Lerman, Amir

AbstractBackgroundWe assessed the long‐term clinical outcomes of an intermediate lesion (IL) according to the presence of a combined culprit lesion (CCL).HypothesisLong‐term clinical outcomes of IL may be affected by the presence of a CCL.MethodsAngiographic findings (n = 1096) and medical chart were reviewed. Patients with IL were divided into two groups: IL without CCL group (n = 383, 64.5%) and IL with CCL group (n = 211, 35.5%).ResultsThe major adverse cardiovascular events (MACE) in the IL with CCL group were significantly higher than those in the IL without CCL group (death: 12.3% vs. 7.0%, myocardial infarction: 3.3%vs. 0.5%, stroke: 6.6% vs. 2.6%, and revascularization [RVSC]: 25.1% vs. 7.6%) during a mean follow up period of 118.4 ± 5.5 months. IL related RVSC rate in the IL with CCL group was higher than that in the IL without CCL group (5.7% vs. 2.1%, p = 0.020). RVSC rate related to IL in total subjects was lower than that related to stented lesion (3.4% vs. 6.4%). The important predictors of total MACE in total subjects were the presence of CCL, IL percent diameter stenosis, hypertension, history of percutaneous coronary intervention, blood glucose and ejection fraction. The predictors of IL related RVSC were IL percent diameter stenosis and IL located in the right coronary artery.Conclusion10‐year clinical outcomes of an IL (especially IL without CCL) were better than those of stented lesions. This study suggests that the IL can be safely followed up in sites that do not have ability to assess functional study.

Abstract Aims Circulating progenitor cells (CPCs) play a role in vascular repair and plaque stability, while osteocalcin (OC) expressing CPCs have been linked to unstable plaque and adverse cardiovascular outcomes. However, their role in cardiac allograft vasculopathy (CAV) has not been elucidated. This cohort study aimed to investigate the contribution of CPCs on CAV progression and cardiovascular events after heart transplantation. Methods and results A total of 80 heart transplant patients (mean age 55 ± 14 years, 72% male) undergoing annual intravascular ultrasound (IVUS) had fresh CPCs marked by CD34, CD133, and OC counted in peripheral blood using flow cytometry, on the same day as baseline IVUS. CAV progression was assessed by IVUS as the change (Δ) in plaque volume divided by segment length (PV/SL), adjusted for the time between IVUS measurements [median 3.0, interquartile range (2.8–3.1) years] and was defined as ΔPV/SL that is above the median ΔPV/SL of study population. Major adverse cardiac events (MACEs) were defined as any incident of revascularization, myocardial infarction, heart failure admission, re-transplantation, stroke, and death. Patients with higher CD34+CD133+ CPCs had a decreased risk of CAV progression [odds ratio 0.58, 95% confidence interval (CI) (0.37–0.92), P = 0.01] and MACE [hazard ratio (HR) 0.79, 95% CI (0.66–0.99), P = 0.05] during a median (interquartile range) follow-up of 8.0 years (7.2–8.3). Contrarily, higher OC+ cell counts were associated with an increased risk of MACE [HR 1.26, 95% CI (1.03–1.57), P = 0.02]. Conclusions Lower levels of CD34+CD133+ CPCs are associated with plaque progression and adverse long-term outcomes in patients who underwent allograft heart transplantation. In contrast, higher circulating OC+ levels are associated with adverse long-term outcomes. Thus, CPCs might play a role in amelioration of transplant vasculopathy, while OC expression by these cells might play a role in progression.

Background Resistive reserve ratio (RRR), or the ratio of baseline to hyperemic microvascular resistance, has prognostic implications in predicting clinical outcomes in patients with obstructive coronary artery disease. However, its value in patients with angina or ischemia with nonobstructive coronary artery disease is unknown. Methods and Results We included 1692 patients with nonobstructive coronary artery disease who underwent invasive coronary vasoreactivity testing. Abnormal coronary flow reserve (CFR, the ratio of hyperemic and baseline resting flow velocities) and RRR were defined as <2.5 and <2.62, respectively. The mortality rate was marginally higher in patients with abnormal CFR (428 patients [25%]) than those with normal CFR (38 [9%] versus 81 [6%]; P =0.08), and was significantly higher in patients with abnormal RRR (716 patients [42%]) than those with normal RRR (70 [10%] versus 49 [5%], P =0.0002) over the median follow‐up of 11.3 years. Patients with abnormal CFR had marginally lower survival than those with normal CFR (log‐rank P =0.08). In contrast, patients with abnormal RRR had significantly lower survival than those with normal RRR (log‐rank P =0.001). Abnormal RRR was associated with shorter time to death even after adjustment for other covariates (adjusted hazard ratio, 1.63; 95% CI, 1.11–2.38; P =0.01). Conclusions In patients with no obstructive coronary artery disease, RRR was superior to CFR in predicting long‐term survival. An RRR <2.62 was associated with 1.6 times increased risk of death in patients with nonobstructive coronary artery disease. Indices of coronary microcirculatory resistive reserve comprising flow‐ and pressure‐derived values may reflect underlying microvascular pathology more faithfully than flow‐alone indices like CFR.

Background Myocardial fibrosis is an important contributor for development of diastolic dysfunction. We investigated the impact of sirolimus as primary immunosuppression on diastolic dysfunction and fibrosis progression among heart transplantation recipients. Methods and Results In 100 heart transplantation recipients who were either treated with a calcineurin inhibitor (CNI) (n=51) or converted from CNI to sirolimus (n=49), diastolic function parameters were assessed using serial echocardiograms and right heart catheterizations. Myocardial fibrosis was quantified on serial myocardial biopsies. After 3 years, lateral e′ increased within the sirolimus group but decreased in the CNI group (0.02±0.04 versus −0.02±0.04 m/s delta change; P =0.003, respectively). Both pulmonary capillary wedge pressure and diastolic pulmonary artery pressure significantly decreased in the sirolimus group but remained unchanged in the CNI group (−1.50±2.59 versus 0.20±2.20 mm Hg/year; P =0.02; and −1.72±3.39 versus 0.82±2.59 mm Hg/year; P =0.005, respectively). A trend for increased percentage of fibrosis was seen in the sirolimus group (8.48±3.17 to 10.10±3.0%; P =0.07) as compared with marginally significant progression in the CNI group (8.76±3.87 to 10.56±4.34%; P =0.04). The percent change in fibrosis did not differ significantly between the groups (1.62±4.67 versus 1.80±5.31%, respectively; P =0.88). Conclusions Early conversion to sirolimus is associated with improvement in diastolic dysfunction and filling pressures as compared with CNI therapy. Whether this could be attributed to attenuation of myocardial fibrosis progression with sirolimus treatment warrants further investigation.

Abstract Background The Seattle Angina Questionnaire (SAQ) is a self-administered questionnaire used in cardiac patients to quantify angina based on five scales: physical limitation scale, anginal stability scale, anginal frequency scale, treatment satisfaction scale, and the disease perception scale. Here we report the use of the SAQ to assess angina symptoms in 18 patients who underwent spinal cord stimulation (SCS) for refractory angina pectoris (RAP) at the Mayo Clinic. Methods Electronic health records were searched to find patients who underwent SCS for the treatment of RAP at a single institution from 2003 to 2018. Eligible patients were asked to participate in a phone survey that included the SAQ. Results Out of 13 patients who still had their implant, six (46%) had minimal physical limitations. Ten patients (76.9%) had favorable anginal frequency scores, defined as minimal or mild. Out of the five patients who had their device removed, one (20%) had minimal physical limitations and three (60%) had favorable anginal frequency scores. There was a high treatment satisfaction score for both those with their implant in place and those with the device removed. Conclusion The SAQ is useful as a comprehensive measure specific to patients with RAP assessing function, pain, and satisfaction. The utilization of this tool pre- and post-operatively may provide additional information to analyze the effectiveness of SCS for RAP.

Chronic kidney disease is a global health care burden, yet clinically-proven treatments are limited. Low-intensity shockwave, which utilizes ≈10% of the energy levels used in clinically indicated shockwave lithotripsy, is a promising technique to ameliorate ischemia and regenerate tissues. It has been demonstrated to improve healing in tissues such as bone, muscle, myocardium, and kidney via several mechanisms, particularly through promoting neovascularization. Low-intensity shockwave stimulates mechanoreceptors located primarily in endothelial and proximal tubular cells and subsequently upregulates vascular endothelial growth factors. This, in turn, promotes angiogenesis and ameliorates renal hypoxia, inflammation, and fibrosis, and ultimately preserves renal function. Furthermore, low-intensity shockwave can stimulate release of homing factors to attract endothelial progenitor or stem cells into injured kidneys for tissue repair. These effects may be beneficial in several kidney disease models, including renal artery stenosis, diabetic kidney disease, and various chronic kidney diseases, although most studies reported to date have been performed in animal models. Because of its low energy intensity, the procedure is relatively tolerable and safe, yet, more clinical studies are needed to establish its efficacy beyond currently existing strategies. Therefore, low-intensity shockwave therapy emerges as an alternative therapeutic approach that may offer a promising noninvasive intervention for treating renal diseases. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02515461; NCT03602807; and NCT03445247.

Abstract The development of novel, non-invasive techniques and standardization of protocols to assess microvascular dysfunction have elucidated the key role of microvascular changes in the evolution of cardiovascular (CV) damage, and their capacity to predict an increased risk of adverse events. These technical advances parallel with the development of novel biological assays that enabled the ex vivo identification of pathways promoting microvascular dysfunction, providing novel potential treatment targets for preventing cerebral-CV disease. In this article, we provide an update of diagnostic testing strategies to detect and characterize microvascular dysfunction and suggestions on how to standardize and maximize the information obtained from each microvascular assay. We examine emerging data highlighting the significance of microvascular dysfunction in the development CV disease manifestations. Finally, we summarize the pathophysiology of microvascular dysfunction emphasizing the role of oxidative stress and its regulation by epigenetic mechanisms, which might represent potential targets for novel interventions beyond conventional approaches, representing a new frontier in CV disease reduction.

Background Elevated levels of serum homocysteine, via impaired nitric oxide production, and coronary microvascular dysfunction are associated with increased risk of major adverse cardiovascular events. However, whether serum homocysteine levels and coronary microvascular endothelial dysfunction (CMED) are linked remains unknown. Methods and Results This study included 1418 patients with chest pain or an abnormal functional stress test and with nonobstructive coronary artery disease (<40% angiographic stenosis), who underwent CMED evaluation with functional angiography and had serum homocysteine levels measured. Patients were classified as having normal microvascular function versus CMED. Patients in the CMED group (n=743; 52%) had higher mean age (52.1±12.2 versus 50.0±12.4 years; P <0.0001), higher body mass index (29.1 [25.0–32.8] versus 27.5 [24.2–32.4]; P =0.001), diabetes mellitus (12.5% versus 9.4%; P =0.03), and fewer women (63.5% versus 68.7%; P =0.04) compared with patients in the normal microvascular function group. However, they had lower rates of smoking history, and mildly lower low‐density lipoprotein cholesterol levels. Serum homocysteine levels were significantly higher in patients with CMED, and the highest quartile of serum homocysteine level (>9 µmol/L) was an independent predictor of CMED (odds ratio, 1.34 [95% CI, 1.03–1.75]; P =0.03) after adjustment for age; sex; body mass index; chronic kidney disease (CKD); diabetes mellitus; smoking exposure; low‐density lipoprotein cholesterol; high‐density lipoprotein cholesterol and triglycerides; and aspirin, statin, and B vitamin use. Conclusions Patients with CMED have significantly higher levels of serum homocysteine. Elevated serum homocysteine levels were associated with a significantly increased odds of an invasive diagnosis of CMED. The current study supports a potential role for homocysteine for diagnosis and target treatment in the patients with early coronary atherosclerosis.

Background We examined feasibility of a unique approach towards gaining insight into heritable risk for early atherosclerosis: surveying gene expression by endothelial cells from living subjects. Methods and Results Subjects aged <50 years (mean age, 37; range, 22–49) without obstructive coronary artery disease underwent coronary reactivity testing that identified them as having normal or abnormal coronary endothelial function. Cultures of Blood Outgrowth Endothelial Cells (BOEC) from 6 normal and 13 abnormal subjects passed rigorous quality control and were used for microarray assessment of gene expression. Of 9 genes differentially expressed at false discovery rate <0.1%, we here focus upon abnormal subjects having elevated expression of HMGB1 (high mobility group box 1) which we unexpectedly found to be linked to low LAMC1 (laminin gamma 1) expression. This linkage was corroborated by 3 of our past studies and confirmed bio‐functionally. Compared with normal BOEC, abnormal BOEC released 13±3‐fold more HMGB1 in response to lipopolysaccharide; and they deposited one tenth as much LAMC1 into collagen subendothelial matrix during culture. Clinical follow‐up data are provided for 4 normal subjects (followed 13.4±0.1 year) and for 12 abnormal subjects (followed 9.1±4.5 years). Conclusions The known pathogenic effects of high‐ HMGB1 and low‐ LAMC1 predict that the combination would biologically converge upon the focal adhesion complex, to the detriment of endothelial shear responsiveness. This gene expression pattern may comprise a heritable risk state that promotes early coronary atherosclerosis. If so, the testing could be applied even in childhood, enabling early intervention. This approach offers a way to bridge the information gap between genetics and clinical phenotype.