[Renal sympathetic denervation in treatment-resistant hypertension]. / Renal sympatisk denervering ved terapiresistent hypertensjon.

BACKGROUND: Renal denervation (RDN) has been introduced as a potential new treatment for patients with treatment-resistant hypertension, defined as a blood pressure above 140/90 mm Hg despite treatment with at least three antihypertensive drugs. We present an overview of this type of treatment, describe the method and discuss its possible future uses. METHOD: The review is based on a discretionary selection of relevant articles from our archive, our own experience and a literature search in PubMed. RESULTS: The use of RDN for treatment-resistant hypertension is based on a single randomised study with a total of 104 patients, in which the intervention group experienced a fall in blood pressure of 32/12 mm Hg, while blood pressure in the control group remained unchanged. More than 16,000 patients, particularly in Germany, have been treated on this basis. In the USA, data from a larger randomised study (n = 530) that includes sham surgery are awaited before any decision is made on whether to approve the method for use. INTERPRETATION: Before RDN can become recommended treatment in Norway, more evidence is required that the method lowers blood pressure, and that this reduces morbidity and mortality.

Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction.

BACKGROUND: Previous studies have shown improvement in left ventricular function after intracoronary injection of autologous cells derived from bone marrow (BMC) in the acute phase of myocardial infarction. We designed a randomized, controlled trial to further investigate the effects of this treatment. METHODS: Patients with acute ST-elevation myocardial infarction of the anterior wall treated with percutaneous coronary intervention were randomly assigned to the group that underwent intracoronary injection of autologous mononuclear BMC or to the control group, in which neither aspiration nor sham injection was performed. Left ventricular function was assessed with the use of electrocardiogram-gated single-photon-emission computed tomography (SPECT) and echocardiography at baseline and magnetic resonance imaging (MRI) 2 to 3 weeks after the infarction. These procedures were repeated 6 months after the infarction. End points were changes in the left ventricular ejection fraction (LVEF), end-diastolic volume, and infarct size. RESULTS: Of the 50 patients assigned to treatment with mononuclear BMC, 47 underwent intracoronary injection of the cells at a median of 6 days after myocardial infarction. There were 50 patients in the control group. The mean (+/-SD) change in LVEF, measured with the use of SPECT, between baseline and 6 months after infarction for all patients was 7.6+/-10.4 percentage points. The effect of BMC treatment on the change in LVEF was an increase of 0.6 percentage point (95% confidence interval [CI], -3.4 to 4.6; P=0.77) on SPECT, an increase of 0.6 percentage point (95% CI, -2.6 to 3.8; P=0.70) on echocardiography, and a decrease of 3.0 percentage points (95% CI, 0.1 to -6.1; P=0.054) on MRI. The two groups did not differ significantly in changes in left ventricular end-diastolic volume or infarct size and had similar rates of adverse events. CONCLUSIONS: With the methods used, we found no effects of intracoronary injection of autologous mononuclear BMC on global left ventricular function.

LV systolic impairment in patients with asymptomatic coronary heart disease and type 1 diabetes is related to coronary atherosclerosis, glycaemic control and advanced glycation endproducts.

AIMS: To evaluate whether heart failure in type 1 diabetes is linked to poor glycaemic control, coronary atherosclerosis or advanced glycation endproducts (AGEs). METHODS: Twenty six patients with type 1 diabetes (mean duration 32+/-5 years), and 16 age matched controls were recruited. Mean HbA(1c) through 18 years (HbA(1c)18), serum levels of AGEs and coronary atherosclerotic burden (CAB) were determined by IVUS. Peak tissue velocities and strain by tissue Doppler imaging were measured in 12 LV regions as an evaluation of LV function. RESULTS: Systolic tissue velocity was inversely correlated to CAB (r=0.53, p<0.01), to HbA(1c)18 (r=0.46, p<0.05) and to the duration of diabetes (r=0.46, p<0.05). Systolic strain was inversely correlated to HbA(1c)18 (r=0.45, p<0.05), to duration of diabetes (r=0.41, p<0.05), and tended to correlate with AGEs (r=0.37, p=0.07). In multiple regression analyses, CAB and HbA(1c)18 were significant independent predictors for systolic velocity, while AGEs and duration of diabetes were significant predictors of systolic strain. CONCLUSION: LV systolic function was impaired by increasing coronary atherosclerosis and worsening of glycaemic control. AGEs might be another mechanism for the increased risk of heart failure in type 1 diabetes.

Intracoronary ultrasound examinations reveal significantly more advanced coronary atherosclerosis in people with type 1 diabetes than in age- and sex-matched non-diabetic controls.

AIMS/HYPOTHESIS: The extent of coronary atherosclerosis is significantly more advanced in symptomatic type 1 diabetes patients than in symptomatic non-diabetic patients. Whether this difference exists between asymptomatic individuals with diabetes and controls is not documented. In vivo imaging techniques allow quantification of the difference at a preclinical stage. METHODS: The degree of coronary atherosclerosis in early onset type 1 diabetes patients without symptoms of cardiovascular disease was compared with that of age- and sex-matched controls. Intracoronary ultrasound (IVUS) examinations were performed to determine the degree of atherosclerosis. The mean age of the patients was 43 years (35-58), they had a mean duration of disease of 30 (23-39) years and the diagnosis of type 1 diabetes was made at a mean age of 12.5 years. The controls were people with transplanted hearts; donors were sex- and age-matched and had a mean age of 43 (35-58) years. RESULTS: The degree of subclinical coronary atherosclerosis was significantly more severe in type 1 diabetes patients than in controls. This was the case for all parameters measured. The mean plaque area was >or= 40% in 71% (54/76) of diabetic arteries as opposed to 33% (25/76) of arteries from controls (p<0.0001). The mean plaque thickness was 0.59+/-0.38 mm vs. 0.44+/-0.30 mm in controls (p<0.0001). The mean lumen area was 8.6+/-3.8 mm2 in type 1 diabetes and 12.1+/-4.3 mm2 in controls (p<0.0001). CONCLUSIONS/INTERPRETATION: Asymptomatic individuals with type 1 diabetes have significantly more advanced subclinical coronary atherosclerosis than controls. Coronary atherosclerosis in type 1 diabetes develops at an early age.

Cardiac accumulation of bone marrow mononuclear progenitor cells after intracoronary or intravenous injection in pigs subjected to acute myocardial infarction with subsequent reperfusion.

OBJECTIVE: The purpose of the present study was to compare the efficacy of intracoronary and intravenous injection of autologous progenitor cells for homing to the acutely infarcted but reperfused myocardium in pigs. METHODS: Myocardial infarction was induced in 11 anesthetized pigs by 60-min balloon inflation in the mid LAD. After balloon deflation, reperfusion was verified and autologous CD31(+) progenitor cells, or bone marrow mononuclear cells, labeled with PKH67, were injected either intracoronarily (n=6) or intravenously (n=3). By autopsy, 4-5 days after induction of infarction, tissue from the heart and other organs was obtained for fluorescence microscopy. RESULTS: In the heart, PKH(+) cells were detected throughout the reperfused infarcted myocardium, and the number of PKH(+) cells was significantly higher after intracoronary than after intravenous injection (3.2+/-0.55 vs. 0.33+/-0.17 cells/high-power field/10(6) cells injected, P=.01). Few PKH(+) cells were detected in the spleen, lung, mesenteric lymph node, and bone marrow. In an additional animal with a coil placed in the mid LAD, progenitor cells were not detected in the infarcted myocardium or in the normal myocardium. CONCLUSION: Autologous mononuclear and CD31(+) cells from bone marrow accumulated in the infarcted myocardium when injected intracoronarily or intravenously after established reperfusion, and the accumulation of cells was significantly greater after intracoronary injection than after intravenous injection. Accumulation of PKH(+) cells did not appear in the normal myocardium or in the nonreperfused infarcted myocardium. PKH(+) cells were detected in spleen, lung, and bone marrow but to a lesser degree than in the infarcted myocardium.

Silent coronary atheromatosis in type 1 diabetic patients and its relation to long-term glycemic control.

Type 1 diabetic patients have a pronounced risk of premature coronary artery disease and death. We sought to evaluate the prevalence of silent coronary atheromatosis and to evaluate the relation between coronary atheromatosis and glycemic control. Coronary atheromatosis was evaluated in type 1 diabetic patients with no symptoms of coronary artery disease by exercise electrocardiogram (ECG) in 39 patients and quantitative coronary angiography and by intravascular ultrasound (IVUS) examinations in 29 patients. The findings from the IVUS examinations were related to mean HbA(1c) collected prospectively over 18 years. Abnormal exercise ECGs were found in 15% of patients, and angiographic diameter stenosis of >50% in one or more of the main coronary arteries was found in 34% of patients. All patients examined with intracoronary ultrasound had developed atherosclerotic plaques with an increased intimal thickness (>0.5 mm) in one or more of the coronary arteries. Coronary artery plaque formation, as judged by ultrasound, was significantly related to mean HbA(1c) during 18 years (P < 0.05) after adjustment for total cholesterol and age. This study demonstrates a high prevalence of silent coronary atheromatosis in type 1 diabetic patients with no symptoms of coronary heart disease. Long-term glycemic control was shown to be associated with coronary atheromatosis.

Release of cardiac biochemical markers after percutaneous myocardial laser or sham procedures.

BACKGROUND: Percutaneous myocardial laser (PML) reduces symptoms in patients with intractable angina. PML leads to a certain loss of viable myocardium, we therefore assessed if troponin or cardiac markers release may explain the clinical effect, and furthermore assessed the markers release during percutaneous sham procedures. METHODS: Eighty-two patients with chronic refractory angina were randomized to either percutaneous myocardial laser or a true sham procedure. Cardiac markers were assessed before the procedure, and (1/2), 2, 4, 6, and 10-12 h postprocedure. RESULTS: Troponin I increased to median peak levels (range) of 4 (0.6-43) microg/L in the laser group vs. 1.5 (0.1-5.9) microg/L, p=0.001, and creatine kinase MB to 14 (6-357) microg/L vs. 11 (3-40) microg/L, p<0.05, within and between-group comparison, the rise of CK-MB occurred significantly earlier in the sham group, 3.8 vs. 2.5 h. A time-dependent between-group difference was only detected for troponin. 88% of sham and 100% of laser patients had marker levels above reference limits. There was no correlation between the number of laser/sham created channels, biomarker levels postprocedure, and changes in left ventricular ejection fraction or angina improvement during 12 months of follow-up. CONCLUSIONS: The release of cardiac markers is not related to relief of angina after myocardial laser. The use of intracardiac catheters induces a considerable marker release, which is not caused by acute ischemia.

Eighteen years of fair glycemic control preserves cardiac autonomic function in type 1 diabetes.

OBJECTIVE: To study the association between 18 years of mean HbA(1c) and cardiac autonomic function in type 1 diabetic patients having used intensive insulin treatment. RESEARCH DESIGN AND METHODS: A total of 39 patients with type 1 diabetes were followed during 18 years, and HbA(1c) was measured yearly. At 18 years follow-up heart rate variability (HRV) measurements were used to assess cardiac autonomic function. Standard cardiac autonomic tests during normal breathing, deep breathing, the Valsalva maneuver, and the tilt test were performed. Maximal heart rate increase during exercise electrocardiogram and minimal heart rate during sleep were also used to describe cardiac autonomic function. RESULTS: We present the results for patients with mean HbA(1c) <8.4% (two lowest HbA(1c) tertiles) compared with those with HbA(1c) > or = 8.4% (highest HbA(1c) tertile). All of the cardiac autonomic tests were significantly different in the high- and the low-HbA(1c) groups, and the most favorable scores for all tests were seen in the low-HbA(1c) group. In the low-HbA(1c) group, the HRV was 40% during deep breathing, and in the high-HbA(1c) group, the HRV was 19.9% (P = 0.005). Minimal heart rate at night was significantly lower in the low-HbA(1c) groups than in the high-HbA(1c) group (P = 0.039). With maximal exercise, the increase in heart rate was significantly higher in the low-HbA(1c) group compared with the high-HbA(1c) group (P = 0.001). CONCLUSIONS: Mean HbA(1c) during 18 years was associated with cardiac autonomic function. Cardiac autonomic function was preserved with HbA(1c) <8.4%, whereas cardiac autonomic dysfunction was impaired in the group with HbA(1c) > or = 8.4%.

Usefulness and safety of percutaneous myocardial laser revascularization for refractory angina pectoris.

This prospective, double-blind, randomized, sham-controlled trial was designed to control for patient and investigator bias in assessing symptomatic improvement after percutaneous myocardial laser revascularization (PMLR) therapy. Eighty-two patients with stable angina pectoris (class III or IV) not amenable to conventional revascularization and with evidence of reversible ischemia, ejection fraction >/=25%, and myocardial wall thickness >/=8 mm were randomized to either PMLR with optimal medical therapy (n = 40) or to a sham procedure with optimal medical therapy (n = 42). With the exception of 1 laser technician, all patients, investigators, and assessors were blinded to treatment through the 12-month follow-up. The primary end point was restricted to Canadian Cardiovascular Society angina class improvement to limit the number of patients exposed to a sham procedure. Secondary assessments included medication usage, quality of life, exercise testing, ejection fraction, and hospitalizations. The incidence of serious adverse events, as determined by cardiac event-free survival at 12 months, was similar between groups. At 12 months, Canadian Cardiovascular Society angina scores improved by >/=2 classes in significantly more PMLR-treated patients than sham control patients (35% vs 14%, p = 0.04). Angina-specific quality-of-life measures were significantly higher in the PMLR group at each follow-up (p <0.05). Exercise and medication usage was similar between groups at 12 months. We conclude that PMLR therapy is reasonably safe and effective as symptomatic improvement in patients refractory to medical therapy, and that the clinical benefit is not attributable to placebo effect or investigator bias.

[Reduction of myocardial infarction size after primary percutaneous coronary intervention]. / Reduksjon av infarktstørrelse etter primaer perkutan koronar intervensjon.

BACKGROUND: Achieving reperfusion as soon as possible is essential in order to reduce myocardial infarction size and thus improve prognosis. An increasing number of patients with myocardial infarction are treated with primary percutaneous coronary intervention (PCI). Technetium 99m-tetrofosmin myocardial perfusion tomography (SPECT) is a valid test for assessing myocardium at risk and final infarct size expressed by a hypoperfusion index (HPI) of the left ventricular mass. MATERIAL AND METHODS: 20 patients with acute ST-elevation myocardial infarction were treated with primary percutaneous coronary intervention within six hours of onset of symptoms. Myocardium at risk and final infarct size were assessed by Technetium 99m-tetrofosmin immediately before and a few hours, one week and six weeks after. RESULTS: The hypoperfusion index immediately before percutaneous coronary intervention was 31%, four to six hours after PCI 25%, one week later 16% and six weeks later 12%, i.e. a relative reduction of 60% (p < 0.01). Anterior wall infarctions had a higher level of myocardium at risk before primary PCI compared to inferior wall infarctions (36% vs. 24%), but anterior wall infarctions had a higher salvage index compared to inferior wall infarctions. INTERPRETATION: This non-controlled study shows a marked reduction in final infarction size in patients with acute ST-elevation myocardial infarction treated with primary PCI.

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.

Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension.

We aimed to investigate for the first time the blood pressure (BP)-lowering effect of renal sympathetic denervation (RDN) versus clinically adjusted drug treatment in true treatment-resistant hypertension (TRH) after excluding patients with confounding poor drug adherence. Patients with apparent TRH (n=65) were referred for RDN, and those with secondary and spurious hypertension (n=26) were excluded. TRH was defined as office systolic BP (SBP) >140 mm Hg, despite maximally tolerated doses of ≥3 antihypertensive drugs including a diuretic. In addition, ambulatory daytime SBP >135 mm Hg after witnessed intake of antihypertensive drugs was required, after which 20 patients had normalized BP and were excluded. Patients with true TRH were randomized and underwent RDN (n=9) performed with Symplicity Catheter System versus clinically adjusted drug treatment (n=10). The study was stopped early for ethical reasons because RDN had uncertain BP-lowering effect. Office SBP and diastolic BP in the drug-adjusted group changed from 160±14/88±13 mm Hg (±SD) at baseline to 132±10/77±8 mm Hg at 6 months (P<0.0005 and P=0.02, SBP and diastolic BP, respectively) and in the RDN group from 156±13/91±15 to 148±7/89±8 mm Hg (P=0.42 and P=0.48, SBP and diastolic BP, respectively). SBP and diastolic BP were significantly lower in the drug-adjusted group at 6 months (P=0.002 and P=0.004, respectively), and absolute changes in SBP were larger in the drug-adjusted group (P=0.008). Ambulatory BPs changed in parallel to office BPs. Our data suggest that adjusted drug treatment has superior BP lowering effects compared with RDN in patients with true TRH. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01673516.

Renal sympathetic denervation in patients with treatment-resistant hypertension after witnessed intake of medication before qualifying ambulatory blood pressure.

It is unknown whether the decline in blood pressure (BP) after renal denervation (RDN) is caused by denervation itself or concomitantly improved drug adherence. We aimed to investigate the BP lowering effect of RDN in true treatment-resistant hypertension by excluding patients with poor drug adherence. Patients with resistant hypertension (n=18) were referred for a thorough clinical and laboratory work-up. Treatment-resistant hypertension was defined as office systolic BP>140 mm Hg, despite maximally tolerated doses of ≥ 3 antihypertensive drugs, including a diuretic. In addition, ambulatory daytime systolic BP>135 mm Hg was required after witnessed intake of antihypertensive drugs to qualify. RDN (n=6) was performed with Symplicity Catheter System. The mean office and ambulatory BPs remained unchanged at 1, 3, and 6 months in the 6 patients, whereas there was no known change in antihypertensive medication. Two patients, however, had a fall in both office and ambulatory BPs. Our findings question whether BP falls in response to RDN in patients with true treatment-resistant hypertension. Additional research must aim to verify potential BP lowering effect and identify a priori responders to RDN before this invasive method can routinely be applied to patients with drug-resistant hypertension. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01673516.

Apheresis in homozygous familial hypercholesterolemia: the results of a follow-up of all Norwegian patients with homozygous familial hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH), which affects 1 in a million individuals, leads to extremely elevated levels of cholesterol and early-onset cardiovascular disease. OBJECTIVE: The aim of this study was to assess all 7 HoFH patients treated with low-density lipoprotein (LDL) apheresis in Norway with respect to quality of life, clinical and laboratory assessments, and cardiovascular status. METHODS: Apheresis treatment and assessment of cardiovascular status was performed at local hospitals but coordinated by the Lipid Clinic that has followed all patients since diagnosis. Quality of life was evaluated by a validated questionnaire. RESULTS: Results are shown as median (min-max). LDL cholesterol at diagnosis (untreated) was 704 (592-1268) mg/dL (18.2 [15.3-32.8] mmol/L). Medication was initiated at age 9 (2-35) years, and apheresis treatment at age 10 (6-44) years. Regular once-weekly apheresis combined with the maximum-tolerable doses of a statin and ezetimibe reduced LDL cholesterol to 197 (170-282) mg/dL (5.1 [4.5-7.3] mmol/L) pre-apheresis and 85 (50-108) mg/dL (2.2 [1.3-2.8] mmol/L) post-apheresis. Calculated interval mean LDL cholesterol was 162 (135-220) mg/dL (4.2 [3.5-5.7] mmol/L). Duration of apheresis treatment was 11 (1-24) years. Cardiovascular manifestations progressed in most patients despite the apheresis treatment. The subjects' quality of life was comparable with that of a healthy population, with the exception of two patients, who were significantly affected by coronary disease. CONCLUSIONS: Well-tolerated, once-weekly LDL apheresis achieves lower interval mean LDL cholesterol levels between apheresis treatments than previously reported for apheresis every second week. However, progressions of cardiovascular manifestations still occurred, which highlights the importance of earlier and even more aggressive treatment and follow-up in HoFH.

Myocardial perfusion in ST-elevation myocardial infarction treated successfully with primary angioplasty.

OBJECTIVES: To study myocardial perfusion in ST-elevation myocardial infarction (STEMI) treated successfully with primary angioplasty. Additionally, to evaluate the predictive value of perfusion on subsequent infarct size. DESIGN: Fifty patients with acute STEMI and restoration of normal epicardial flow after primary angioplasty were included in the study. TIMI myocardial perfusion (TMP) grades were determined at the end of the procedure. Contrast enhanced magnetic resonance imaging (MRI) including first-pass perfusion and delayed enhancement imaging were performed within five days and after three months. RESULTS: The patients were divided into two groups: A=TMP 0-1, B=TMP 2-3. The early MRI showed significantly reduced myocardial perfusion in the infarct zone compared to remote myocardium in both groups (p<0.001), but the reduction was more pronounced in group A. The infarct sizes were smaller (p=0.0017) and the ejection fractions higher (p=0.0001) in group B than in group A at follow-up. CONCLUSIONS: In STEMI, early impairments in myocardial perfusion were observed in spite of successful treatment with angioplasty. Marked early impairments in perfusion were associated with larger infarct sizes on MRI after three months.

[Left ventricular function and infarction size after primary angioplasty for acute myocardial infarction]. / Venstre ventrikkel-funksjon og infarktstørrelse etter primaer angioplastikk for akutt hjerteinfarkt.

BACKGROUND: There is little information available on long-term changes in left ventricular function and infarct size after acute myocardial infarction treated with primary angioplasty. MATERIAL AND METHODS: From 1996 to 1998, 100 consecutive patients were treated with primary angioplasty for acute ST-elevation myocardial infarction. Left ventricular ejection fraction was determined by radionuclide ventriculography before discharge, after six weeks and after a mean follow-up time of 20 months (range 11-37). Infarct size was assessed by technetium 99m-tetrofosmin myocardial perfusion tomography (SPECT) at rest, performed at the same time intervals. RESULTS: Mean ejection fraction was 56% at discharge, 55% after six weeks and 57% after 20 months of follow-up. A mean perfusion defect of 19% was measured by SPECT after one week. After six weeks and 20 months of follow-up, the mean perfusion defects were reduced to 14% (p < 0.001) and 15%, respectively. INTERPRETATION: Left ventricular function was well preserved and infarct sizes small to moderate 20 months (range 11-37) after primary angioplasty for acute myocardial infarction, demonstrating that the initial successful effect of the treatment was maintained.