS and controls. The RV of HLHS was compared to both RV and left ventricle (LV) of controls. HLHS deformation parameters [RV peak global longitudinal strain (GLS), global longitudinal strain rate (GLSR)] and tricuspid annular plane systolic excursion (TAPSE) were decreased compared to RV of controls. The LV-fractional area change, peak GLS, GLSR, circumferential strain, and strain rate of controls were higher than the RV of HLHS. Calculated cardiac output (CO) was higher in the HLHS group (592 vs. 183mL/kg/min, p = 0.0001) but similar to the combined LV and RV output of controls. Later mortality or cardiac transplantation was associated with the RV CO and RV stroke distance at initial echocardiogram. Cox proportional hazard regression determined that restriction at atrial septum, decreased initial RV stroke distance and decreased TAPSE had a higher risk of death or cardiac transplantation. TAPSE and RV stroke distance by velocity time integral had adequate inter-reader variability by Bland-Altman plot and Pearson's correlation. Our study found that the HLHS RV deformation is decreased in the early postnatal period when compared to both LV and RV of controls, but deformation was not associated with mid- and long-term outcomes. Later mortality or cardiac transplantation was associated with decreased initial stroke distance and cardiac output. Early evaluation of patients with HLHS should include an assessment of stroke distance and future research should evaluate its implication in management strategies.

Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells

Tissue engineers and stem cell biologists have made exciting progress toward creating simplified models of human heart muscles or aligned monolayers to help bridge a longstanding gap between experimental animals and clinical trials. However, no existing human in vitro systems provide the direct measures of cardiac performance as a pump. Here, we developed a next-generation in vitro biomimetic model of pumping human heart chamber, and demonstrated its capability for pharmaceutical testing. From human pluripotent stem cell (hPSC)-derived ventricular cardiomyocytes (hvCM) embedded in collagen-based extracellular matrix hydrogel, we engineered a three-dimensional (3D) electro-mechanically coupled, fluid-ejecting miniature human ventricle-like cardiac organoid chamber (hvCOC). Structural characterization showed organized sarcomeres with myofibrillar microstructures. Transcript and RNA-seq analyses revealed upregulation of key Ca2+-handling, ion channel, and cardiac-specific proteins in hvCOC compared to lower-order 2D and 3D cultures of the same constituent cells. Clinically-important, physiologically complex contractile parameters such as ejection fraction, developed pressure, and stroke work, as well as electrophysiological properties including action potential and conduction velocity were measured: hvCOC displayed key molecular and physiological characteristics of the native ventricle, and showed expected mechanical and electrophysiological responses to a range of pharmacological interventions (including positive and negative inotropes). We conclude that such “human-heart-in-a-jar” technology could facilitate the drug discovery process by providing human-specific preclinical data during early stage drug development.

The effect of sevoflurane induction on the myocardial performance index in healthy individuals

Background: The myocardial performance (Tei) index is a simple, reproducible and easily performed measure of cardiac performance. Its ease of use and proven clinical application make this an attractive measure perioperatively. For appropriate use of this index under sevoflurane anaesthesia, drug effects on normal values need to be defined.Methods: A total of 38 ASA 1 patients were consecutively included in this study. Induction was by sevoflurane inhalation. Steady state was defined as 3–5 min spontaneous tidal ventilation with an end-tidal sevoflurane concentration of at least 2.3%. Baseline and steady-state measurements included haemodynamics and four-chamber transthoracic echocardiographic image acquisition. Offline analysis focused on tissue Doppler studies of the lateral mitral annulus. Discrete variables before and after induction were compared.Results: Changes in simple haemodynamic variables were as expected (Systolic blood pressure: mean [95% CI] –11.62 [–15.96 to –7.27]; diastolic blood pressure...

Serial measures of cardiac performance using tissue Doppler imaging velocity in preterm infants < 29 weeks gestations

IntroductionTissue Doppler imaging (TDI) is a useful marker of myocardial performance in preterm infants. We aimed to demonstrate serial changes in TDI velocity in preterm infants <29weeks gestation, to assess the impact of inotropes and a haemodynamically significant patent ductus arteriosus (hsPDA). MethodsThis was a prospective observational study of preterm infants <29weeks gestation. Echocardiography was performed at days 1, 2, 5–7 and at 36weeks, or before hospital discharge. Infants with hsPDA's on day 5–7 and those who received inotropes in the first week of life were not included in the Reference Cohort. Systolic (s`) and diastolic (e` and a`) velocity waves were assessed at the mitral and tricuspid annulus and basal septum. ResultsOne hundred and thirty nine infants with a mean (SD) gestation and birthweight of 26.7 (1.5) weeks and 946 (247) grams were enrolled. The 66 infants (47%) in the Reference Cohort demonstrated an increase in functional parameters with increasing age [LV s`, Septal s`, and RV s`, Day 1–36weeks: 2.8 (0.6) to 4.7 (1.0), 2.4 (0.6) to 4.6 (0.8), 3.6 (0.6) to 6.9 (1.0) cm/s respectively; all p<0.05). The 24 infants who received inotropes had lower LV e` [2.9 vs. 3.6cm/s], Septal e` [2.3 vs. 2.8cm/s] and a` [3.2 vs. 3.9cm/s], and lower RV a` [3.3 vs. 3.9cm/s] on Day 1 (all p<0.05). Fifty five infants had a hsPDA on Day 5–7, demonstrating higher LV [4.7 vs. 4.0cm/s] and Septal e` [3.9 vs. 3.3cm/s], and a higher LV E/e` [13 vs. 10] (all p<0.05). ConclusionExtremely preterm infants display a gradual increase in tissue Doppler velocities from birth until 36weeks corrected age. The presence of a hsPDA increases diastolic TDI velocities. Infants requiring inotropes have lower diastolic myocardial velocities on Day 1.

Echocardiographic consequences of smoking status in middle-aged subjects.

Smoking is known to have many short- and long-term cardiovascular effects. Cardiac index (CI), which is cardiac output indexed to body surface area, is considered to be a valid measure of cardiac performance. We investigated whether there were any differences in CI or other echocardiographic variables between never smokers, ex-smokers, and current smokers in a cardiopulmonary healthy population. Subjects (n=355) from a previous population-based respiratory questionnaire survey (never smokers, ex-smokers, and current smokers without significant chronic obstructive lung disease) were examined with echocardiography, and CI (L/min/m2 ) was calculated. Current smokers had a higher CI than never smokers 2.61±0.52L/min/m2 vs. 2.42±0.49L/min/m2 (P<.01). Ex-smokers had a nonsignificant, numerically higher value for CI than never smokers 2.54±0.54L/min/m2 vs. 2.42±0.49L/min/m2 (P>.05). Smoking status had no significant effect on other echocardiographic variables. We conclude that currents smokers without known cardiac disease or significant chronic obstructive lung disease show signs of slightly altered hemodynamics.

Abstract 10876: Speckle-tracking vs. Pressure-Volume Loop Measures of Left Ventricular Systolic Function in Children: An Inter-vendor Comparison

Introduction: The variability in speckle-tracking echocardiography (STE) algorithms between vendors is well recognized. While some are attempting to standardize algorithms across vendors, it is currently unknown which algorithm best compares to gold-standard measures of systolic function. The objective of this study was to compare STE measures of deformation from two vendors vs. gold-standard measures of LV contractility and global ventricular efficiency in children. Methods: Children with normal loading conditions undergoing routine left heart catheterization were prospectively enrolled. Pressure-volume loops were obtained via conductance catheterization. The gold-standard measure of contractility, end-systolic elastance (Ees), was obtained via balloon occlusion of the vena cavae. Ventriculo-arterial coupling was assessed using the arterial elastance to Ees ratio (Ea/ Ees). STE was performed immediately after PVL analysis under the same anesthetic conditions. Offline STE analysis was perfomed using both QLAB v9.0 (Phillips, Andover, MA) and Cardiac Performance Analysis v3.0 (Tomtec, Hamden, CT) by a single blinded observer. The relationships between PVL and STE measures of systolic function were determined using Spearman’s correlation. Results: Of 24 patients, 18 patients were s/p heart transplant, 6 patients had a small patent ductus arteriosus or small coronary fistula. Mean age was 9.1 ± 5.6 years. The average invasive Ees was 3.04 ± 1.65 mmHg/mL. The average Ea/Ees was 0.88 ± 0.35. Correlations between invasive Ees and Ea/Ees to STE measures of deformation are reported in the Table. Conclusion: STE measures of GLS and GLSR derived from Cardiac Performance Analysis have better correlation with gold-standard measures of cardiac performance when compared to QLAB. GCS derived from both vendors has no correlation to invasive measures. Attempts to standardize STE algorithms should take these results into consideration.

Skeletal Muscle Changes in Chronic Cardiac Disease and Failure.

Peak exercise performance in healthy man is limited not only by pulmonary or skeletal muscle function but also by cardiac function. Thus, abnormalities in cardiac function will have a major impact on exercise performance. Many cardiac diseases affect exercise performance and indeed for some cardiac conditions such as atherosclerotic heart disease, exercise testing is frequently used not only to measure functional capacity but also to make a diagnosis of heart disease, evaluate the efficacy of treatment, and predict prognosis. Early in the course of cardiac diseases, exercise performance will be minimally affected but with disease progression impairment in exercise capacity will become apparent. Ejection fraction, that is, the percent of blood volume ejected with each cardiac cycle is often used as a measure of cardiac performance but frequently there is a dissociation between the ejection fraction and exercise capacity in patients with heart disease. How abnormalities in cardiac function impacts the muscles, vasculature, and lungs to impact exercise performance will here be reviewed. The focus of this work will be on patients with systolic heart failure as the incidence and prevalence of heart failure is reaching epidemic proportions and heart failure is the end result of many other chronic cardiac diseases. The prognostic role of exercise and benefits of exercise training will also be discussed.

Abnormal circumferential strain measured by echocardiography is present in patients with Shwachman-Diamond syndrome despite normal shortening fraction.

Shwachman-Diamond Syndrome (SDS) is an autosomal recessive disorder characterized by bone marrow failure and exocrine pancreatic dysfunction. Heart failure has been described in patients with SDS. Circumferential strain (ε(cc)) is a measure of cardiac performance that may identify dysfunction when standard measures are normal. Patients with SDS were identified and the echocardiographic database queried. Cardiac anatomy and function were recorded, and ε(cc) was measured retrospectively. From 1995-2013, 27 patients with biallelic SBDS mutations confirming the diagnosis of SDS were identified at our institution: 14 had at least one echocardiogram available; 10 underwent HSCT, with echocardiograms available in nine. Ejection fraction (EF) was normal in all 14 patients evaluated; however, ε(cc) was decreased in 4/12 studies prior to HSCT. In two patients, ε(cc) was abnormal both before and after HSCT, in one, ε(cc) changed from normal to abnormal after HSCT, and in one, ε(cc) was normal after HSCT despite being abnormal prior. Echocardiogram reports were also available for six patients in the North American SDS registry, all with normal EF. While EF was normal in all patients with SDS, ε(cc) was abnormal in 33% prior to HSCT and 33% of those who had undergone HSCT. This suggests that SDS is associated with systolic dysfunction. Further studies are needed to define the incidence of dysfunction in this group and the progression to heart failure.

Increased normalized pulmonary transit times and pulmonary blood volumes in cardiomyopathic cats with or without congestive heart failure

ObjectivesTo estimate heart rate-normalized pulmonary transit times (nPTTs) in cardiomyopathic cats with or without congestive heart failure (CHF). To assess potential associations of echocardiographic variables and nPTT and to evaluate nPTT as a test for the presence of CHF. AnimalsForty-eight privately owned cats. MethodsnPTT was measured using echocardiography and the ultrasound contrast media SonoVue® in 3 groups of cats: healthy cats (group 1), cats with cardiomyopathy (CM) but without CHF (group 2), and cats with CM and CHF (group 3). Interrelations between pulmonary blood volume (PBV), nPTT, stroke volume (SV), and echocardiographic variables were investigated by means of linear univariate and multivariate analysis. ResultsMedian nPTT values in group 1, group 2, and group 3 were 3.63 (interquartile range [IQR], 3.20–4.22), 6.09 (IQR, 5.0–7.02), and 8.49 (IQR, 7.58–11.04), respectively. Values were significantly different between all 3 groups. Median PBVs in group 1, group 2, and group 3 were 27.94 mL (IQR, 21.02–33.17 mL), 42.83 mL (IQR, 38.46–50.36 mL) and 49.48 mL (IQR, 38.84–64.39 mL). SV, PBV, and shortening fraction <30% were significant predictors of nPTT. nPTT and left atrial to aortic root (LA:AO) ratio, not SV, were the main predictors of PBV. ConclusionnPTT may be useful as a test for the presence of CHF in cats with CM and as a measure of cardiac performance. nPTT and LA:AO ratios predict CHF with equal accuracy. Increased PBV is significantly associated with higher nPTT and LA:AO ratios.

Non-invasive assessment of cardiac hemodynamics in patients with advanced cancer and with chronic heart failure: a pilot feasibility study

IntroductionRelationships between cardiac pressure and volume have been suggested as markers of cardiac contractility; parameters include stroke work and the maximal rate of pressure rise during isovolumic contraction (dP/dtmax). Patients with cancer often display dyspnea and fatigue. These are also frequent symptoms in patients with chronic heart failure (HF). The reasons for similar symptoms in cancer patients are unknown. Using the novel Nexfin Finapres technique, we sought to assess measures of cardiac performance in patients with cancer and compare these values with those from control subjects and patients with chronic HF.Material and methodsWe prospectively studied 98 patients (control n = 18, chronic HF n = 37, advanced pancreatic or colorectal cancer n = 43) and assessed blood pressure (BP), stroke volume (SV), cardiac output (CO), and dP/dtmax at rest.ResultsAll parameters of interest could be assessed using the Nexfin Finapres technique with SV and CO being significantly higher in patients with cancer than in controls (both p < 0.05). The SV was significantly higher in patients with chronic HF than in controls (p < 0.05). In patients with cancer, SV correlated with age (r = –0.45, p < 0.01) and body weight (r = +0.55, p = 0.0001). In chronic HF, SV declined with increasing age (r = –0.49, p < 0.01); in control subjects, SV increased with increasing body weight (r = +0.57, p = 0.01).ConclusionsPatients with cancer tended to display elevated BP, CO, SV, and dP/dtmax as compared to control subjects and patients with HF. These findings may reveal an elevated risk for cardiovascular diseases in this group.

A Designed Zinc-finger Transcriptional Repressor of Phospholamban Improves Function of the Failing Heart

Selective inhibition of disease-related proteins underpins the majority of successful drug–target interactions. However, development of effective antagonists is often hampered by targets that are not druggable using conventional approaches. Here, we apply engineered zinc-finger protein transcription factors (ZFP TFs) to the endogenous phospholamban (PLN) gene, which encodes a well validated but recalcitrant drug target in heart failure. We show that potent repression of PLN expression can be achieved with specificity that approaches single-gene regulation. Moreover, ZFP-driven repression of PLN increases calcium reuptake kinetics and improves contractile function of cardiac muscle both in vitro and in an animal model of heart failure. These results support the development of the PLN repressor as therapy for heart failure, and provide evidence that delivery of engineered ZFP TFs to native organs can drive therapeutically relevant levels of gene repression in vivo. Given the adaptability of designed ZFPs for binding diverse DNA sequences and the ubiquity of potential targets (promoter proximal DNA), our findings suggest that engineered ZFP repressors represent a powerful tool for the therapeutic inhibition of disease-related genes, therefore, offering the potential for therapeutic intervention in heart failure and other poorly treated human diseases.