Long-term prognostic impact of fasting plasma glucose and myocardial flow reserve beyond other risk factors and heart disease phenotypes.

Cardiometabolic risk factors, including high fasting plasma glucose (hFPG), are emerging prognostic determinants in patients with coronary artery disease (CAD) or heart failure (HF). Coronary microvascular dysfunction might be a comprehensive risk predictor in these patients. The purpose of this study was to assess whether hFPG and global myocardial blood flow (MBF) reserve measured by positron emission tomography (PET), expressing global coronary function, predict long-term prognosis beyond other risk factors and presence of obstructive CAD or left ventricular (LV) dysfunction associated with HF. We retrospectively collected long-term follow-up data in 103 patients (mean age 61 ± 10 years, 74 males) with stable chest pain or dyspnoea who underwent cardiac PET/computerized tomography and coronary angiography. Disease phenotypes included obstructive CAD (35%), LV dysfunction without obstructive CAD (43%), or none (22%). At multivariable logistic regression analysis, MBF reserve lower than the median value (OR 1.8, 95% CI 1.5-2.2) was significantly associated with male gender (OR 3.45, 95% CI 1.21-9.83) and hFPG (OR 3.87, 95% CI 1.17-12.84) among all risk factors. In a median follow-up of 10.9 years (interquartile range 7.8-13.9), 39 patients (37.8%) died (13.6% cardiac death). At multivariable Cox analyses including all risk factors and disease phenotypes, age (HR 1.07, 95% CI 1.02-1.12), hFPG (HR 2.18, 95% CI 1.02-4.63), and depressed MBF reserve (HR 4.47, 95% CI 1.96-10.18) were independent predictors of death (global χ 2 37.41, P = 0.0004). These results suggest a strong long-term prognostic role of hFPG and depressed MBF reserve in a high-risk population of patients with a high prevalence of obstructive CAD or HF.

Prevalence and Prognostic Importance of Abnormal Positron Emission Tomography Among Asymptomatic Patients With Diabetes Mellitus.

BACKGROUND: Ischemia and reduced global myocardial blood flow reserve (MBFR) are associated with high cardiovascular risk among symptomatic patients with diabetes mellitus (DM). OBJECTIVES: This study aimed to assess the prevalence and prognostic importance of silent ischemia and reduced MBFR among asymptomatic patients with DM. METHODS: This study included 2,730 consecutive patients with DM, without known coronary artery disease (CAD) or cardiomyopathy, who underwent rubidium-82 rest/stress positron emission tomography (PET) myocardial perfusion imaging (MPI) from 2010 to 2016. These patients were followed up for all-cause mortality (n = 461) for a median follow-up of 3 years. Patients were considered asymptomatic if neither chest pain nor dyspnea was elicited. Rates of ischemia, reduced MBFR, and coronary microvascular dysfunction on PET were assessed in both groups. Cox regression was used to define the independent association of abnormal MPI markers with mortality. RESULTS: One-quarter of patients with DM (23.7%; n = 647) were asymptomatic; ischemia was present in 30.5% (n = 197), reduced MBFR in 62.3% (n = 361), and coronary microvascular dysfunction in 32.7% (n = 200). In adjusted analyses, reduced MBFR (HR per 0.1 unit decrease in MBFR: 1.08 [95% CI: 1.03-1.12]; P = 0.001) and reduced ejection fraction (HR per 5% decrease: 1.10 [95% CI: 1.01-1.18]; P = 0.02) were independently prognostic of mortality among asymptomatic patients, but ischemia was not. This was comparable to DM patients with symptoms. Insulin use and older age were significant predictors of reduced MBFR among asymptomatic patients with DM. CONCLUSIONS: In both symptomatic and asymptomatic patients with DM, impairment in MBFR is common and associated with greater mortality risk.

Coronary vascular dysfunction is associated with increased risk of death in patients with peripheral artery disease.

BACKGROUND: Peripheral artery disease (PAD) and coronary vascular dysfunction are common in patients with cardiometabolic disease. Neither the prevalence of coronary vascular dysfunction among patients with PAD nor the prognostic impact with these two conditions present together has been well studied. METHODS: Consecutive patients who underwent PET MPI were analyzed for presence of coronary vascular dysfunction [myocardial blood flow reserve (MBFR) < 2]. Cox regression was used to examine the association of reduced MBFR with mortality in patients with PAD, as well as the association of comorbid MBFR < 2 and PAD with all-cause death. RESULTS: Among 13,940 patients, 1936 (14%) had PAD, 7782 (56%) had MBFR < 2 and 1346 (10%) had both PAD and MBFR < 2. Reduced MBFR was very common (69.5%) and was associated with increased risk of all-cause death (HR 1.69, 95%CI 1.32, 2.16, p < 0.01) in patients with PAD. Patients with both PAD and MBFR < 2, and those with either PAD or reduced MBFR had increased risk of death compared to those with neither condition: PAD + MBFR < 2 [(HR 95%CI), 2.30; 1.97-2.68], PAD + MBFR ≥ 2 (1.37; (1.08-1.72), PAD - MBFR < 2 (1.98; 1.75-2.25), p < 0.001 for all). CONCLUSION: Coronary vascular dysfunction was common in patients with PAD and was associated with increased risk of death.

Prognostic implications of myocardial perfusion imaging by 82-rubidium positron emission tomography in male and female patients with angina and no perfusion defects.

AIMS: Myocardial perfusion imaging with 82-rubidium positron emission tomography (82Rb-PET) is increasingly used to assess stable coronary artery disease (CAD). We aimed to evaluate the prognostic value of 82Rb-PET-derived parameters in patients with symptoms suggestive of CAD but no significant reversible or irreversible perfusion defects. METHODS AND RESULTS: Among 3726 consecutive patients suspected of stable CAD who underwent 82Rb-PET between January 2018 and August 2020, 2175 had no regional perfusion defects. Among these patients, we studied the association of 82Rb-PET-derived parameters with a composite endpoint of all-cause mortality, hospitalization for unstable angina pectoris, acute myocardial infarction, heart failure, or ischaemic stroke. During a median follow up of 1.7 years (interquartile range 1.1-2.5 years), there were 148 endpoints. Myocardial blood flow (MBF) reserve (MFR), MBF during stress, left ventricular ejection fraction (LVEF), LVEF-reserve, heart rate reserve, and Ca score were associated with adverse outcomes. In multivariable Cox model adjusted for patient and 82Rb-PET characteristics, MFR < 2 (hazard ratio (HR) 1.75, 95% confidence interval (CI) 1.24-2.48), LVEF (HR 1.38 per 10% decrease, 95% CI 1.24-1.54), and LVEF-reserve (HR 1.19 per 5% decrease, 95% CI 1.07-1.31) were significant predictors of endpoints. Results were consistent in subgroups defined by gender, history of ischaemic heart disease, low LVEF, and atrial fibrillation. CONCLUSION: MFR, LVEF, and LVEF-reserve derived from 82Rb-PET provide prognostic information on cardiovascular outcomes in patients with no perfusion defects. This may aid in identifying patients at risk and might provide an opportunity for preventive interventions.

How Do PET Myocardial Blood Flow Reserve and FFR Differ?

PURPOSE OF REVIEW: This review discusses similarities and differences between cardiac positron emission tomography (PET), absolute myocardial blood flow, and flow reserve with invasive fractional flow reserve (FFR). RECENT FINDINGS: Fundamentally, cardiac PET measures absolute myocardial blood flow whereas FFR provides a relative flow reserve. Cardiac PET offers a non-invasive and therefore lower risk alternative, able to image the entire left ventricle regardless of coronary anatomy. While cardiac PET can provide unique information about the subendocardium, FFR pullbacks offer unparalleled spatial resolution. Both diagnostic tests provide a highly repeatable and technically successful index of coronary hemodynamics that accounts for the amount of distal myocardial mass, albeit only indirectly with FFR. The randomized evidence base for FFR and its associated cost effectiveness remains unsurpassed. Cardiac PET and FFR have been intertwined since the very development of FFR over 25 years ago. Recent work has emphasized the ability of both techniques to guide revascularization decisions by high-quality physiology. In the past few years, cardiac PET has expanded its evidence base regarding clinical outcomes, whereas FFR has solidified its position in randomized studies as the invasive reference standard.

Myocardial blood flow reserve assessed by positron emission tomography myocardial perfusion imaging identifies patients with a survival benefit from early revascularization.

AIMS: Positron emission tomography (PET) myocardial perfusion imaging (MPI) can non-invasively measure myocardial blood flow reserve (MBFR). We aimed to examine whether MBFR identifies patients with a survival benefit after revascularization, helping to guide post-test management. METHODS AND RESULTS: We examined all-cause mortality in 12 594 consecutive patients undergoing Rb82 rest/stress PET MPI from January 2010 to December 2016, after excluding those with cardiomyopathy, prior coronary artery bypass surgery (CABG), and missing MBFR. Myocardial blood flow reserve was calculated as the ratio of stress to rest absolute myocardial blood flow. A Cox model adjusted for patient and test characteristics, early revascularization (percutaneous coronary intervention or CABG ≤90 days of MPI), and the interaction between MBFR and early revascularization was developed to identify predictors of all-cause mortality. After a median follow-up of 3.2 years, 897 patients (7.1%) underwent early revascularization and 1699 patients (13.5%) died. Ischaemia was present in 4051 (32.3%) patients, with 1413 (11.2%) having ≥10% ischaemia. Mean MBFR was 2.0 ± 1.3, with MBFR <1.8 in 4836 (38.5%). After multivariable adjustment, every 0.1 unit decrease in MBFR was associated with 9% greater hazard of all-cause death (hazard ratio 1.09, 95% confidence interval 1.08-1.10; P < 0.001). There was a significant interaction between MBFR and early revascularization (P < 0.001); such that patients with MBFR ≤1.8 had a survival benefit with early revascularization, regardless of type of revascularization or level of ischaemia. CONCLUSION: Myocardial blood flow reserve on PET MPI is associated with all-cause mortality and can identify patients who receive a survival benefit with early revascularization compared to medical therapy. This may be used to guide revascularization, and prospective validation is needed.

Transthoracic Doppler echocardiography compared with positron emission tomography for assessment of coronary microvascular dysfunction: The iPOWER study.

BACKGROUND: Coronary microvascular function can be assessed by transthoracic Doppler echocardiography as a coronary flow velocity reserve (TTDE CFVR) and by positron emission tomography as a myocardial blood flow reserve (PET MBFR). PET MBFR is regarded the noninvasive reference standard for measuring coronary microvascular function but has limited availability. We compared TTDE CFVR with PET MBFR in women with angina pectoris and no obstructive coronary artery disease and assessed repeatability of TTDE CFVR. METHODS: From a cohort of women with angina and no obstructive coronary artery stenosis at invasive coronary angiography, TTDE CFVR by dipyridamole induced stress and MBFR by rubidium-82 PET with adenosine was successfully measured in 107 subjects. Repeatability of TTDE CFVR was assessed in 10 symptomatic women and in 10 healthy individuals. RESULTS: MBFR was systematically higher than CFVR. Median MBFR (interquartile range, IQR) was 2.68 (2.29-3.10) and CFVR (IQR) was 2.31 (1.89-2.72). Pearson's correlation coefficient was 0.36 (p<0.01). Limits of agreement (2·standard deviation) assessed by the Bland-Altman (confidence interval, CI) method was 1.49 (1.29;1.69) and unaffected by time-interval between examinations. Results were similar when adjusting for rate pressure product or focusing on perfusion of the left anterior descending artery region. Limits of agreement (CI) for repeated CFVR in 10 healthy individuals and in 10 women with angina was 0.44 (0.21;0.68) and 0.48 (0.22; 0.74), respectively. CONCLUSION: CFVR had a good repeatability, but the agreement between CFVR and MBFR was modest. Divergence could be due to methodology differences; TTDE estimates flow velocities whereas PET estimates myocardial blood flow.

Insulin in Acute Coronary Syndrome: a Narrative Review with Contemporary Perspectives.

The role of insulin in the treatment of acute coronary syndrome (ACS) has been widely studied over the past 100 years. The current indication for its use in this context is the treatment of hyperglycemia, irrespective of diabetes, which is associated with adverse outcome. Initial theories proposed that glucose was beneficial in the context of myocardial ischemia and insulin was required to enable glucose cell uptake. However, studies testing this hypothesis with routine insulin administration during ACS have produced disappointing results and research interest has therefore declined. We propose that the less well known but important vasodilator effect of insulin has been overlooked by some of these studies and warrants further consideration. Previous reports have shown that hyperinsulinemic euglycaemia improves myocardial blood flow reserve. With this in mind, this review considers the role of insulin in the context of ACS from the perspective of a vasodilator rather than a metabolic modulator. We discuss the importance of time to treatment, dosage of insulin administered, problems with hypoglycaemia and insulin resistance, and how they may have affected the outcomes of the major trials. Finally, we propose new study designs that allow determination of the optimal vasodilator conditions for the use of insulin as adjunctive pharmacotherapy during myocardial ischaemia.

Abnormal Myocardial Blood Flow Reserve Observed in Cardiac Amyloidosis.

We performed real-time myocardial contrast echocardiography on a patient with cardiac amyloidosis and previous normal coronary angiography presenting with atypical chest pain to assess myocardial blood flow reserve (MBFR). Myocardial contrast echocardiography was performed and flash microbubble destruction and replenishment analysis was used to calculate myocardial blood flow. Dipyridamole was used to achieve hyperemia. MBFR was derived from the ratio of peak myocardial blood flow at hyperemia and rest. The results show a marked reduction in MBFR in our patient. Previous reports of luminal obstruction of intramyocardial rather than epicardial vessels by amyloid deposition may be causing microvascular dysfunction.

Estudo comparativo do fluxo da artéria torácica interna utilizada "in situ" na revascularização miocárdica, com e sem a ligadura dos ramos proximais, utilizando a ecocardiografia Doppler / Comparative study of the internal thoracic artery flow used "in situ" for myocardial revascularization, with and without ligation of its proximal branches using Doppler echocardiography

Fundamento: A artéria torácica interna (ATI) "in situ" apresenta predomínio de fluxo sistólico, mas após sua anastomose no sistema coronariano esquerdo torna-se um sistema híbrido com predomínio de fluxo diastólico, sendo a relevância da patência ou não dos grandes ramos proximais da ATI anastomosada controversa quanto à possibilidade de roubo de fluxo. Porém, constata-se que durante o ecocardiograma sob estresse com dobutamina (EED), o estado funcional da ATI anastomosada pode ser avaliado através da reserva coronariana, além da verificação dos distintos efeitos no fluxo sistólico (FS), diastólico (FD) e total (FT = sistólico + diastólico). Objetivo: Verificar por meio da ecocardiografia e Doppler o efeito dos ramos proximais importantes da ATI no fluxo, na reserva de velocidade (RVFC) e de fluxo (RFC) coronariano, em pacientes com fração de ejeção do ventrículo esquerdo (FEVE) preservada (>50%). Métodos: Em ensaio clínico prospectivo controlado e randomizado, foram avaliados pacientes com (Grupo I) e sem (Grupo II), a ligadura dos ramos proximais importantes da ATI anastomosada na coronária descendente anterior. As avaliações das ATIs em nível supraclavicular e os ecocardiogramas transtorácicos foram realizados no pré-operatório, no pós-operatório precoce, seis meses após a cirurgia em condição basal e durante o EED. Neste, foi alcançada a frequência cardíaca submáxima [(220 - idade) x (0,85)] sem a ocorrência de isquemia no território subjacente à ATI anastomosada em todos os pacientes. Foram medidos o FS, o FD, o FT e o percentual de FD, nos quatro momentos do estudo. O percentual de FD resultou da divisão da integral da velocidade diastólica do fluxo pela integral da velocidade total (sistólica + diastólica) do fluxo. A reserva coronariana foi obtida através do Doppler da ATI anastomosada seis meses após a cirurgia, sendo calculada através da razão entre o valor da variável registrado no EED e em condição basal, utilizando-se para as RVFCs o pico e a...

Background: The internal thoracic artery (ITA) "in situ" has systolic flow predominance, but when grafted to the left coronary artery system, the ITA becomes a hybrid system with diastolic flow predominance. The relevance of the patency or not-patency of the large proximal branches of the ITA graft is controversial in regards to the possibility of flow steal. During dobutamine stress echocardiography (DSE), the functional status of the ITA graft can be assessed by the coronary reserve in addition to assessment of the distinct effects of DSE on systolic (SF), diastolic (DF), and total flow (TF = systolic + diastolic). Objective: To assess, by Doppler echocardiography, the effects of the significant proximal branches of ITA graft in the flow, coronary flow velocity reserve (CFVR) and coronary flow reserve (CFR), in patients with preserved (> 50%) left ventricular ejection fraction (LVEF). Methods: In a prospective randomized controlled clinical trial we evaluate patients with (Group I) and without (Group II) ligation of important proximal branches of the ITA grafted to the anterior descending coronary artery. Supraclavicular assessment of the ITAs and transthoracic echocardiograms were performed, at rest and during DSE, on pre-operative, early and six months post-operative. In all patients, the submaximal heart rate [(220 - age) x (0.85)] was achieved during DSE with no ischemia to the area matching the ITA graft. The SF, DF, TF and percentage of DF were measured in the four moments of this study. The percentage of DF was calculated by the ratio of the integral of the diastolic flow velocity by the integral of the total flow velocity (systolic + diastolic). The coronary reserve was assessed at six months post-operative, and it was calculated by the ratio of the variable during DSE and at rest, using the maximum and the mean of the diastolic flow velocity to calculate the CFVR; and the TF to calculate the CFR. Student's t-tests or Wilcoxon's rank sum test (Mann...

Impaired left ventricular function and myocardial blood flow reserve in patients with long-term type 1 diabetes and no significant coronary artery disease: associations with protein glycation.

Our aims were to study left ventricular (LV) function and myocardial blood flow reserve (MBFR) in long-term type 1 diabetes and associations with advanced glycation end products (AGEs). A total of 20 type 1 diabetes patients from the Oslo Study without significant stenosis on coronary angiography were compared with 26 controls. LV systolic and diastolic functions were assessed by two-dimensional strain and the ratio between pulsed Doppler transmitral early (E) velocity and tissue Doppler velocity (E'), respectively. MBFR was evaluated by contrast echocardiography. The AGE methylglyoxal-derived hydroimidazolone was analysed in serum. Glyoxal hydroimidazolone in skin collagen was determined by liquid chromatography-mass spectrometry. Strain was significantly reduced (-19.5% ± 1.9% vs -21.4% ± 3.5%, p < 0.05), and E/E' increased in the diabetes patients compared to controls, 7.3 ± 2 versus 6.0 ± 1.5, p < 0.05. Significant lower MBFR was present in the diabetes patients, 3.4 (2.1, 5.3) versus 5.9 (3.9, 9.6), p < 0.01. Both AGEs correlated significantly with E/E'. The impaired LV function with correlation to AGEs in concert with reduced MBFR in diabetics without coronary artery disease may indicate possible mechanisms for diabetic cardiomyopathy.