Effects of Rosuvastatin on Coronary Flow Reserve and Metabolic Mismatch in Patients With Heart Failure (from the CORONA Study)




In patients with heart failure (HF), statin treatment might improve myocardial perfusion, but could also have detrimental effects on myocardial metabolism. A predefined substudy of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) trial sought to determine the effects of statin treatment on myocardial blood flow reserve and cardiac metabolism. Sixteen patients with HF (New York Heart Association class II or III) were randomized to rosuvastatin 10 mg/day (n = 8) or placebo treatment (n = 8). At baseline and after 6 months of treatment, nitrogen-13 ammonia at rest and after dipyridamole stress and 18-fluorodeoxyglucose positron emission tomography were performed. Rosuvastatin treatment significantly lowered total (−36%, p <0.01) and low-density lipoprotein (−47%, p <0.001) cholesterol and C-reactive protein levels (−36%, p <0.05). Myocardial perfusion reserve (ratio) changed from 1.64 ± 0.90 to 1.30 ± 0.37 in placebo-treated and from 1.51 ± 0.18 to 1.55 ± 0.34 in rosuvastatin-treated patients (p = NS). Metabolic mismatch changed from 4.25 ± 2.37% to 4.38 ± 3.81% in placebo-treated and from 5.13 ± 2.75% to 3.50 ± 2.73% in rosuvastatin-treated patients (p = NS). In conclusion, changes regarding myocardial perfusion and metabolic mismatch after 6 months of rosuvastatin treatment in patients with HF did not suggest any beneficial or adverse effects in this pilot study, although due to the small numbers of patients small effects might have been missed.


Statin treatment is cornerstone therapy to decrease cardiovascular morbidity and mortality in patients with coronary artery disease and in those at increased risk to develop it. However, the findings of the recent Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Heart Failure (GISSI-HF) trials continued the controversy surrounding the prescription of statins in patients with chronic heart failure (HF). Theoretically, statin treatment could have beneficial and harmful effects in patients with HF. For that reason, statins have been classified as a IIb recommendation in the most recent guidelines on the treatment of HF. Beneficial effects of statins include improvement of endothelial function and neoangiogenesis and consequently an improved cardiac blood flow. In contrast, potential harmful effects include a decrease of intracardiac ubiquinone and consequently cardiac metabolism. In HF changes in all 3 components of cardiac energy metabolism occur, namely changes in substrate use, phosphorylation, and high-energy phosphate metabolism. To study the effects of rosuvastatin on myocardial blood flow and metabolism, we performed a predefined substudy of CORONA, using dynamic positron emission tomographic (PET) imaging. The primary objective was to determine whether rosuvastatin treatment affects myocardial blood flow reserve and cardiac metabolism in patients with HF.


Methods


Exclusion criteria of the CORONA trial have been reported in detail previously. In brief, patients were ≥60 years of age and had New York Heart Association (NYHA) class II and III or IV chronic HF of ischemic origin and an ejection fraction ≤40% (≤35% in patients in NYHA class II). All patients enrolled in the University Medical Center Groningen (Groningen, The Netherlands) were also asked to participate in this substudy. Signed informed consent for this substudy was obtained separately. The CORONA study and CORONA-PET study were approved by the ethics committee. This substudy has been registered at http://ClinicalTrials.gov (number NCT00228514 ).


Before randomization for rosuvastatin or placebo treatment, a baseline PET scan was performed. After 6 months of treatment, a follow-up PET scan was performed.


The predefined primary end point of the CORONA-PET substudy was the effect of rosuvastatin on myocardial perfusion reserve. The predefined secondary end point was the effect of rosuvastatin on perfusion/metabolic mismatch.


PET studies were performed after patients had refrained from caffeinated beverages for a minimum of 12 hour before the studies. PET scans were performed on an Ecat Exact HR+PET camera (Siemens/CTI, Knoxville, Tennessee). Transmission scan for subsequent attenuation correction was done according to standard procedures of this camera for 5 minutes with an external ring source filled with gallium-68/germanium-68, which is built in the camera. Data were automatically corrected for accidental coincidence and dead time. Myocardial perfusion (at rest) 2-dimensional imaging was performed after injection of nitrogen-13 ( 13 N)-ammonia 400 MBq intravenously in 30 seconds. In 16 minutes 36 frames are recorded. A second identical 13 N-ammonia imaging procedure was performed after intravenous infusion of dipyridamole 0.56 mg/kg during a 4-minute period to obtain maximal vasodilation. The 13 N-ammonia acquisition was started 2 minutes after the end of the dipyridamole infusion. Myocardial glucose uptake was studied according to the methods described by Choi et al using fluorine-18 fluorodeoxyglucose (FDG) as a tracer. Twenty minutes after the dipyridamole stress 13 N-ammonia study, FDG 200 MBq was injected. Insulin-glucose clamping technique was used to overcome insulin resistance. Frames were collected in 35 minutes.


From PET data, dynamic parametric polar maps were constructed. Myocardial blood flow data were corrected for partial volume effect and spillover and quantified by the Hutchins model. Myocardial perfusion data were also normalized on the segmental region with the highest perfusion, using the 17-segment model. Data analysis of FDG was performed with Patlak analysis. Quantification of mismatch was done by first normalizing the FDG uptake to the highest segmental region of dipyridamole blood flow, using the 17-segment model. The FDG segment fitting to the segment with the highest dipyridamole blood flow was assigned as a normal metabolic segment. The other 16 FDG segments were normalized on this normal metabolic segment. Mismatch was defined as decreased myocardial perfusion ≤75% of the peak flow and ≥50% FDG uptake.


Differences between treatment groups were compared with t test, Wilcoxon rank-sum test, and chi-square test when appropriate. All analysis were performed using STATA 10.0 for Windows (STATA Corp. LP, College Station, Texas) and a 2-sided p value ≤0.05 was interpreted to indicate statistical significance.




Results


We studied 16 patients; 8 were randomized to rosuvastatin treatment and 8 patients to placebo. Baseline characteristics of rosuvastatin- and placebo-treated patient groups are presented in Table 1 . Mean age was 73 ± 8 years, 19% were women, left ventricular ejection fraction was 0.27 ± 0.09%, and 63% had NYHA class III HF symptoms. Slightly more patients were reported to have a history of hypertension in the placebo group. Baseline lipid levels were only mildly increased and did not differ between rosuvastatin- and placebo-allocated patients. After 3 months of treatment, patients treated with rosuvastatin had significantly lower total (36%, p <0.01) and lower low-density lipoprotein (47%, p <0.001) cholesterol levels and lower C-reactive protein levels (36%, p <0.05; Table 2 ).



Table 1

Characteristics of patients

































































































































































































































Treatment Age/Sex NYHA Ejection Fraction Heart Rate Systolic Blood Pressure Diastolic Blood Pressure Body Mass Index Loop Diuretics β Blockade ACE Inhibitor ARB
Rosuvastatin 60/F 2 0.30 66 144 90 30 yes yes yes no
67/F 3 0.37 72 130 74 23 yes yes no yes
67/M 3 0.30 51 110 80 30 yes yes yes no
72/M 3 0.29 60 125 70 24 yes yes yes no
78/M 3 0.28 53 148 74 29 yes yes yes no
85/M 2 0.35 43 124 66 19 no yes yes no
86/M 3 0.30 86 112 73 28 yes no yes no
86/M 2 0.20 40 126 64 26 yes yes yes no
Placebo 64/M 2 0.32 78 100 63 24 yes yes yes no
66/M 2 0.27 77 166 113 25 no no yes no
67/M 3 0.09 60 114 67 22 no yes yes no
69/M 3 0.29 65 115 70 28 yes yes yes no
73/M 3 0.10 61 110 75 22 yes yes no yes
74/M 3 0.38 69 155 80 28 no yes yes no
80/M 2 0.18 55 125 80 24 yes yes yes no
81/F 3 0.23 67 133 65 28 no yes yes no

Body mass index is weight in kilograms divided by the square of height in meters.

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker.


Table 2

C-reactive protein and lipids at baseline and three months after randomization

































































































Baseline Follow-up Difference
Placebo Rosuvastatin p Value Placebo Rosuvastatin p Value Placebo Rosuvastatin p Value
C-reactive protein 3.83 (1.75–8.35) 2.95 (1.45–4.75) 0.50 7.50 (2.25–31.05) 1.9 (0.95–2.20) 0.016 3.1 (0.40–12.4) −1.05 (−1.8 to −0.48) 0.018
Cholesterol
Total 5.43 ± 0.71 5.49 ± 1.00 0.90 5.20 ± 1.13 3.52 ± 0.59 0.002 −0.24 ± 0.79 −1.98 ± 0.59 0.0002
Low-density lipoprotein 3.75 ± 0.67 3.65 ± 0.92 0.82 3.55 ± 0.94 1.94 ± 0.46 0.0007 −0.19 ± 0.60 −1.71 ± 0.54 0.0001
High-density lipoprotein 1.09 ± 0.20 1.08 ± 0.39 0.92 1.10 ± 0.27 1.12 ± 0.35 0.92 0.01 ± 0.09 0.04 ± 0.11 0.55
Triglycerides 2.31 ± 0.78 2.50 ± 1.67 0.77 2.10 ± 1.07 1.69 ± 0.78 0.39 −0.21 ± 0.61 −0.81 ± 1.21 0.23
Apo-B:Apo-A1 ratio 0.96 ± 0.15 1.05 ± 0.27 0.41 0.96 ± 0.24 0.60 ± 0.122 0.002 −0.004 ± 0.15 −0.45 ± 0.18 0.0001

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Dec 23, 2016 | Posted by in CARDIOLOGY | Comments Off on Effects of Rosuvastatin on Coronary Flow Reserve and Metabolic Mismatch in Patients With Heart Failure (from the CORONA Study)

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