Treatment following Triple-AAV Delivery in Mature Murine Model of Human CDH23-Associated Hearing Loss.

This study aimed to investigate the transduction efficiency of triple adeno-associated virus (AAV) vectors in the cochleae of adult mice, focusing on large-gene-associated hearing loss (HL). Additionally, we sought to evaluate the feasibility of cochlear gene therapy in a mouse model of human CDH23-mediated HL using the triple AAV approach. To create a reporter protein, we fused EGFP to mCherry, which was then divided into three parts, each packaged in a separate AAV2/2 vector. Four weeks after co-injecting the triple AAV vectors into 4-5-week-old mice, we assessed transduction efficiency. We found that up to 5.9% of inner hair cells were positive for both EGFP and mCherry. Subsequently, we developed triple Cdh23 AAV vectors for therapeutic purposes. After administering these vectors to 4- to 5-week-old C57/BL6 mice, we conducted auditory tests and immunohistochemistry studies over a period of 60 weeks. Co-injecting triple Cdh23-AAVs did not alter auditory function or lead to hair cell degeneration. In conclusion, this study confirms the feasibility of the triple-AAV approach for cochlear gene delivery. While this strategy did not produce any treatment effects, our findings suggest that large deafness genes could be potential future targets for cochlear gene therapy.

Feasibility and limitations of head MRI in patients with cochlear implants.

OBJECTIVE: Cochlear implants (CIs) were noncompatible with magnetic resonance imaging (MRI) initially; however, recently, implants have become available that are compatible with MRI without the need for magnet removal or bandage fixation. The images produced by MRI scans are sometimes deteriorated by artifacts and are not clinically useful. In this study, we discussed the size differences of such artifacts with respect to the imaging modality and sequences with their clinical validity. METHODS: We performed a head MRI, using a head bandage and without magnet removal in five patients who underwent cochlear implantation at our department and analyzed the MRI findings. RESULTS: Without magnet removal, diffusion-weighted images and T2 star-weighted images had larger artifacts and less useful images. T1-weighted images, T2-weighted images (T2WIs), T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) images, and heavy T2WIs could evaluate the unimplanted side and middle of the head but had limited applicability on the CI side. CONCLUSION: The characteristic features of MRI scan images vary with the method used as well as with the sequence, suggesting that the choice of MRI is largely determined on the basis of clinical feasibility and the requirement. Accordingly, we need to judge well in advance of imaging whether the images would be clinically relevant.

Does fractional flow reserve overestimate severity of LAD lesions?

BACKGROUND: Fractional Flow Reserve (FFR) is increasingly used to estimate the severity of coronary stenoses, prior to coronary revascularization. However, it has been suggested that FFR overestimates the severity of Left Anterior Descending (LAD) lesions. Our aim was to verify whether in patients without ischemia on Myocardial Perfusion Imaging, FFR of the LAD is more often abnormal in comparison to FFR of other coronary arteries. METHODS: Prospective cohort study of consecutive patients who underwent FFR measurement because of persistent or worsening of angina complaints, within 6 months after normal Myocardial Perfusion Imaging. FFR measurements of a graft or diagonal branch were excluded. A FFR ≤ 0.80 denoted a functionally relevant stenosis. RESULTS: In 133 patients, 167 FFR measurements were performed, of which 85 in the LAD. Mean age of the patients was 64.8 ± 10.5 years, 40% were women. There were no differences in baseline characteristics between patients undergoing LAD and non-LAD measurements. An abnormal FFR was observed in 35.3% of the LAD measurements, compared to 9.8% in the non-LAD measurements (P = 0.001). Also after adjusting for age and gender, the FFR remained more frequently abnormal in the LAD with OR 5.2 (95% CI 2.2 to 12.3). Of the abnormal FFR LAD measurements, 70% were visually considered non-obstructive on invasive angiography. CONCLUSIONS: In selected patients without ischemia on MPI, FFR measurement of the LAD is significantly more often abnormal. The majority of these patients has no obstructive lesions on invasive angiography. Possibly, FFR overestimates severity of LAD lesions, with risk of unnecessary revascularization.

Coronary calcium score influences referral for invasive coronary angiography after normal myocardial perfusion SPECT.

BACKGROUND: In patients with normal SPECT but persistent complaints, invasive angiography may exclude obstructive coronary disease. We assessed whether high coronary artery calcium (CAC) scores are associated with increased referral for invasive angiography following normal SPECT. METHODS AND RESULTS: 2286 consecutive patients (mean age 60 ± 12, 39% male) with normal SPECT were assessed. All patients underwent simultaneous CAC scoring. Patients were categorized into four groups based on their CAC score: CAC = 0 (n = 694), CAC 1 to 100 (n = 891), CAC 101 to 400 (n = 368), and CAC >400 (n = 333). The decision to perform angiography was left to the discretion of treating physician. Follow-up angiography was confined to the first 60 days after SPECT. Occurrence of MACE (late revascularization, myocardial infarction or death) was recorded. Overall, 100 patients (4.4%) underwent early angiography with increasing rates in higher CAC score groups (1.0%, 2.6%, 8.4%, and 11.7%), respectively, P < .001). A CAC score >400 (OR 3.56, 95% CI 2.19 to 5.77, P < .001) was independently associated with referral to angiography. Similarly, CAC score >400 was an independent predictor for MACE (HR 9.26, 95% CI 5.06 to 16.93). Early angiography did not influence prognosis (HR 1.57, 95% CI 0.91 to 2.73). CONCLUSIONS: CAC scoring impacts clinical decision-making and increases referral rates for invasive angiography after normal SPECT.

Anatomically and functionally relevant coronary stenoses in patients with normal single-photon emission computed tomography but persistent stable angina.

Aims: Single-photon emission computed tomography (SPECT) is widely used for the assessment of coronary artery disease and for decision making regarding revascularization. Concerns about possible false negative findings exist. Our aim was to assess the prevalence of stenoses which are both functionally and anatomically significant in patients referred for invasive fractional flow reserve (FFR) measurements following a normal SPECT, because of persistent complaints. Methods and results: One hundred and thirty-three consecutive patients with normal SPECT were included, with a total of 180 FFR measurements. Luminal narrowing of ≥70% (≥50% for left main) together with a FFR ≤0.80 denoted an anatomically and functionally significant coronary artery stenosis. Separate analyses were performed for FFR <0.75. Mean age of the patients was 65, 40% were women. Sixteen percent of the study population had both anatomically and functionally significant stenoses. Besides the use of nitrate, no differences in baseline characteristics, symptoms, coronary history, or pre-test likelihood could be identified for the prediction of functionally relevant obstructive coronary disease. If FFR <0.75 was used, only 7.5% of the patients had both anatomically and functionally significant stenoses. Conclusion: In patients with normal SPECT who undergo FFR measurements because of persistent complaints, the prevalence of stenoses which are both anatomically and functionally significant is low. This suggests that the prevalence of false-negative SPECT is (very) low.

Prognostic value of normal stress-only myocardial perfusion imaging: a comparison between conventional and CZT-based SPECT.

PURPOSE: Single photon emission computed tomography (SPECT) myocardial perfusion imaging has proven to have prognostic importance in patients with suspected stable coronary artery disease (CAD). The recently introduced ultrafast cadmium zinc telluride (CZT)-based gamma cameras have been associated with less equivocal findings and more normal interpretations, allowing stress-only imaging to be performed more often. However, it is yet unclear whether normal stress-only CZT SPECT has comparable prognostic value as normally interpreted stress-only conventional SPECT. METHODS: The study population consisted of 1,650 consecutive patients without known CAD with normal stress-only myocardial perfusion results with either conventional (n = 362) or CZT SPECT (n = 1,288). The incidence of major adverse cardiac events (MACE, all-cause death, non-fatal myocardial infarction and/or coronary revascularization) was compared between the conventional SPECT and CZT SPECT groups. Multivariable analyses using the Cox model were used to adjust for differences in baseline variables. RESULTS: Patients scanned with CZT were less often male (33 vs 39 %), had less often hypercholesterolaemia (41 vs 50 %) and had more often a family history of CAD (57 vs 49 %). At a median follow-up time of 37 months (interquartile range 28-45 months) MACE occurred in 68 patients. The incidence of MACE was 1.5 %/year in the CZT group, compared to 2.0 %/year in the conventional group (p = 0.08). After multivariate analyses, there was a trend to a lower incidence of MACE in the CZT SPECT group (hazard ratio 0.61, 95 % confidence interval 0.35-1.04, p = 0.07). CONCLUSION: The prognostic value of normal stress-only CZT SPECT is at least comparable and may be even better than that of normal conventional stress SPECT.

Prevalence, location, and extent of significant coronary artery disease in patients with normal myocardial perfusion imaging.

BACKGROUND: False-negative myocardial perfusion imaging (MPI) can by due to left main (LM) or three-vessel disease causing "balanced ischemia". However, so far prevalence of LM or three-vessel-disease in patients with normal MPI is unclear. We assessed prevalence, location, and extent of significant coronary artery disease (CAD) in patients with normal MPI. METHODS: Between 2006 and 2010, 256 patients with normal MPI who had invasive angiography because of persisting or worsening of the same initial symptoms were studied. Significant CAD was defined as stenosis > 70% or LM > 50%. RESULTS: A total of 93 patients (36%) had significant CAD. Significant CAD was observed more frequently in males, higher age and those with typical angina complaints. Significant LM disease was present in 7%, three-vessel disease in 10%, two-vessel disease in 22%, and single vessel disease (not left main) in 61%. In those with single vessel disease, the location was the LAD in 40%, the RCA in 30%, and the LCX in 30%. CONCLUSIONS: In selected patients with normal MPI, one-third had significant CAD. The majority of these patients had single vessel disease (not left main). LM or three vessel disease, causing "balanced ischemia", is a less common cause of false-negative MPI.

Impact of diabetes on outcome in patients with non-ST-elevation myocardial infarction.

BACKGROUND: Diabetes mellitus contributes to the increase of cardiovascular deaths worldwide. Despite continuous treatment evolution, patients with diabetes suffering from an acute coronary syndrome still have a high morbidity and mortality. We aimed to analyze the impact of diabetes on one-year outcome in an unselected patient population with non-ST-elevation myocardial infarction (non-STEMI). METHODS: Retrospective analysis of 847 unselected patients with non-STEMI. We compared the baseline characteristics, treatment and outcome of patients versus those without diabetes. RESULTS: A total of 138 patients had diabetes (16%) and 709 (84%) had no diabetes. Patients with diabetes were older, often had hypertension, hyperlipidemia, previous myocardial infarction and Killip class ≥2 on admission. Approximately 80% of both patients, with and without diabetes, underwent diagnostic coronary angiography. Multivessel disease was more present among patients with diabetes, but patients with diabetes were treated more often conservatively. At one-year follow up rates of death and major adverse cardiac events were significantly higher in patients with diabetes compared to those without diabetes (8% vs. 3%; P=0.001 and 23% vs. 14%; P=0.008, respectively). Even after adjustment for differences in baseline characteristics, diabetes remained an independent predictor of mortality (OR: 2.25; CI95%: 1.05-3.91). CONCLUSIONS: In an unselected patient population with non-STEMI, patients with diabetes have higher risk factors on admission, less often undergo coronary revascularisation and have worse outcome at one-year follow-up. Diabetes is an independent predictor of one-year mortality in patients with non-STEMI.