Impact of sex on the assessment of the microvascular resistance reserve.

BACKGROUND: The microvascular resistance reserve (MRR) is an innovative index to assess the vasodilatory capacity of the coronary circulation while accounting for the presence of concomitant epicardial disease. The MRR has shown to be a valuable diagnostic and prognostic tool in the general coronary artery disease (CAD) population. However, considering the fundamental aspects of its assessment and the unique hemodynamic characteristics of women, it is crucial to provide additional considerations for evaluating the MRR specifically in women. AIM: The aim of this study was to assess the diagnostic and prognostic applicability of the MRR in women and assess the potential differences across different sexes. METHODS: From the ILIAS Registry, we enrolled all patients with a stable indication for invasive coronary angiography, ensuring complete physiological and follow-up data. We analyzed the diagnostic value by comparing differences between sexes and evaluated the prognostic value of the MRR specifically in women, comparing it to that in men. RESULTS: A total of 1494 patients were included of which 26% were women. The correlation between MRR and CFR was good and similar between women (r = 0.80, p < 0.005) and men (r = 0.81, p < 0.005). The MRR was an independent and important predictor of MACE in both women (HR 0.67, 0.47-0.96, p = 0.027) and men (HR 0.84, 0.74-0.95, p = 0.007). The optimal cut-off value for MRR in women was 2.8 and 3.2 in men. An abnormal MRR similarly predicted MACE at 5-year follow-up in both women and men. CONCLUSION: The MRR seems to be equally applicable in both women and men with stable coronary artery disease.

Combined Assessment of FFR and CFR for Decision Making in Coronary Revascularization: From the Multicenter International ILIAS Registry.

OBJECTIVES: The aim of this study was to demonstrate the clinical implications of combined assessment of fractional flow reserve (FFR) and coronary flow reserve (CFR). BACKGROUND: Combined assessment of FFR and CFR allows detailed characterization of pathophysiology in chronic coronary syndromes. Data on the clinical implications of distinct FFR and CFR patterns are limited, leading to uncertainty regarding their relevance. METHODS: Patients with chronic coronary syndromes and obstructive coronary artery disease were selected from the multicenter ILIAS (Inclusive Invasive Physiological Assessment in Angina Syndromes) registry. Patients were classified into 4 groups on the basis of FFR ≤0.80 and CFR <2.0. The endpoint was the 5-year target vessel failure (TVF) rate. RESULTS: A total of 2,143 patients with 2,725 lesions were included. Compared with normal FFR/normal CFR, low FFR/low CFR carried the highest risk for TVF (HR: 5.4; 95% CI: 3.2-9.3; P < 0.001), significantly higher than in revascularized vessels (P = 0.007). Discordance, with either low FFR/normal CFR or normal FFR/low CFR, was associated with increased TVF rates compared with normal FFR/normal CFR (low FFR/normal CFR: HR: 3.5 [95% CI: 2.2-5.4; P < 0.001]; normal FFR/low CFR: HR: 3.0 [95% CI: 1.9-4.7; P < 0.001]). No difference in 5-year TVF was observed between the 2 discordant groups (P = 0.57) or between the discordant groups and the revascularized group (P = 0.26 vs low FFR/normal CFR; P = 0.60 vs normal FFR/low CFR). CONCLUSIONS: Impaired coronary hemodynamics are uniformly associated with increased 5-year TVF rates. Nonrevascularized vessels with discordant FFR and CFR are associated with 5-year event rates that are equivalent to those of vessels that undergo revascularization, whereas vessels with combined low FFR and CFR exhibit event rates that are significantly higher than after revascularization. (Inclusive Invasive Physiological Assessment in Angina Syndromes Registry [ILIAS Registry]; NCT04485234).

Finding very high lipoprotein(a): the need for routine assessment.

AIMS: To validate the reported increased atherosclerotic cardiovascular disease (ASCVD) risk associated with very high lipoprotein(a) [Lp(a)] and to investigate the impact of routine Lp(a) assessment on risk reclassification. METHODS AND RESULTS: We performed a cross-sectional case-control study in the Amsterdam UMC, a tertiary hospital in The Netherlands. All patients in whom a lipid blood test was ordered between October 2018 and October 2019 were included. Individuals with Lp(a) >99th percentile were age and sex matched to individuals with Lp(a) ≤20th percentile. We computed odds ratios (ORs) for myocardial infarction (MI) and ASCVD using multivariable logistic regression adjusted for age, sex, and systolic blood pressure. Furthermore, we assessed the additive value of Lp(a) to established ASCVD risk algorithms. Lipoprotein(a) levels were determined in 12 437 individuals, out of whom 119 cases [Lp(a) >99th percentile; >387.8 nmol/L] and 119 matched controls [Lp(a) ≤20th percentile; ≤7 nmol/L] were included. Mean age was 58 ± 15 years, 56.7% were female, and 30.7% had a history of ASCVD. Individuals with Lp(a) levels >99th percentile had an OR of 2.64 for ASCVD [95% confidence interval (CI) 1.45-4.89] and 3.39 for MI (95% CI 1.56-7.94). Addition of Lp(a) to ASCVD risk algorithms led to 31% and 63% being reclassified into a higher risk category for Systematic Coronary Risk Evaluation (SCORE) and Second Manifestations of ARTerial disease (SMART), respectively. CONCLUSION: The prevalence of ASCVD is nearly three-fold higher in adults with Lp(a) >99th percentile compared with matched subjects with Lp(a) ≤20th percentile. In individuals with very high Lp(a), addition of Lp(a) resulted in one-third of patients being reclassified in primary prevention, and over half being reclassified in secondary prevention.

MRI-guided pulmonary vein isolation for atrial fibrillation: what is good enough? An early health technology assessment.

Next to anticoagulation, pulmonary vein isolation (PVI) is the most important interventional procedure in the treatment of atrial fibrillation (AF). Despite widespread clinical application of this therapy, patients often require multiple procedures to reach clinical success. In contrast to conventional imaging modalities, MRI allows direct visualisation of the ablation lesion. Therefore, the use of real-time MRI to guide cardiac electrophysiology procedures may increase clinical effectiveness. An essential aspect, from a decision-making point of view, is the effect on costs and the potential cost-effectiveness of new technologies. Generally, health technology assessment (HTA) studies are performed when innovations are close to clinical application. However, early stage HTA can inform users, researchers and funders about the ultimate clinical and economic potential of a future innovation. Ultimately, this can guide funding allocation. In this study, we performed an early HTA evaluate MRI-guided PVIs. Methods: We performed an economic evaluation using a decision tree with a time-horizon of 1 year. We calculated the clinical effectiveness (defined as the proportion of patients that is long-term free of AF after a single procedure) required for MRI-guided PVI to be cost-effective compared with conventional treatment. Results: Depending on the cost-effectiveness threshold (willingness to pay for one additional quality-of-life adjusted life year (QALY), interventional MRI (iMRI) guidance for PVI can be cost-effective if clinical effectiveness is 69.8% (at €80 000/QALY) and 77.1% (at €20 000/QALY), compared with 64% for fluoroscopy-guided procedures. Conclusion: Using an early HTA, we established a clinical effectiveness threshold for interventional MRI-guided PVIs that can inform a clinical implementation strategy. If crucial technologies are developed, it seems plausible that iMRI-guided PVIs will be able to reach this threshold.

Endogenous assessment of diffuse myocardial fibrosis in patients with T1ρ -mapping.

PURPOSE: Recently, it was shown that a significantly higher T1ρ is found in compact myocardial fibrosis after chronic myocardial infarction. In this study, we investigated the feasibility of native T1ρ -mapping for the detection of diffuse myocardial fibrosis in patients with dilated cardiomyopathy (DCM). MATERIALS AND METHODS: T1ρ -mapping was performed on three explanted hearts from DCM patients at 3 Tesla (T). Histological fibrosis quantification was performed, and compared with the T1ρ -relaxation times in the heart. Furthermore, twenty DCM patients underwent an MRI at 1.5T. Native T1ρ -maps, native T1 -maps, and extracellular volume (ECV)-maps were acquired. Additionally, eight healthy volunteers were scanned for reference values. RESULTS: A significant correlation (Pearson r = 0.49; P = 0.005) was found between ex vivo T1ρ -values and fibrosis fraction from histology. Additionally, a significantly higher T1ρ -relaxation time (55.2 ± 2.7 ms) was found in DCM patients compared with healthy control subjects (51.5 ± 1.2 ms) (P = 0.0024). The relation between in vivo T1ρ -values and ECV-values was significant (Pearson r = 0.66). No significant relation was found between native T1 - and ECV-values in this study (P = 0.89). CONCLUSION: This study showed proof of principle for the endogenous detection of diffuse myocardial fibrosis with T1ρ -MRI. Ex vivo and in vivo experiments showed promising results that T1ρ -MRI can be used to measure the extent of diffuse myocardial fibrosis in the myocardium. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:132-138.

Conceptual model for early health technology assessment of current and novel heart valve interventions.

OBJECTIVE: The future promises many technological advances in the field of heart valve interventions, like tissue-engineered heart valves (TEHV). Prior to introduction in clinical practice, it is essential to perform early health technology assessment. We aim to develop a conceptual model (CM) that can be used to investigate the performance and costs requirements for TEHV to become cost-effective. METHODS: After scoping the decision problem, a workgroup developed the draft CM based on clinical guidelines. This model was compared with existing models for cost-effectiveness of heart valve interventions, identified by systematic literature search. Next, it was discussed with a Delphi panel of cardiothoracic surgeons, cardiologists and a biomedical scientist (n=10). RESULTS: The CM starts with the valve implantation. If patients survive the intervention, they can remain alive without complications, die from non-valve-related causes or experience a valve-related event. The events are separated in early and late events. After surviving an event, patients can experience another event or die due to non-valve-related causes. Predictors will include age, gender, NYHA class, left ventricular function and diabetes. Costs and quality adjusted life years are to be attached to health conditions to estimate long-term costs and health outcomes. CONCLUSIONS: We developed a CM that will serve as foundation of a decision-analytic model that can estimate the potential cost-effectiveness of TEHV in early development stages. This supports developers in deciding about further development of TEHV and identifies promising interventions that may result in faster take-up in clinical practice by clinicians and reimbursement by payers.

Single Breath-Hold T1ρ-Mapping of the Heart for Endogenous Assessment of Myocardial Fibrosis.

OBJECTIVES: In this study, we propose a method to acquire high spatial-resolution T1ρ-maps, which allows bright and black-blood imaging, in a single breath-hold. To validate this innovative method, the reproducibility was tested in phantoms and volunteers. Lastly, the sensitivity and specificity for infarct detection was compared with the criterion standard late gadolinium enhancement (LGE). METHODS: T1ρ-mapping was performed using a T1ρ-prepared balanced steady-state free precession sequence at 1.5 T and 3 T. Five images with increasing spin-lock preparation times (spin-lock = 0, 10, 20, 30, 40 milliseconds, amplitude = 500 Hz) were acquired with an interval of 3 beats. Black-blood imaging was performed using a double inversion pulse sequence. The method was tested in 2 times 10 healthy volunteers at 1.5 and 3 T and in 9 myocardial infarction patients at 1.5 T. T1ρ-maps, and LGE images were scored for presence and extent of myocardial scarring. RESULTS: Phantom results show that the proposed T1ρ-mapping method gives accurate T1ρ-values. The mean T1ρ-relaxation time of the myocardium in healthy controls was 52.8 ± 1.8 milliseconds at 1.5 T and 46.4 ± 1.8 milliseconds at 3 T. In patients, the T1ρ of infarcted myocardium was (82.4 ± 5.2 milliseconds), and the T1ρ of remote myocardium was (54.2 ± 2.8 milliseconds; P < 0.0001). Sensitivity of infarct detection on a T1ρ-map was 70%, with a specificity of 94%, compared with LGE. CONCLUSIONS: In this study, we have investigated a method to acquire high spatial-resolution T1ρ-maps of the heart in a single breath-hold. This method proved to be reproducible and had high specificity compared with LGE and can thus be used for the endogenous detection of myocardial fibrosis in patients with ischemic cardiomyopathy.

Endogenous assessment of chronic myocardial infarction with T(1ρ)-mapping in patients.

BACKGROUND: Detection of cardiac fibrosis based on endogenous magnetic resonance (MR) characteristics of the myocardium would yield a measurement that can provide quantitative information, is independent of contrast agent concentration, renal function and timing. In ex vivo myocardial infarction (MI) tissue, it has been shown that a significantly higher T(1ρ) is found in the MI region, and studies in animal models of chronic MI showed the first in vivo evidence for the ability to detect myocardial fibrosis with native T(1ρ)-mapping. In this study we aimed to translate and validate T(1ρ)-mapping for endogenous detection of chronic MI in patients. METHODS: We first performed a study in a porcine animal model of chronic MI to validate the implementation of T(1ρ)-mapping on a clinical cardiovascular MR scanner and studied the correlation with histology. Subsequently a clinical protocol was developed, to assess the feasibility of scar tissue detection with native T(1ρ)-mapping in patients (n = 21) with chronic MI, and correlated with gold standard late gadolinium enhancement (LGE) CMR. Four T1ρ-weighted images were acquired using a spin-lock preparation pulse with varying duration (0, 13, 27, 45 ms) and an amplitude of 750 Hz, and a T(1ρ)-map was calculated. The resulting T(1ρ)-maps and LGE images were scored qualitatively for the presence and extent of myocardial scarring using the 17-segment AHA model. RESULTS: In the animal model (n = 9) a significantly higher T(1ρ) relaxation time was found in the infarct region (61 ± 11 ms), compared to healthy remote myocardium (36 ± 4 ms) . In patients a higher T(1ρ) relaxation time (79 ± 11 ms) was found in the infarct region than in remote myocardium (54 ± 6 ms). Overlap in the scoring of scar tissue on LGE images and T(1ρ)-maps was 74%. CONCLUSION: We have shown the feasibility of native T(1ρ)-mapping for detection of infarct area in patients with a chronic myocardial infarction. In the near future, improvements on the T(1ρ)-mapping sequence could provide a higher sensitivity and specificity. This endogenous method could be an alternative for LGE imaging, and provide additional quantitative information on myocardial tissue characteristics.

Myocardial infarction and functional outcome assessment in pigs.

Introduction of newly discovered cardiovascular therapeutics into first-in-man trials depends on a strictly regulated ethical and legal roadmap. One important prerequisite is a good understanding of all safety and efficacy aspects obtained in a large animal model that validly reflect the human scenario of myocardial infarction (MI). Pigs are widely used in this regard since their cardiac size, hemodynamics, and coronary anatomy are close to that of humans. Here, we present an effective protocol for using the porcine MI model using a closed-chest coronary balloon occlusion of the left anterior descending artery (LAD), followed by reperfusion. This approach is based on 90 min of myocardial ischemia, inducing large left ventricle infarction of the anterior, septal and inferoseptal walls. Furthermore, we present protocols for various measures of outcome that provide a wide range of information on the heart, such as cardiac systolic and diastolic function, hemodynamics, coronary flow velocity, microvascular resistance, and infarct size. This protocol can be easily tailored to meet study specific requirements for the validation of novel cardioregenerative biologics at different stages (i.e. directly after the acute ischemic insult, in the subacute setting or even in the chronic MI once scar formation has been completed). This model therefore provides a useful translational tool to study MI, subsequent adverse remodeling, and the potential of novel cardioregenerative agents.

Impact of hyperaemic microvascular resistance on fractional flow reserve measurements in patients with stable coronary artery disease: insights from combined stenosis and microvascular resistance assessment.

BACKGROUND: Fractional flow reserve (FFR) aims to identify the extent of epicardial disease, but may be obscured by involvement of the coronary microvasculature. We documented the impact of hyperaemic stenosis resistance (HSR) and hyperaemic microvascular resistance (HMR) on FFR, and its relationship with myocardial ischaemia in patients with stable coronary artery disease. METHODS AND RESULTS: We evaluated 255 coronary arteries with stenoses of intermediate severity by means of intracoronary pressure and flow measurements to determine FFR, HSR and HMR. Myocardial perfusion scintigraphy (MPS) was performed to identify inducible myocardial ischaemia. In 178 patients, HMR was additionally determined in a reference coronary artery. Target vessel HMR was stratified according to reference vessel HMR tertiles. The diagnostic OR for inducible ischaemia on MPS of a positive compared with a negative FFR was significantly higher only in the presence of a high HMR (at the 0.75 and 0.80 FFR cut-off). Among stenoses with a positive FFR, the prevalence of ischaemia was significantly higher when HMR was high despite equivalent FFR across the HMR groups. This was paralleled by a concomitant significant increase in HSR with increasing HMR across groups. The relation between FFR and HSR (r(2)=0.54, p<0.001) was modulated by the magnitude of HMR, and improved substantially after adjustment for HMR (adjusted-r(2)=0.73, p<0.001), where, for epicardial disease of equivalent severity, FFR increased with increasing HMR. CONCLUSIONS: Identification of epicardial disease severity by FFR is partly obscured by the microvascular resistance, which illustrates the necessity of combined pressure and flow measurements in daily practice.

Assessment of coronary microvascular resistance in the chronic infarcted pig heart.

Pre-clinical studies aimed at treating ischemic heart disease (i.e. stem cell- and growth factor therapy) often consider restoration of the impaired microvascular circulation as an important treatment goal. However, serial in vivo measurement hereof is often lacking. The purpose of this study was to evaluate the applicability of intracoronary pressure and flow velocity as a measure of microvascular resistance in a large animal model of chronic myocardial infarction (MI). Myocardial infarction was induced in Dalland Landrace pigs (n = 13; 68.9 ± 4.1 kg) by a 75-min. balloon occlusion of the left circumflex artery (LCX). Intracoronary pressure and flow velocity parameters were measured simultaneously at rest and during adenosine-induced hyperemia, using the Combowire (Volcano) before and 4 weeks after MI. Various pressure- and/or flow-derived indices were evaluated. Hyperemic microvascular resistance (HMR) was significantly increased by 28% in the infarct-related artery, based on a significantly decreased peak average peak flow velocity (pAPV) by 20% at 4 weeks post-MI (P = 0.03). Capillary density in the infarct zone was decreased compared to the remote area (658 ± 207/mm(2) versus 1650 ± 304/mm(2) , P = 0.017). In addition, arterioles in the infarct zone showed excessive thickening of the alpha smooth muscle actin (αSMA) positive cell layer compared to the remote area (33.55 ± 4.25 µm versus 14.64 ± 1.39 µm, P = 0.002). Intracoronary measurement of HMR successfully detected increased microvascular resistance that might be caused by the loss of capillaries and arteriolar remodelling in the chronic infarcted pig heart. Thus, HMR may serve as a novel outcome measure in pre-clinical studies for serial assessment of microvascular circulation.

Multidetector row computed tomography assessment of the native aortic and mitral valve: a call for routine assessment of left-sided heart valves during coronary computed tomography.

Aortic valve stenosis and mitral valve regurgitation are the most common valvular heart diseases (VHD) in Western countries. In daily clinical practice, the diagnosis and evaluation of the severity of VHD is based on clinical findings and imaging. Transthoracic echocardiography is the preferred imaging technique for the initial evaluation of VHD. In patients with inconclusive transthoracic echocardiography, transoesophageal echocardiography can have additional diagnostic value. Cardiac multidetector row computed tomography (MDCT) has proven to have diagnostic value in the evaluation of coronary artery disease in symptomatic patients with a low-to-intermediate pretest probability. The images acquired for coronary assessment also contain diagnostic information on heart valves. The purpose of this review was to discuss the diagnostic value of MDCT for the evaluation of left-sided VHD. We provide an overview of the literature comparing echocardiography and MDCT for VHD assessment focusing on aortic valve and mitral valve disease, and we present clinical recommendations.

Diagnostic accuracy of combined intracoronary pressure and flow velocity information during baseline conditions: adenosine-free assessment of functional coronary lesion severity.

BACKGROUND: The assessment of functional coronary lesion severity using intracoronary physiological parameters such as coronary flow velocity reserve and the more widely used fractional flow reserve relies critically on the establishment of maximal hyperemia. We evaluated the diagnostic accuracy of the stenosis resistance index during nonhyperemic conditions, baseline stenosis resistance index, compared with established hyperemic intracoronary hemodynamic parameters, because achievement of hyperemia can be cumbersome in daily clinical practice. METHODS AND RESULTS: A total of 232 patients, including 299 lesions (mean stenosis diameter 55%±11%), underwent myocardial perfusion scintigraphy for documentation of reversible perfusion defects. Distal coronary pressure and flow velocity were assessed with sensor-equipped guidewires during baseline and maximal hyperemia, induced by an intracoronary bolus of adenosine (20-40 µg). We determined stenosis resistance (SR) during baseline and hyperemic conditions as well as fractional flow reserve and coronary flow velocity reserve. The discriminative value for myocardial ischemia on myocardial perfusion scintigraphy of all parameters was compared using receiver-operating-characteristic curves. Baseline SR showed good agreement with myocardial perfusion scintigraphy. The diagnostic performance of baseline SR (area under the curve, 0.77; 95% CI, 0.71-0.83) was as accurate as fractional flow reserve and coronary flow velocity reserve (area under the curve, 0.77; 95% CI, 0.71-0.83 and area under the curve, 0.75; 95% CI, 0.68-0.81 respectively; P>0.05 compared with baseline SR for both). However, hyperemic SR, combining both pressure and flow velocity information during hyperemia, was superior to all other parameters (area under the curve, 0.81; 95% CI, 0.76-0.87; P<0.05 compared with all other parameters). CONCLUSIONS: Combined pressure and flow velocity measurements during baseline conditions may provide a useful tool for functional lesion severity assessment without the need for potent vasodilators.

Coronary artery assessment by multidetector computed tomography in patients with prosthetic heart valves.

OBJECTIVES: Patients with prosthetic heart valves may require assessment for coronary artery disease. We assessed whether valve artefacts hamper coronary artery assessment by multidetector CT. METHODS: ECG-gated or -triggered CT angiograms were selected from our PACS archive based on the presence of prosthetic heart valves. The best systolic and diastolic axial reconstructions were selected for coronary assessment. Each present coronary segment was scored for the presence of valve-related artefacts prohibiting coronary artery assessment. Scoring was performed in consensus by two observers. RESULTS: Eighty-two CT angiograms were performed on a 64-slice (n = 27) or 256-slice (n = 55) multidetector CT. Eighty-nine valves and five annuloplasty rings were present. Forty-three out of 1160 (3.7%) present coronary artery segments were non-diagnostic due to valve artefacts (14/82 patients). Valve artefacts were located in right coronary artery (15/43; 35%), left anterior descending artery (2/43; 5%), circumflex artery (14/43; 32%) and marginal obtuse (12/43; 28%) segments. All cobalt-chrome containing valves caused artefacts prohibiting coronary assessment. Biological and titanium-containing valves did not cause artefacts except for three specific valve types. CONCLUSIONS: Most commonly implanted prosthetic heart valves do not hamper coronary assessment on multidetector CT. Cobalt-chrome containing prosthetic heart valves preclude complete coronary artery assessment because of severe valve artefacts. KEY POINTS: • Most commonly implanted prosthetic heart valves do not hamper coronary artery assessment • Prosthetic heart valve composition determines the occurrence of prosthetic heart valve-related artefacts • Björk-Shiley and Sorin tilting disc valves preclude diagnostic coronary artery segment assessment.