Coronary angiography in heart failure: when and why? Uncertainty reigns

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A keen eye for risk

No abstract available

Hydralazine in heart failure: a study of the mechanism of action in human blood vessels

Hydralazine is a vasodilator that has been in clinical use for nearly six decades. Despite this, the mechanism of its action in human blood vessels is uncertain. Understanding how hydralazine works may have importance for the better treatment of heart failure and other cardiovascular diseases. In the first Vasodilator Heart Failure trial, hydralazine was shown, in combination with oral nitrates, to reduce mortality in patients with heart failure, treated at a time when the benefits of ACE inhibitors, beta-blockers and mineralocorticoid receptor antagonists were not known. As the combination of hydralazine and isosorbide dinitrate was subsequently shown to be less effective than an ACE inhibitor in the second Vasodilator Heart Failure trial, it was little used. Recently, however, the same combination was shown to reduce mortality and morbidity in the African-American Heart Failure Trial. Crucially, in this trial, the patients were already treated with the best currently available drug therapy. Though the patients studied were self-designated African-Americans, it is widely believed that the incremental benefits of the combination of hydralazine and isosorbide dinitrate are as likely to be obtained in other patients. While the vasodilator action of nitrates is well understood, a better understanding of the action of hydralazine (and its interaction with nitrates) could lead to the development of more effective and/or better-tolerated drugs. Nitrate therapy is limited by the development of pharmacological tolerance, possibly secondary to the increased production of reactive oxygen species. Hydralazine co-treatment has been shown to prolong the vasodilator effect of nitrates in animal models and clinical studies, although the mechanism of this protection in humans is uncertain. There are many postulated mechanisms of the vasodilator action of hydralazine, based upon studies carried out - mostly in animals - or animal tissues. Hydralazine reduces contractile responses to a number of vasoconstrictors, and this effect appears greater in arteries than in veins. The most (though not entirely) consistent findings are those suggesting that hydralazine leads to the activation of guanylate cyclase. This action to increase intracellular cGMP, could explain the favourable clinical benefits of its combination with oral nitrates. Hydralazine may affect a number of other vascular enzymes. These include key regulators of vascular superoxide production such as NAD(P)H oxidases. These systems are regulated in vivo and ex vivo by angiotensin-II and aldosterone, and are believed to be pivotal in the development of endothelial dysfunction, a key pathophysiological abnormality in heart failure. Renin-angiotensin system activation and oxidative stress are important (and inter-related) pathophysiological processes in heart failure and other cardiovascular problems. There is experimental evidence that hydralazine may inhibit these vascular and mitochondrial oxidases, and may also act as a radical scavenger, thus helping restore the balance between NO and superoxide in endothelial dysfunction. Inhibition of superoxide production may also help prevent nitrate tolerance: this may be critical in permitting therapeutic synergy between hydralazine and nitrates. However, the evidence emanating from different animal species is contradictory. Surprisingly, the antioxidant effect of hydralazine has never been directly characterised in human blood vessels. In this thesis I investigated the action of hydralazine in human blood vessels. To make this project clinically relevant, I characterised the actions of hydralazine in arteries and veins of various calibre (saphenous vein and internal mammary artery taken at the time of coronary artery bypass surgery and subcutaneous resistance arteries dissected from gluteal biopsies), from patients with low ejection fraction heart failure secondary to coronary artery disease. I also investigated the purported ability of hydralazine to reduce vascular superoxide production. 40 patients undergoing elective coronary artery bypass surgery were recruited for large vessel studies and 20 patients underwent gluteal biopsy, which yielded subcutaneous resistance arteries. Vascular reactivity was assessed using organ bath techniques and wire myography with the construction of cumulative concentration response curves. Production of vascular superoxide was measured using lucigenin chemiluminescence. Summary of results: 1. There was no direct vasodilator effect of hydralazine at therapeutic concentrations (<1 µmol/L). This suggests that the favourable benefits of hydralazine are not simply dependent on direct vasodilatation. 2. There was a modest – but not statistically significant – interaction between hydralazine and endothelium-dependent vasodilatation using carbachol. This is consistent with a trend of potential biological relevance. There was a similarly modest interaction with organic nitrates. These data are consistent with theories that the therapeutic benefits of hydralazine may be partly explained by improved endothelium-dependent vasodilatation and that the interaction with organic nitrates in vivo is not simply dependent on augmented vasodilatation. 3. Hydralazine reduced basal superoxide production in both internal mammary artery [1.09 ± 0.14 nmol/mg/min vs. 0.77 ± 0.16 nmol/mg/min (P=0.026) controls and pre-treated vessels respectively] and saphenous veins [0.77 ± 0.08 nmol/mg/min vs. 0.68 ± 0.08 nmol/mg/min (P=0.018) controls and pre-treated vessels respectively]. A dose-response in superoxide production in saphenous vein (which were more readily available for experimentation) was also evident. 4. Hydralazine significantly inhibited angiotensin-II mediated superoxide production in internal mammary arteries [1.68 ± 0.434 nmol/mg/min vs. 0.843 ± 0.144 nmol/mg/min (P=0.032) controls and pre-treated vessels respectively]. Angiotensin II plays a key role in the pathophysiology of heart failure, with pleotropic effects including increased vascular superoxide production through stimulation of NAD(P)H oxidase. Attenuation of angiotensin-II stimulated superoxide production by hydralazine could mechanistically be through interaction with the NAD(P)H oxidase enzyme group; supporting the best available animal data suggesting that hydralazine prevents nitrate tolerance through modulation of this enzyme group. Appropriate recognition must be had to the limitations innate in this work and recognise that all protocols were ex vivo and, as such, none could accurately reflect the complex phenotype recognised in chronic heart failure. The relatively small sample sizes in the study protocols must also be given recognition; however, my group - and others - have published, scientifically meaningful results utilising similar sample sizes. Future developments ought to include larger scale bench and in vivo studies of hydralazine and organic nitrate interaction with particular emphasis on assessing endothelium-dependent vasodilatation. In my studies hydralazine functionally reduced vascular superoxide production; future studies will evaluate this mechanistically with particular emphasis on the NAD(P)H oxidase system

Post-operative myocardial infarction following aortic root surgery with coronary reimplantation: a case series treated with percutaneous coronary intervention

Background: Coronary ostial stenosis is an uncommon but potentially lethal complication following aortic root replacement with or without aortic valve replacement (including Bentall and David procedures). This manifests clinically as acute myocardial ischaemia in the early or late post-operative period. Traditionally, this might be managed with redo open-heart surgery. Case summary:  This case series describes two presentations where urgent percutaneous coronary intervention was used to manage myocardial infarction complicating aortic root surgery with coronary reimplantation. Discussion: This series highlights the risk of acute myocardial infarction after cardiac surgery involving coronary reimplantation. Emergency percutaneous coronary intervention is feasible and illustrates the importance of shared post-operative care involving the cardiac surgeons and the cardiology team

Rationale and design of the British Heart Foundation (BHF) Coronary Microvascular Angina (CorMicA) stratified medicine clinical trial.

BACKGROUND: Coronary angiography is performed to assess for obstructive coronary artery disease (CAD), but "nonobstructive CAD" is a common finding. Microvascular or vasospastic angina may be relevant, but routine confirmatory testing is not evidence based and thus rarely performed. AIM: The aim was to assess the effect of stratified medicine guided by coronary function testing on the diagnosis, treatment, and well-being of patients with angina and nonobstructive CAD. DESIGN: The BHF CorMicA trial is a prospective, multicenter, randomized, blinded, sham-controlled trial of stratified medicine (NCT03193294). All-comers referred for elective coronary angiography for investigation of suspected CAD will be screened. Following informed consent, eligible patients with angina and nonobstructive CAD will be randomized 1:1 immediately in the catheter laboratory to either coronary artery function-guided diagnosis and treatment (intervention group) or not (control group). Coronary function will be assessed using a pressure-temperature-sensitive guidewire and adenosine followed by pharmacological testing with intracoronary acetylcholine. Patients will be stratified into endotypes with linked therapy. The primary outcome is change in Seattle Angina Questionnaire score at 6 months. Secondary outcomes include safety, feasibility, diagnostic utility (impact on diagnosis and diagnostic certainty), and clinical utility (impact on treatment and investigations). Health status is a key secondary outcome assessed according to the following domains: quality of life, treatment satisfaction, illness perception, physical activity, and anxiety-depression score. Patients with obstructive disease who are not randomized will form a registry group who will be followed up as a comparator for secondary outcomes including health status. Health and economic outcomes will be evaluated in the longer term using electronic health record linkage. VALUE: CorMicA is a proof-of-concept clinical trial of a disruptive stratified intervention with potential benefits to patients and health care providers

ER stress and Rho kinase activation underlie the vasculopathy of CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) leads to premature stroke and vascular dementia. Mechanism-specific therapies for this aggressive cerebral small vessel disease are lacking. CADASIL is caused by NOTCH3 mutations that influence vascular smooth muscle cell (VSMC) function through unknown processes. We investigated molecular mechanisms underlying the vasculopathy in CADASIL focusing on endoplasmic reticulum (ER) stress and RhoA/Rho kinase (ROCK). Peripheral small arteries and VSMCs were isolated from gluteal biopsies of CADASIL patients and mesentery of TgNotch3R169C mice (CADASIL model). CADASIL vessels exhibited impaired vasorelaxation, blunted vasoconstriction, and hypertrophic remodeling. Expression of NOTCH3 and ER stress target genes was amplified and ER stress response, Rho kinase activity, superoxide production, and cytoskeleton-associated protein phosphorylation were increased in CADASIL, processes associated with Nox5 upregulation. Aberrant vascular responses and signaling in CADASIL were ameliorated by inhibitors of Notch3 (γ-secretase inhibitor), Nox5 (mellitin), ER stress (4-phenylbutyric acid), and ROCK (fasudil). Observations in human CADASIL were recapitulated in TgNotch3R169C mice. These findings indicate that vascular dysfunction in CADASIL involves ER stress/ROCK interplay driven by Notch3-induced Nox5 activation and that NOTCH3 mutation–associated vascular pathology, typical in cerebral vessels, also manifests peripherally. We define Notch3-Nox5/ER stress/ROCK signaling as a putative mechanism-specific target and suggest that peripheral artery responses may be an accessible biomarker in CADASIL

Discordance between resting and hyperemic indices of coronary stenosis severity: the VERIFY 2 study (a comparative study of resting coronary pressure gradient, instantaneous wave-free ratio and fractional flow reserve in an unselected population referred for invasive angiography)

Background—Distal coronary to aortic pressure ratio (Pd/Pa) and instantaneous wave-free ratio (iFR) are indices of functional significance of a coronary stenosis measured without hyperemia. It has been suggested that iFR has superior diagnostic accuracy to Pd/Pa when compared with fractional flow reserve (FFR). We hypothesized that in comparison with FFR, revascularization decisions based on either binary cutoff values for iFR and Pd/Pa or hybrid strategies incorporating iFR or Pd/Pa will result in similar levels of disagreement. Methods and Results—This is a prospective study in consecutive patients undergoing FFR for clinical indications using proprietary software to calculate iFR. We measured Pd/Pa, iFR, FFR, and hyperemic iFR. Diagnostic accuracy versus FFR ≤0.80 was calculated using binary cutoff values of ≤0.90 for iFR and ≤0.92 for Pd/Pa, and adenosine zones for iFR of 0.86 to 0.93 and Pd/Pa of 0.87 to 0.94 in the hybrid strategy. One hundred ninety-seven patients with 257 stenoses (mean diameter stenosis 48%) were studied. Using binary cutoffs, diagnostic accuracy was similar for iFR and resting Pd/Pa with misclassification rates of 21% versus 20.2% (P=0.85). In the hybrid analysis, 54% of iFR cases and 53% of Pd/Pa cases were outside the adenosine zone and rates of misclassification were 9.4% versus 11.9% (P=0.55). Conclusions—Binary cutoff values for iFR and Pd/Pa result in misclassification of 1 in 5 lesions. Using a hybrid strategy, approximately half of the patients do not receive adenosine, but 1 in 10 lesions are still misclassified. The use of nonhyperemic indices of stenosis severity cannot be recommended for decision making in the catheterization laboratory. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT02377310

Percutaneous coronary intervention versus medical therapy in patients with angina and grey-zone fractional flow reserve values: a randomised clinical trial

Introduction: There is conflicting evidence regarding the benefits of percutaneous coronary intervention (PCI) in patients with grey zone fractional flow reserve (GZFFR artery) values (0.75–0.80). The prevalence of ischaemia is unknown. We wished to define the prevalence of ischaemia in GZFFR artery and assess whether PCI is superior to optimal medical therapy (OMT) for angina control. Methods: We enrolled 104 patients with angina with 1:1 randomisation to PCI or OMT. The artery was interrogated with a Doppler flow/pressure wire. Patients underwent Magnetic Resonance Imaging (MRI) with follow-up at 3 and 12 months. The primary outcome was angina status at 3 months using the Seattle Angina Questionnaire (SAQ). Results: 104 patients (age 60±9 years), 79 (76%) males and 79 (76%) Left Anterior Descending (LAD) stenoses were randomised. Coronary physiology and SAQ were similar. Of 98 patients with stress perfusion MRI data, 17 (17%) had abnormal perfusion (≥2 segments with ≥25% ischaemia or ≥1 segment with ≥50% ischaemia) in the target GZFFR artery. Of 89 patients with invasive physiology data, 26 (28%) had coronary flow velocity reserve &lt;2.0 in the target GZFFR artery. After 3 months of follow-up, compared with patients treated with OMT only, patients treated by PCI and OMT had greater improvements in SAQ angina frequency (21 (28) vs 10 (23); p=0.026) and quality of life (24 (26) vs 11 (24); p=0.008) though these differences were no longer significant at 12 months. Conclusions: Non-invasive evidence of major ischaemia is uncommon in patients with GZFFR artery. Compared with OMT alone, patients randomised to undergo PCI reported improved symptoms after 3 months but these differences were no longer significant after 12 months

Sex differences in procedural and clinical outcomes following rotational atherectomy

Aim: Evaluate sex differences in procedural net adverse clinical events and long‐term outcomes following rotational atherectomy (RA). Methods and Results: From August 2010 to 2016, 765 consecutive patients undergoing RA PCI were followed up for a median of 4.7 years. 285 (37%) of subjects were female. Women were older (mean 76 years vs. 72 years; p &lt; .001) and had more urgent procedures (64.6 vs. 47.3%; p &lt; .001). Females received fewer radial procedures (75.1 vs. 85.1%; p &lt; .001) and less intravascular imaging guidance (16.8 vs. 25.0%; p = .008). After propensity score adjustment, the primary endpoint of net adverse cardiac events (net adverse clinical events: all‐cause death, myocardial infarction, stroke, target vessel revascularization plus any procedural complication) occurred more often in female patients (15.1 vs. 9.0%; adjusted OR 1.81 95% CI 1.04–3.13; p = .037). This was driven by an increased risk of procedural complications rather than procedural major adverse cardiac events (MACE). Specifically, women were more likely to experience coronary dissection (4.6 vs. 1.3%; p = .008), cardiac tamponade (2.1 vs. 0.4%; p = .046) and significant bleeding (BARC ≥2: 5.3 vs. 2.3). Despite this, overall MACE‐free survival was similar between males and females (adjusted HR 1.03; 95% CI 0.80–1.34; p = .81). Procedural complications during RA were associated with almost double the incidence of MACE at long‐term follow‐up (HR 1.92; 95% CI 1.34–2.77; p &lt; .001). Conclusion: Women may be at greater risk of procedural complications following rotational atherectomy. These include periprocedural bleeding episodes and coronary perforation leading to cardiac tamponade. Despite this, the adjusted overall long‐term survival free of major adverse cardiac events was similar between males and females

Comparative significance of invasive measures of microvascular injury in acute myocardial infarction

Background: The resistive reserve ratio (RRR) expresses the ratio between basal and hyperemic microvascular resistance. RRR measures the vasodilatory capacity of the microcirculation. We compared RRR, index of microcirculatory resistance (IMR), and coronary flow reserve (CFR) for predicting microvascular obstruction (MVO), myocardial hemorrhage, infarct size, and clinical outcomes, after ST-segment–elevation myocardial infarction. Methods: In the T-TIME trial (Trial of Low-Dose Adjunctive Alteplase During Primary PCI), 440 patients with acute ST-segment–elevation myocardial infarction from 11 UK hospitals were prospectively enrolled. In a subset of 144 patients, IMR, CFR, and RRR were measured post-primary percutaneous coronary intervention. MVO extent (% left ventricular mass) was determined by cardiovascular magnetic resonance imaging at 2 to 7 days. Infarct size was determined at 3 months. One-year major adverse cardiac events, heart failure hospitalizations, and all-cause death/heart failure hospitalizations were assessed. Results: In these 144 patients (mean age, 59±11 years, 80% male), median IMR was 29.5 (interquartile range: 17.0–55.0), CFR was 1.4 (1.1–2.0), and RRR was 1.7 (1.3–2.3). MVO occurred in 41% of patients. IMR&gt;40 was multivariably associated with more MVO (coefficient, 0.53 [95% CI, 0.05–1.02]; P=0.031), myocardial hemorrhage presence (odds ratio [OR], 3.20 [95% CI, 1.25–8.24]; P=0.016), and infarct size (coefficient, 5.05 [95% CI, 0.84–9.26]; P=0.019), independently of CFR≤2.0, RRR≤1.7, myocardial perfusion grade≤1, and Thrombolysis in Myocardial Infarction frame count. RRR was multivariably associated with MVO extent (coefficient, −0.60 [95% CI, −0.97 to −0.23]; P=0.002), myocardial hemorrhage presence (OR, 0.34 [95% CI, 0.15–0.75]; P=0.008), and infarct size (coefficient, −3.41 [95% CI, −6.76 to −0.06]; P=0.046). IMR&gt;40 was associated with heart failure hospitalization (OR, 5.34 [95% CI, 1.80–15.81] P=0.002), major adverse cardiac events (OR, 4.46 [95% CI, 1.70–11.70] P=0.002), and all-cause death/ heart failure hospitalization (OR, 4.08 [95% CI, 1.55–10.79] P=0.005). RRR was associated with heart failure hospitalization (OR, 0.44 [95% CI, 0.19–0.99] P=0.047). CFR was not associated with infarct characteristics or clinical outcomes. Conclusions: In acute ST-segment–elevationl infarction, IMR and RRR, but not CFR, were associated with MVO, myocardial hemorrhage, infarct size, and clinical outcomes