Association of Right Ventricular Myocardial Blood Flow With Pulmonary Pressures and Outcome in Cardiac Amyloidosis.

BACKGROUND: Cardiac amyloidosis (CA) is a restrictive and infiltrative cardiomyopathy, characterized by increased biventricular filling pressures and low output. Symptoms are predominantly of right heart origin. The role of right ventricular (RV) myocardial blood flow (MBF) in CA has not been studied. OBJECTIVES: This study aimed to first associate RV MBF measured by using positron emission tomography (PET) with reference standards of RV pressures and then to explore its prognostic value in CA. METHODS: Cardiac PET was performed at rest in 52 patients with CA and 9 healthy control subjects. MBF was quantified from the right and left ventricles by using 11C-acetate, 15O-water, or both (n = 25). RV pressure was measured invasively or by echocardiography. Associations between biventricular MBF toward symptoms, RV function, and outcome (death or acute heart failure) were studied in patients with CA. RESULTS: MBF of the right ventricle (MBFRV) and the ratio of MBFRV and MBF of the left ventricle (MBFRV/LV) for the 2 tracers were significantly correlated (r > 0.92). MBFRV was directly correlated with RV systolic pressures with both tracers (P ≤ 0.005). MBFLV was inversely correlated with wall thickness (P < 0.0001). MBFRV/LV was significantly associated with N-terminal pro-B-type natriuretic peptide levels, NYHA functional class, RV pressures, and RV systolic function (all; P < 0.001). Twenty-six cardiac events (25 deaths) occurred during follow-up (median 44 months). MBFRV/LV higher than 56% was associated with a diagnosis of pulmonary hypertension (AUC: 0.96 [95% CI: 0.91-1.00]; P < 0.0001); and predicted outcome with HR: 9.0 (95% CI: 4.2-14.5), P < 0.0001). CONCLUSIONS: Measurements of MBFRV using PET are feasible, as confirmed with 2 different tracers. Imbalance between RV and LV myocardial perfusion is associated with increased RV load and adverse events in cardiac amyloidosis.

Diagnosis of left ventricular hypertrophy using non-ECG-gated 15O-water PET.

AIM: To develop a method for diagnosing left ventricular (LV) hypertrophy from cardiac perfusion 15O-water positron emission tomography (PET). METHODS: We retrospectively pooled data from 139 subjects in four research cohorts. LV remodeling patterns ranged from normal to severe eccentric and concentric hypertrophy. 15O-water PET scans (n = 197) were performed with three different PET devices. A low-end scanner (66 scans) was used for method development, and remaining scans with newer devices for a blinded evaluation. Dynamic data were converted into parametric images of perfusable tissue fraction for semi-automatic delineation of the LV wall and calculation of LV mass (LVM) and septal wall thickness (WT). LVM and WT from PET were compared to cardiac magnetic resonance (CMR, n = 47) and WT to 2D-echocardiography (2DE, n = 36). PET accuracy was tested using linear regression, Bland-Altman plots, and ROC curves. Observer reproducibility were evaluated using intraclass correlation coefficients. RESULTS: High correlations were found in the blinded analyses (r ≥ 0.87, P < 0.0001 for all). AUC for detecting increased LVM and WT (> 12 mm and > 15 mm) was ≥ 0.95 (P < 0.0001 for all). Reproducibility was excellent (ICC ≥ 0.93, P < 0.0001). CONCLUSION: 15O-water PET might detect LV hypertrophy with high accuracy and precision.

Prognostic implications of left ventricular myocardial work indices in cardiac amyloidosis.

AIMS: Left ventricular (LV) myocardial work index (LVMWI) derived from pressure-strain analysis resembles a novel non-invasive method for LV function evaluation. LV global longitudinal strain (LVGLS) has proven beneficial for risk stratification in cardiac amyloidosis (CA) patients. This study aimed to evaluate the potential additive value of LVMWI for outcome prediction in CA patients. METHODS AND RESULTS: We enrolled 100 CA patients in the period 2014-19 from Aarhus University Hospital, Denmark and Uppsala University Hospital, Sweden. All patients underwent comprehensive echocardiographic evaluation and were prospectively followed until censuring date on 31 March 2019 or death. During follow-up, we registered major adverse cardiac events (MACE) comprising heart failure requiring hospitalization and all-cause mortality. The median follow-up was 490 (228-895) days. During follow-up, a total of 42% of patients experienced MACE and 29% died. Patients with LVMWI <1043 mmHg% had higher MACE risk than patients with LVMWI >1043 mmHg% [hazard ratio (HR) 2.3, 95% confidence interval (CI) 1.2-4.3; P = 0.01]. Furthermore, patients with LVMWI <1039 mmHg% also had higher all-cause mortality risk than patients with LVMWI >1039 mmHg% (HR 2.6, 95% CI 1.2-5.5; P < 0.05). Moreover, the apical-to-basal segmental work ratio was a significant MACE and all-cause mortality predictor. By combining LVMWI and apical-to-basal segmental work ratio, we obtained an independent model for all-cause mortality prediction (high vs. low risk: HR 6.4, 95% CI 2.4-17.1; P < 0.0001). In contrast, LVGLS did not predict all-cause mortality. CONCLUSION: LV myocardial work may be of prognostic value in CA patients by predicting both MACE and all-cause mortality.

Diagnostic Accuracy of [11C]PIB Positron Emission Tomography for Detection of Cardiac Amyloidosis.

OBJECTIVES: This dual-site study evaluated the diagnostic accuracy of the method. BACKGROUND: Pittsburgh compound ([11C]PIB) positron emission tomography (PIB-PET) has shown promise as a specific and noninvasive method for the diagnosis of cardiac amyloidosis (CA). METHODS: The study had 2 parts. In the initial study, 51 subjects were included, 36 patients with known CA and increased wall thickness (15 immunoglobulin light chain [AL] and 21 transthyretin [ATTR] amyloidosis) and 15 control patients (7 were nonamyloid hypertrophic and 8 healthy volunteers). Subjects underwent PIB-PET and echocardiography. Sensitivity and specificity of PIB-PET were established for 2 simple semiquantitative approaches, standardized uptake value ratio (SUVR) and retention index (RI). The second part of the study included 11 amyloidosis patients (5 AL and 6 hereditary ATTR) without increased wall thickness to which the optimal cutoff values of SUVR (>1.09) and RI (>0.037 min-1) were applied prospectively. RESULTS: The diagnostic accuracy of visual inspection of [11C]PIB uptake was 100% in discriminating CA patients with increased wall thickness from controls. Semiquantitative [11C]PIB uptake discriminated CA from controls with a 94% (95% confidence interval [CI]: 80% to 99%) sensitivity for both SUVR and RI and specificity of 93% (95% CI: 66% to 100%) for SUVR and 100% (95% CI: 75% to 100%) for RI. [11C]PIB uptake was significantly higher in AL-CA than in ATTR-CA patients (p < 0.001) and discriminated AL-CA from controls with 100% (95% CI: 88% to 100%) accuracy for both the semiquantitative measures. In the prospective group without increased wall thickness, RI was elevated compared to controls (p = 0.001) and 5 of 11 subjects were evaluated as [11C]PIB PET positive. CONCLUSIONS: In a dual-center setting, [11C]PIB PET was highly accurate in detecting cardiac involvement in the main amyloid subtypes, with 100% accuracy in AL amyloidosis. A proportion of amyloidosis patients without known cardiac involvement were [11C]PIB PET positive, indicating that the method may detect early stages of CA.

Left Ventricular Pressure-Strain-Derived Myocardial Work at Rest and during Exercise in Patients with Cardiac Amyloidosis.

BACKGROUND: Left ventricular pressure-strain-derived myocardial work index (LVMWI) is a novel, noninvasive method for left ventricular (LV) function evaluation in relation to LV pressure dynamics. LV global longitudinal strain (LVGLS) has proven benefit for diagnosis and risk stratification in patients with cardiac amyloidosis (CA), but LVGLS does not adjust for loading conditions. The aim of the present study was to characterize LVMWI at rest and during exercise in patients with CA. METHODS: A total of 155 subjects were retrospectively included. These subjects comprised 100 patients with CA and 55 healthy control subjects. All patients had previously undergone comprehensive two-dimensional echocardiographic examinations at rest. Furthermore, a subgroup 27 patients with CA and 41 control subjects was examined using semisupine exercise stress echocardiography. RESULTS: Patients with CA had significantly lower LVGLS, LVMWI, and LV myocardial work efficiency (LVMWE) than control subjects (P < .0001 for all). The reduction in LV myocardial performance was more pronounced in the basal segments, which led to significant alterations in the average apical-to-basal segmental ratios between patients with CA and control subjects (LVGLS, 2.6 [1.9 to 4.1] vs 1.3 [1.2 to 1.5]; LVMWI, 2.6 [1.7 to 3.8] vs 1.3 [1.1 to 1.5]; LVMWE, 1.1 [1.0 to 1.3] vs 1.0 [1.0 to 1.1]; P < .0001 for all). The average increase in LVMWI from rest to peak exercise was 1,974 mm Hg% (95% CI, 1,699 to 2,250 mm Hg%; P < .0001) in control subjects and 496 mm Hg% (95% CI, 156 to 835 mm Hg%; P < .01) in patients with CA. The absolute numeric LVGLS increase was 5.6% (95% CI, 3.9% to 7.3%; P < .0001) in control subjects and only 1.2% (95% CI, -0.9% to 3.3%; P = .26) in patients with CA (between groups, P < .0001) from rest to peak exercise. The LVMWI increase in patients with CA was mediated by improvement in the apical segments (P < .0001), whereas there was no significant LVMWI alterations in the midventricular or basal segments. LVMWE remained stable during exercise in control subjects (Δ -0.6%; 95% CI, -2.5% to 1.2%; P = .50) but decreased significantly in patients with CA (Δ -2.5%; 95% CI, -4.8% to -0.2%; P < .05). CONCLUSIONS: Patients with CA have significantly reduced magnitude of LVMWI compared with healthy control subjects. With exercise, the differences are even more pronounced. Even though LVMWI increased with exercise, LVMWE decreased, suggesting inefficient myocardial energy exploitation in patients with CA.

Effects of Oral Supplementation With Nitrate-Rich Beetroot Juice in Patients With Pulmonary Arterial Hypertension-Results From BEET-PAH, an Exploratory Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

BACKGROUND: The nitrate-nitrite-nitric oxide (NO) pathway may represent a potential therapeutic target in patients with pulmonary arterial hypertension (PAH). We explored the effects of dietary nitrate supplementation, with the use of nitrate-rich beetroot juice (BRJ), in patients with PAH. METHODS AND RESULTS: We prospectively studied 15 patients with PAH in an exploratory randomized, double-blind, placebo-controlled, crossover trial. The patients received nitrate-rich beetroot juice (∼16 mmol nitrate per day) and placebo in 2 treatment periods of 7 days each. The assessments included; exhaled NO and NO flow-independent parameters (alveolar NO and bronchial NO flux), plasma and salivary nitrate and nitrite, biomarkers and metabolites of the NO-system, N-terminal pro-B-type natriuretic peptide, echocardiography, ergospirometry, diffusing capacity of the lung for carbon monoxide, and the 6-minute walk test. Compared with placebo ingestion of BRJ resulted in increases in; fractional exhaled NO at all flow-rates, alveolar NO concentrations and bronchial NO flux, and plasma and salivary levels of nitrate and nitrite. Plasma ornithine levels decreased and indices of relative arginine availability increased after BRJ compared to placebo. A decrease in breathing frequency was observed during ergospirometry after BRJ. A tendency for an improvement in right ventricular function was observed after ingestion of BRJ. In addition a tendency for an increase in the peak power output to peak oxygen consumption ratio (W peak/VO2 peak) was observed, which became significant in patients reaching an increase of plasma nitrite >30% (responders). CONCLUSIONS: BRJ administered for 1 week increases pulmonary NO production and the relative arginine bioavailability in patients with PAH, compared with placebo. An increase in the W peak/VO2 peak ratio was observed after BRJ ingestion in plasma nitrite responders. These findings indicate that supplementation with inorganic nitrate increase NO synthase-independent NO production from the nitrate-nitrite-NO pathway.

Coronary heart disease in systemic lupus erythematosus is associated with interferon regulatory factor-8 gene variants.

BACKGROUND: Patients with systemic lupus erythematosus have increased morbidity and mortality in coronary heart disease (CHD). We asked whether there was a genetic influence on CHD in systemic lupus erythematosus. METHODS AND RESULTS: The association between single-nucleotide polymorphisms (SNPs) and CHD in 2 populations of patients with systemic lupus erythematosus was assessed. Patients were genotyped on a custom 12k Illumina Array. The allele frequencies were compared between patients with (n=66) and without (n=509) CHD. We found 61 SNPs with an association (P<0.01) to CHD, with the strongest association for 3 SNPs located in the interferon regulatory factor-8 (IRF8) gene. Comparison of the allele frequencies of these 61 SNPs in patients with (n=27) and without (n=212) CHD in the second study population revealed that 2 SNPs, rs925994 and rs10514610 in IRF8 (linkage disequilibrium, r²=0.84), were associated with CHD in both study populations. Meta-analysis of the SNP rs925994 gave an odds ratio of 3.6 (2.1-6.3), P value 1.9×10⁻6. The identified IRF8 allele remained as a risk factor for CHD after adjustment for traditional CHD risk factors. The IRF8 risk allele was associated with the presence of carotid plaques (P<0.001) and increased intima-media thickness (P=0.01). By electrophoretic mobility shift assays, we show weaker binding of protein to the risk allele of the highly linked SNP rs11117415, and by flow cytometry, a reduced frequency of circulating B cells was detected in patients with the IRF8 risk allele. CONCLUSIONS: There is a considerable genetic component for CHD in systemic lupus erythematosus, with IRF8 as a strong susceptibility locus.

Use of echocardiographic pulmonary acceleration time and estimated vascular resistance for the evaluation of possible pulmonary hypertension.

BACKGROUND: During ultrasound examination, tricuspid regurgitation may be absent or gives a signal that is not reliable for the estimation of systolic pulmonary pressure. The aim of this study was to evaluate the usefulness of acceleration time (AT) from the right ventricular outflow tract (RVOT) as an estimation of the trans-tricuspid valve gradient (TTVG) and to investigate the correlation between estimated and invasive pulmonary vascular resistance (PVR). METHODS: The AT was correlated to the TTVG measured with routine standard echocardiography in 121 patients. In a subgroup of 29 patients, systolic pulmonary pressure (SPAP) and mean pulmonary arterial pressure (MPAP) were obtained from recent right heart catheterization (RHC). RESULTS: We found no significant correlation between the estimation of right atrial pressure (RAP) by echocardiography and the RAP obtained by RHC. Estimated SPAP (TTGV + RAP mean from RHC) showed a good linear relation to invasively measured SPAP. TTVG and AT showed a non-linear relation, similar to SPAP and MPAP measured by catheterization and AT. For detection of SPAP above 38 mmHg a cut-off for AT of 100 ms resulted in a sensitivity of 89% and a specificity of 84%. For detection of MPAP above 25 mmHg a cut-off for AT of 100 ms resulted in similar sensitivity and specificity. Invasive PVR and the ratio of TTVG and the time velocity integral of the RVOT (TVI (RVOT) ) had a strong linear relation. CONCLUSIONS: Our study confirms that AT appears to be useful for the evaluation of pulmonary hypertension. In high risk patients, an AT of less than 100 ms indicates a high probability of pulmonary hypertension. Furthermore, PVR estimation by ultrasound seems preferably be done by using the ratio of TTVG and TVI RVOT.

Evaluation of patients with cardiac amyloidosis using echocardiography, ECG and right heart catheterization.

AIMS: To characterize patients with cardiac amyloidosis using echocardiography, electrocardiogram (ECG) and right heart catheterization (RHC). METHODS AND RESULTS: Fourteen patients with biopsy verified light chain or transthyretin cardiac amyloidosis were included. All patients had heart failure with markedly elevated NT-proBNP. Echocardiography demonstrated biventricular hypertrophy, left atrial enlargement and normal to slightly reduced left ventricular ejection fraction. Tissue Doppler septal é was low and median E/é was high. Within 6 months RHC was performed in eight of the patients. The restrictive filling pattern demonstrated by echocardiography corresponded well to median pulmonary wedge pressure (21 mmHg). Systolic pulmonary artery pressure (SPAP) was increased, whereas cardiac output and stroke volume were seen to be decreased with both methods. ECG demonstrated: low voltage (36%), abnormal R-progression (65%), ST-T abnormalities (71%) and high incidence of fibrillation (36%). In addition, a case report following the treatment of melphalan and dexamethasone is presented with improvement of hypertrophy, SPAP, left ventricular mass and é. CONCLUSION: These findings should lead to a suspicion of cardiac amyloidosis and suggest further investigation.

In vivo visualization of amyloid deposits in the heart with 11C-PIB and PET.

UNLABELLED: Cardiac amyloidosis is a differential diagnosis in heart failure and is associated with high mortality. There is currently no noninvasive imaging test available for specific diagnosis. N-[methyl-(11)C]2-(4'-methylamino-phenyl)-6-hydroxybenzothiazole ((11)C-PIB) PET is used in the evaluation of brain amyloidosis. We evaluated the potential use of (11)C-PIB PET in systemic amyloidosis affecting the heart. METHODS: Patients (n = 10) diagnosed with systemic amyloidosis-including heart involvement of either monoclonal immunoglobulin light-chain (AL) or transthyretin (ATTR) type-and healthy volunteers (n = 5) were investigated with PET/CT using (11)C-PIB to study cardiac amyloid deposits and with (11)C-acetate to measure myocardial blood flow to study the impact of global and regional perfusion on PIB retention. RESULTS: Myocardial (11)C-PIB uptake was visually evident in all patients 15-25 min after injection and was not seen in any volunteer. A significant difference in (11)C-PIB retention in the heart between patients and healthy controls was found. The data indicate that myocardial amyloid deposits in patients diagnosed with systemic amyloidosis could be visualized with (11)C-PIB. No correlation between (11)C-PIB retention index and myocardial blood flow as measured with (11)C-acetate was found on the global level, whereas a positive correlation on the segmental level was seen in a single patient. CONCLUSION: (11)C-PIB and PET could be a method to study systemic amyloidosis of type AL and ATTR affecting the heart and should be investigated further both as a diagnostic tool and as a noninvasive method for treatment follow-up.

Endothelin-induced changes in blood flow in STZ-diabetic and non-diabetic rats: relation to nitric oxide synthase and cyclooxygenase inhibition.

In this study, using the microsphere method, the hemodynamic response to endothelin-1 (ET-1) in healthy and streptozotocin (STZ)-diabetic rats was evaluated as well as the influences of inhibition of nitric oxide (NO)-synthase using L-NAME (Nω-nitro-L: -arginine methyl ester) and the cyclooxygenase inhibitor indomethacin. Blood flow (Q) was measured in tissues of interest for vascular complications in diabetes such as kidney, eye, brain, heart and skeletal muscle with the main focus on ophthalmic circulation. Under resting conditions, evidence for renal vasoconstriction was found in diabetic animals. In both groups, administration of L-NAME reduced Q in all investigated tissues indicating a basal NO influence. In the normal rats, ET-1 induced a significant increase in blood pressure and intense vasoconstriction in all tissues except in the choroid of the eye and in the brain, where it induced an increased Q. In the STZ-diabetic rats, effects of ET-1 were less pronounced. Pretreatment with L-NAME, but not the cyclooxygenase inhibitor, abolished the ET-1-induced vasodilation in the choroid of both groups. Administration of ET A receptor antagonist BQ-123 reduced the ET-1-induced vasodilation in the choroid only in diabetic animals. In conclusion, evidence for altered vascular endothelial response to ET-1 in STZ-diabetic animals was found particularly in the ophthalmic circulation. The findings suggest differential involvement of receptors in the response to ET-1 in normal and STZ-diabetic animals.

Assessment of intravascular volume by transthoracic echocardiography during therapeutic hypothermia and rewarming in cardiac arrest survivors.

AIM: To study haemodynamic effects and changes in intravascular volume during hypothermia treatment, induced by ice-cold fluids and maintained by ice-packs followed by rewarming in patients after resuscitation from cardiac arrest. MATERIALS AND METHODS: In 24 patients following successful restoration of spontaneous circulation (ROSC), hypothermia was induced with infusion of 4 degrees C normal saline and maintained with ice-packs for 26 h after ROSC. This was followed by passive rewarming. Transthoracic echocardiography was performed at 12, 24 and 48 h after ROSC to evaluate ejection fraction and intravascular volume status. Central venous pressure (CVP), central venous oxygen saturation (ScvO(2)) and serum lactate were measured. Fluid balance was calculated. RESULTS: Twelve hours after ROSC, two separate raters independently estimated that 10 and 13 out of 23 patients had a decreased intravascular volume using transthoracic echocardiography. After 24 and 48 h this number had increased further to 14 and 13 out of 19 patients and 13 and 12 out of 21 patients. Calculated fluid balance was positive (4000 ml the day 1 and 2500 ml day 2). There was no difference in ejection fraction between the recording time points. Serum lactate and ScvO(2) were in the normal range when echocardiography exams were performed. CVP did not alter over time. CONCLUSIONS: Our results support the hypothesis that inducing hypothermia following cardiac arrest, using cold intravenous fluid infusion does not cause serious haemodynamic side effects. Serial transthoracic echocardiographic estimation of intravascular volume suggests that many patients are hypovolaemic during therapeutic hypothermia and rewarming in spite of a positive fluid balance.