David Langholz

The effect of pulmonary hypertension on ovine tricuspid annular dynamics

OBJECTIVES Pulmonary hypertension (PHT) is associated with tricuspid annular dilatation, but the effect of acute increase of pulmonary pressure on three-dimensional (3D) tricuspid annular dynamics and shape is unknown. Better understanding of tricuspid annular dynamics may lead to improved and more durable surgical reparative techniques. METHODS In nine open-chest anaesthetized sheep nine sonomicrometry crystals were implanted on the right ventricle while on cardiopulmonary bypass. Additional nine crystals were implanted around the tricuspid annulus (TA) with one crystal at each commissure defining three separate annular regions: anterior, posterior and septal. Two additional equidistant crystals were implanted between each commissure, creating three segments for every region. Pressure transducers were placed in the left ventricular (LV), right ventricular (RV) and right atrium. PHT was induced by acute pulmonary artery constriction with a pneumatic occluder. Sonomicrometry and echocardiographic data were collected before and after induction of PHT. TA area, regional and total perimeter, and 3D annular geometry were calculated from 3D crystal coordinates. Regional annular contraction was defined as the percentage difference between maximal and minimal region length during the cardiac cycle. RESULTS PHT increased RV pressure from 31 ± 9 mmHg to 46 ± 13 mmHg (P = 0.001) and decreased left ventricular (LV) pressure from 111 ± 24 mmHg to 78 ± 36 mmHg (P = 0.018). There was no significant tricuspid regurgitation observed with PHT. During PHT, the TA area increased by 12 ± 13% from 641 ± 139 mm(2) to 721 ± 177 mm(2) (P = 0.037). The total perimeter increased from 103 ± 11 mm to 109 ± 13 mm (P = 0.02). All annular regions dilated significantly with PHT with 8 ± 10, 5 ± 5 and 5 ± 5% increase in anterior, posterior and septal annular length, respectively (P < 0.05). PHT reduced regional annular contraction in the anterior region only (17 ± 7 vs 14 ± 8%; P = 0.02). The TA had a complex 3D saddle geometry and the shape of the annulus was altered during PHT only in the antero-posterior region. CONCLUSIONS The changes in tricuspid annular conformation, contractility and its 3D geometry observed during acute ovine PHT may help in the design of new pathology-specific tricuspid annular rings.

The effect of acute mechanical left ventricular unloading on ovine tricuspid annular size and geometry

OBJECTIVES Left ventricular assist device (LVAD) implantation may alter right ventricular shape and function and lead to tricuspid regurgitation. This in turn has been reported to be a determinant of right ventricular (RV) failure after LVAD implantation, but the effect of mechanical left ventricular (LV) unloading on the tricuspid annulus is unknown. The aim of the study was to provide insight into the effect of LVAD support on tricuspid annular geometry and dynamics that may help to optimize LV unloading with the least deleterious effect on the right-sided geometry. METHODS In seven open-chest anaesthetized sheep, nine sonomicrometry crystals were implanted on the right ventricle. Additional nine crystals were implanted around the tricuspid annulus, with one crystal at each commissure defining three separate annular regions: anterior, posterior and septal. Left ventricular unloading was achieved by connecting a cannula in the left atrium and the aorta to a continuous-flow pump. The pump was used for 15 min at a full flow of 3.8 ± 0.3 l/min. Epicardial echocardiography was used to assess the degree of tricuspid insufficiency. Haemodynamic, echocardiographic and sonomicrometry data were collected before and during full unloading. Tricuspid annular area, and the regional and total perimeter were calculated from crystal coordinates, while 3D annular geometry was expressed as the orthogonal distance of each annular crystal to the least squares plane of all annular crystals. RESULTS There was no significant tricuspid regurgitation observed either before or during LV unloading. Right ventricular free wall to septum diameter increased significantly at end-diastole during unloading from 23.6 ± 5.8 to 26.3 ± 6.5 mm (P = 0.009), but the right ventricular volume, tricuspid annular area and total perimeter did not change from baseline. However, the septal part of the annulus significantly decreased its maximal length (38.6 ± 8.1 to 37.9 ± 8.2 mm, P = 0.03). Annular contraction was not altered. The tricuspid annulus had a complex 3D saddle-shaped geometry that was unaffected during experimental conditions. CONCLUSIONS In healthy sheep hearts, left ventricular unloading increased septal-free wall RV diameter and reduced the length of the septal annulus, without altering the motion or geometry of the tricuspid annulus. Acute left ventricular unloading alone in healthy sheep was not sufficient to significantly perturb tricuspid annular dynamics and result in tricuspid insufficiency.

Large animal model of functional tricuspid regurgitation in pacing induced end-stage heart failure

OBJECTIVES Functional tricuspid regurgitation (FTR) is common in patients with advanced heart failure and frequently complicates left ventricular assist device implantation yet remains poorly understood. We set out to establish large animal model of FTR that could serve as a research platform to investigate the pathogenesis of FTR associated with end-stage heart failure. METHODS : Through right thoracotomy, ten adult sheep underwent implantation of pacemaker with epicardial LV lead, five sonomicrometry crystals on the right ventricle, and left and right ventricular telemetry pressure sensors during a beating heart off-pump procedure. After 5 ± 1 days of recovery, baseline haemodynamic, echocardiographic and sonomicrometry data were collected. Animals were paced thereafter at a rate of 220-240 beats/min until the development of heart failure and concomitant tricuspid regurgitation. RESULTS : Three animals died during early recovery period and one during the pacing phase. Six surviving animals were paced for a mean of 14 ± 5 days. Cardiac function was significantly depressed compared to baseline, with LV ejection fraction falling from 69 ± 2% to 22 ± 4% ( P  < 0.001) and RV fractional area change from 52 ± 11% to 25 ± 9% ( P  = 0.005). All animals developed significant enlargement of tricuspid annulus (from 29.5 ± 1.6 to 36.5 ± 4.5 mm; P  = 0.01) and right ventricle (from 21.9 ± 0.2 to 30.3 ± 0.6 mm; P  = 0.03). Sonomicrometry derived contractility of RV free wall was depressed and at least moderate tricuspid insufficiency developed in all animals. CONCLUSIONS : Biventricular dysfunction, tricuspid annular dilatation and significant FTR were observed in our model of ovine tachycardia induced cardiomyopathy. This animal model reflects the clinical situation of end-stage heart failure patients presenting for mechanical support.

Multimodality Intracoronary Imaging With Near-Infrared Spectroscopy and Intravascular Ultrasound in Asymptomatic Individuals With High Calcium ScoresCLINICAL PERSPECTIVE

Background— This study sought to determine the frequency of large lipid-rich plaques (LRP) in the coronary arteries of individuals with high coronary artery calcium scores (CACS) and to determine whether the CACS correlates with coronary lipid burden. Methods and Results— Combined near-infrared spectroscopy and intravascular ultrasound was performed in 57 vessels in 20 asymptomatic individuals (90% on statins) with no prior history of coronary artery disease who had a screening CACS ≥300 Agatston units. Among 268 10-mm coronary segments, near-infrared spectroscopy images were analyzed for LRP, defined as a bright yellow block on the near-infrared spectroscopy block chemogram. Lipid burden was assessed as the lipid core burden index (LCBI), and large LRP were defined as a maximum LCBI in 4 mm ≥400. Vessel plaque volume was measured by quantitative intravascular ultrasound. Vessel-level CACS significantly correlated with plaque volume by intravascular ultrasound (r=0.69; P<0.0001) but not with LCBI by near-infrared spectroscopy (r=0.24; P=0.07). Despite a high CACS, no LRP was detected in 8 (40.0%) subjects. Large LRP having a maximum LCBI in 4 mm ≥400 were infrequent, found in only 5 (25.0%) of 20 subjects and in only 5 (1.9%) of 268 10-mm coronary segments analyzed. Conclusions— Among individuals with a CACS ≥300 Agatston units mostly on statins, CACS correlated with total plaque volume but not LCBI. This observation may have implications on coronary risk among individuals with a high CACS considering that it is coronary LRP, rather than calcification, that underlies the majority of acute coronary events.

Genetic Factors Influencing B-type Natriuretic Peptide-Mediated Production of Cyclic Guanosine Monophosphate and Blood Pressure Effects in Heart Failure Patients

Natriuretic peptides (NPs) represent a critical pathway in heart failure (HF). We explored genetic determinants of pharmacodynamic effects of B-type NP (BNP) and changes in plasma cyclic guanosine monophosphate (cGMP) and blood pressure (BP). HF patients (n = 135) received recombinant human BNP (nesiritide) at standard doses, and plasma cGMP levels were measured at baseline and during infusion. We tested the association of 119 single nucleotide polymorphisms (SNPs) in 4 candidate genes (NPR1, NPR2, NPR3, and membrane metallo-endopeptidase (MME)) with the change in cGMP and BP. Gene-based testing for association of genetic variation with endpoints was significant only for MME. Upon individual SNP testing, two loci in MME were associated with ΔcGMP; another (rs16824656) showed association with BP change. In summary, the pharmacodynamic effects of BNP vary substantially in HF patients and are associated with genetic variation in MME. MME genetic variation may be an important determinant of NP-mediated effects in humans.

Tricuspid valvular dynamics and 3-dimensional geometry in awake and anesthetized sheep

Objectives Clinical and experimental tricuspid valve physiology data are derived predominantly from anesthetized subjects, but normal tricuspid valve geometry and dynamics may be altered by general anesthesia and mechanical ventilation. We set out to investigate 3‐dimensional geometry and dynamics of the tricuspid valve complex in awake and anesthetized sheep. Methods While on cardiopulmonary bypass and with the heart beating, 6 adult sheep (50 ± 8 kg) underwent implantation of 6 sonomicrometry crystals around the tricuspid annulus. One crystal was implanted on the anterior, posterior, and septal papillary muscle tips, 4 on the right ventricular free wall and 1 on its apex. Pressure transducers were placed in both ventricles. Sonomicrometry and pressure transducer cables were externalized to subcutaneous buttons. After 7 days of recovery, hemodynamic and sonomicrometry data were recorded with animals awake and anesthetized. Results Hemodynamic parameters did not differ between groups. Tricuspid annular area contraction decreased with anesthesia (16.4% ± 4.2% vs 11.2% ± 3.2%, P = .047) as did tricuspid annular perimeter contraction (8.1% ± 2.2% vs 5.4% ± 1.7%, P = .050), predominantly due to reduced contraction of the septal annulus (10.5% ± 2.9% vs 7.5% ± 3.5%, P = .019). Tricuspid annular height did not differ between groups. Minimal distance from anterior, posterior, and septal papillary muscle tips to the annular plane did not change with anesthesia. Regional right ventricle free wall contraction was depressed under anesthesia in anterior (16.3% ± 3.1% vs 12.3% ± 2.2%, P = .027) and lateral (14.9% ± 1.3% vs 11.5% ± 2.8%, P = .016) segments, whereas the posterior remained unchanged. Conclusions General anesthesia did not alter tricuspid annular or subvalvular 3‐dimensional geometry but reduced right ventricular contraction and tricuspid annular dynamics. Graphical abstract Figure. No Caption available.

Large animal model of acute right ventricular failure with functional tricuspid regurgitation

BACKGROUND Functional tricuspid regurgitation (FTR) commonly arises secondary to conditions affecting the left heart and is associated with right ventricular dysfunction and tricuspid annular dilatation. We set out to establish an animal model of acute RV failure (RVF) with FTR resembling the clinical features. METHODS Ten adult sheep had pressure sensors placed in the LV, RV, and right atrium while sonomicrometry crystals were implanted around tricuspid annulus and on the RV. Animals were studied open-chest to assess for RV function and FTR after: (1) volume infusion, (2) pulmonary artery constriction, (3) 5 min posterior descending artery occlusion, and (4) combination of all interventions. Hemodynamic, echocardiographic, and sonomicrometry data were collected at baseline and after every intervention. RV dimensions, RV strain, and annular area, perimeter, and size were calculated from crystal coordinates. The model was validated in six additional sheep studied only before and after combined interventions. RESULTS Neither volume infusion, pulmonary hypertension, nor ischemia were associated with RVF or clinically significant TR when applied separately but combined resulted in RVF and greater than moderate FTR. In the validation group, maximal RV volume increased (62 ± 14 vs 70 ± 16 ml, p = 0.006), contractility decreased (20 ± 6 vs 12 ± 2%, p = 0.02), and strain increased. FTR increased from 0.4 ± 0.5 to 2.5 ± 0.8 (p < 0.001) and annular area from 652 ± 87 mm2 to 739 ± 87 mm2 (p = 0.005). CONCLUSIONS The developed ovine model of acute RVF was associated with significant annular and RV enlargement and FTR. This novel and clinically pertinent research platform offers insight into the acute RVF pathophysiology and can be utilized to evaluate treatment interventions.

Response by Madder et al to Letter Regarding Article, “Multimodality Intracoronary Imaging With Near-Infrared Spectroscopy and Intravascular Ultrasound in Asymptomatic Individuals With High Calcium Scores”

We agree with Drs Shaikh and Budoff on the necessity of additional studies to investigate whether detection of lipid-rich plaque (LRP) by near-infrared spectroscopy (NIRS) can add incremental value to the coronary artery calcium score (CACS) in the prediction of future cardiovascular events. In our recent study, we demonstrated that NIRS adds information on the presence or absence of LRP among individuals with a high CACS.1 A logical next step is to determine if …

CHEMOTHERAPY INDUCED CARDIOTOXICITY, ITS PREVENTION, TREATMENT AND RISK FACTORS

Background: Cardiovascular disease is the second leading cause of death among cancer survivors. Chemotherapy is associated with increased risk of non-ischemic cardiomyopathy and heart failure. The incidence of cardiomyopathy is dependent upon the class of chemotherapeutics; there is also a reported